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Trial registered on ANZCTR


Registration number
ACTRN12618000164291
Ethics application status
Approved
Date submitted
24/01/2018
Date registered
2/02/2018
Date last updated
9/12/2019
Date data sharing statement initially provided
8/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
HABIT-ILE: A randomised trial of hand arm bimanual intensive training including lower extremity training for children with bilateral cerebral palsy
Scientific title
HABIT-ILE: A randomised trial of hand arm bimanual intensive training including lower extremity training to improve manual ability and gross motor function for children with bilateral cerebral palsy
Secondary ID [1] 293777 0
None
Universal Trial Number (UTN)
Trial acronym
HABIT-ILE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cerebral Palsy 306173 0
Condition category
Condition code
Physical Medicine / Rehabilitation 305284 305284 0 0
Physiotherapy
Neurological 305285 305285 0 0
Other neurological disorders
Physical Medicine / Rehabilitation 305291 305291 0 0
Occupational therapy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
HABIT-ILE is a motor learning approach simultaneously addressing coordination of the upper and lower limbs. Key elements of HABIT-ILE are:

Dose: We will deliver a total dose of 65 hours of HABIT-ILE. The 65 hours of HABIT-ILE will be achieved through a 2 week intensive group delivered day camp for 6.5 hrs/day over 10 days. The model of HABIT-ILE to be tested has been adapted to maximise future clinical translation to ensure acceptability and feasibility to children with bilateral CP and their families in Australia.

Mode: Groups of 10-12 children delivered (1:1 or 2:1 therapist / volunteer / student to child ratio according to ability).

Content and tailoring: Upper extremity: Intervention will be based on the child’s motor abilities (determined at baseline), age, interests and self-identified functional goals. Tasks/activities are made incrementally more challenging. Practice is structured, using whole task practice with high repetition and ongoing feedback about performance. Tasks that will be performed include: (i) incremented table top fine motor activities; (ii) activities of daily living when standing/walking; (iii) gross motor play and physical activities. Based on the pilot study of HABIT-ILE, we expect that 40% of the time will be spent engaged in activities requiring gross upper limb dexterity, 30% on activities of daily living, 20% manipulative games, and 10% on other card games, arts and crafts. Lower extremity: Based on the child’s motor abilities, postural control/sitting balance will be progressed from sitting on a stool to sitting on fitness balls to build core strength; progression of standing balance with use of balance boards. Based on the pilot study of HABIT-ILE, we expect that sessions will be structure so that 40% of time is spent sitting on fitness balls, 20% sitting on stools, 20% standing and 20% walking/running.

Intervention providers: Physiotherapists and occupational therapists delivering HABIT-ILE will complete standardised training provided by the developer of HABIT-ILE. This will coincide with the first intensive intervention camp conducted. The trained therapists will in turn train and supervise therapy students and coach parents to deliver HABIT-ILE.

Target intensity: We expect that sessions will be structured so that 40% of time is spent sitting on fitness balls, 20% sitting on stools, 20% walking/running, 40% of the time will be spent engaged in activities requiring gross upper limb dexterity, 30% on activities of daily living, 20% manipulative games, and 10% on other card games, arts and crafts.

Fidelity: Standardised therapist training will be provided to therapists employed to deliver the intervention. the training package will include:
• Intervention manual
• Onsite training during the first HABIT-ILE camp lead by a master trainer

Training sessions will be video recorded and accessible at any time for established or new therapists delivering the intervention. All group intervention sessions will be videotaped and a random selection viewed for fidelity adherence and competence criteria.
Intervention code [1] 300031 0
Rehabilitation
Intervention code [2] 300164 0
Treatment: Other
Comparator / control treatment
Usual care over the six month wait-list period will vary for children with CP across Australia and can range from weekly clinic-based therapy sessions to school-based consultative services provided on a monthly, quarterly or yearly basis. In order to understand the variability in usual care received, all families in both groups will complete a usual care diary for the duration of study involvement. The diary (via an APP) will record the frequency and duration of physiotherapy, and occupational therapy and any other concurrent medical interventions such as intramuscular Botulinum Toxin A injections and/or serial casting. All children in the control group will be offered HABIT-ILE commencing at the subsequent school holiday following the 6 month retention time point (T3).
Control group
Active

Outcomes
Primary outcome [1] 304442 0
Manual ability (ABILHAND-Kids)

A Rasch-built parent completed questionnaire measuring manual ability of children with CP. The ABILHAND-KIDS has demonstrated content, construct and evaluative validity, high internal consistency (a equals 0.94), excellent test retest reliability (r equals 0.91) and is responsive in detecting change following intensive upper limb motor training interventions (SDD equals 0.81-1.03 logits). The ABILHANDS has the strongest evidence of validity and reliability to measure hand function in children with bilateral CP.
Timepoint [1] 304442 0
Immediately post intervention (at 3 weeks) is the primary end point and 26 weeks for retention
Primary outcome [2] 304443 0
Gross motor function (Gross Motor Function Measure (GMFM-66))

The GMFM-66 is a criterion referenced observation measure developed using Rasch modelling to measure gross motor function of children with CP. The GMFM-66 has established construct validity, high test retest reliability (ICC 0.99) and is responsive to change (MCID equals 1.5).
Timepoint [2] 304443 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [1] 341945 0
Brain structural connectivity

Brain MRI will be conducted using 3T scanners. The child will be familiarised with the MRI procedures before the scan. During the MRI, the child will watch an age-appropriate movie of their choice, except during the acquisition of the functional MRI. Structural brain images will be acquired using high-resolution 3D T1-weighted MPRAGE and high-resolution 3D T2-weighted FLAIR. Diffusion MRI data will be acquired using a multi-shell approach with 20 directions at b=1000s/mm2 and 60 directions at b=3000s/mm2. Functional MRI data will be acquired using a block design, with a simple hand and foot tapping task. The total scan time will be <1 hour.
Structural brain images will be used for lesion scoring using the Fiori scale, a semi-quantitative scale for use in brain imaging of cerebral palsy. This data will be used to determine whether a relationship exists between the type and severity of brain lesions, and functional improvements. We do not expect to see a change in brain lesion scores in response to the intervention.
The developing connectivity and symmetry of the thalamocortical pathways connecting M1 with the thalamus is as important as the symmetry of the cortico-spinal (CS) tracts for unimanual capacity and bimanual co-ordination. High Angular Resolution Diffusion Imaging can be performed to elucidate symmetry in the CS (motor) and thalamocortical (sensorimotor) tracts, ideally using our surface-based fMRI-guided seeding approaches, which are more accurate than traditional approaches using anatomically defined seed regions, Our approach relies on selecting a particular region of interest based on changes in signal during blood oxygen level dependent contrast MRI during motor tasks carefully selected to activate particular regions of the brain as the source for white-matter pathways to project through the brain. The project paths are subsequently characterised in terms of the speed with which water diffuses in the region of the tract (mean diffusion) and how much a particular direction is favoured (anisotropy). The fMRI-guided approach results in a better definition of the extracted pathways compared to traditional approaches, where the entire motor strip is used as a seed region. Additionally, in children with CP, the location of the motor region may be shifted for this population.
Timepoint [1] 341945 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [2] 341946 0
Walking endurance (6 Minute Walk Test: 6MWT)

The Six Minute Walk Test is a clinical exercise test measuring walking endurance with excellent test retest reliability (ICC 0.98) for children with CP. The test requires participants to walk as far as possible in six minutes using a 10 meter track with cones demarcating the turning points. Participants will be given verbal and visual instructions before testing. Participants will be instructed to walk as far as possible without running in six minutes. Participants will be given verbal encouragement and every 30 seconds will be advised of the distance covered (in laps) and the time remaining. Distance will be measured to the nearest five-meter mark.
Timepoint [2] 341946 0
Post intervention at 3 (primary time point) weeks and retention at 26 weeks
Secondary outcome [3] 341947 0
Bimanual hand performance (Both Hands Assessment: BoHA)

The Both Hands Assessment (BoHA) measures how children who have bilateral CP use their hands together in bimanual activities. The measure was developed through adaptation of the Assisting Hand Assessment. Rasch measurement modelling showed strong evidence of internal construct validity, with two separate item difficulty hierarchies; for children with (a) symmetric upper limb use; (b) asymmetric upper limb use. The test uses a selection of toys to elicit bimanual hand behaviour and can be administered in a structured play session or using the board game version depending on the age of the child. The BoHA takes 15 minutes to complete. The assessment is video-taped for later scoring by a rater blinded to group allocation and who has been certified in its use.
Timepoint [3] 341947 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [4] 341948 0
Self care (Pediatric Evaluation of Disability Inventory Computer Adapted Test: PEDI-CAT)

The PEDI-CAT is a standardised, norm-referenced assessment of independence in self-care. The test is valid, reliable and responsive in this population. The PEDI-CAT is completed by parents using an ipad application. The item bank of the PEDI-CAT was developed using Rasch measurement modelling on large samples of typically developing children and those with disabilities. The domain, Self-Care will be completed by caregivers.
Timepoint [4] 341948 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [5] 341949 0
Performance score on the Canadian Occupational Performance Measure (COPM)

This will be used to measure performance of individually defined self-care, leisure or productivity goals. Test retest reliability is high (ICC 0.76-0.89) and the COPM is responsive to change. Children eight years and older can self-report, and caregivers can complete the COPM for younger children or those with cognitive difficulties which would preclude then from completing it independently. Children and their caregivers will set up to three goals. Perceived performance of an individualized goal is rated on a 1-10 scale with higher scores reflecting higher perceived performance.
Timepoint [5] 341949 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [6] 342003 0
Quality of Life (Cerebral Palsy Quality of Life Questionnaire – CPQOL, parent proxy and child report)

The CP-QOL Child is a 52-item, condition-specific self-report measure of child quality of life (QOL) that is specifically developed for measuring QOL in children with CP. The majority of items have the stem “How do you feel about…” with a response scale of 9 points from 1=very unhappy to 9=very happy. The domains covered in the child self-report version include physical wellbeing, social wellbeing, emotional wellbeing, school, and acceptance by others. It has good concurrent validity, internal consistency (Cronbach’s alpha 0.80-0.90) and test-retest reliability for children 9 years of age and over. Significant discordance exists between child and parent proxy reports in many health-related QOL instruments and the child perspective will be sought in the present study. The CP-QOL will therefore be completed by all children, including children aged 8 and children with intellectual disabilities. An adult who is not participating in the study as the primary parent/caregiver will read the questionnaire alongside the child, and clarify the meaning of the questions and response scale if necessary.
Timepoint [6] 342003 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [7] 342481 0
Mobility (Paediatric Evaluation of Disability Inventory Computer Adapted Test: PEDI-CAT)

The PEDI-CAT is a standardised, norm-referenced assessment of independence in self-care. The test is valid, reliable, and responsive in this population. The PEDI-CAT is completed by parents using an ipad application. The item bank of the PEDI-CAT was developed using Rasch measurement modelling on large samples of typically developing children and those with disabilities. The domain of Mobility will be completed by caregivers.
Timepoint [7] 342481 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [8] 342482 0
Satisfaction scores on the Canadian Occupational Performance Measure (COPM)

This will be used to measure satisfaction with individually defined self-care, leisure or productivity goals. Test retest reliability is high (ICC 0.76-0.89) and the COPM is responsive to change. Children eight years and older can self-report, and caregivers can complete he COPM for younger children or those with cognitive difficulties which would preclude then from completing it independently. Children and their caregivers will set up three goals. Perceived satisfaction with performance is rated on a 1-10 scale with higher scored reflecting higher perceived satisfaction.
Timepoint [8] 342482 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [9] 342553 0
Brain morphometry (cortical thickness)

Brain MRI will be conducted using 3T scanners. The child will be familiarised with the MRI procedures before the scan. During the MRI, the child will watch an age-appropriate movie of their choice, except during the acquisition of the functional MRI. Structural brain images will be acquired using high-resolution 3D T1-weighted MPRAGE and high-resolution 3D T2-weighted FLAIR. Diffusion MRI data will be acquired using a multi-shell approach with 20 directions at b=1000s/mm2 and 60 directions at b=3000s/mm2. Functional MRI data will be acquired using block design, with a simple hand and foot tapping task. The total scan time will be <1hour.
Structural brain images will used for lesion scoring using the Fiori scale, a semi-quantitative scale for use in brain imaging of cerebral palsy. Structural brain images will also be used to assess alterations in cortical thickness in response to therapy, using methods designed specifically for populations with severe brain lesions. These diffusion data will allow both traditional analysis using the diffusion tensor model (fractional anisotropy and mean diffusivity), as well as state-of-the-art tractography and calculation of advanced imaging microstructural biomarkers thought to closely reflect the status of the underlying brain tissue.
Timepoint [9] 342553 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks
Secondary outcome [10] 342571 0
Quality of Life (The Child Health Utility Index (CHU9))

The Child Health Utility Index (CHU9) is a paediatric health related quality of life measure for use in economic evaluation, The measure consists of nine questions. Children can self-report from seven years of age and parents can proxy report for their child. In this study, the CHU9 will be completed by the child's primary caregiver.
Timepoint [10] 342571 0
Post intervention at 3 weeks (primary time point) and retention at 26 weeks

Eligibility
Key inclusion criteria
(a) diagnosed with bilateral CP (diplegia/quadriplegia), GMFCS levels II (walks with limitations) to IV (limited self-mobility but able to do a standing transfer with the assistance of 1 person);
(b) aged 6 to 16 years;
(c) ability to grasp light objects and lift more impaired arm 15cm above a table surface;
(d) able to understand instructions and complete testing.
Minimum age
6 Years
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) uncontrolled seizures
(b) orthopaedic surgery in the six months prior to or scheduled during study period (eligible for inclusion if at least 12 months orthopedic surgery)
(c) visual impairment interfering with treatment/testing; and
(d) inability to undertake standing transfers and/or walk a few steps (with a walker).

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)
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 assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Analyses will follow standard principles for RCTs using two-group comparisons on all participants on an intention-to-treat basis. Imputation techniques will avoid bias as a consequence of non-ignorable missing data during follow up. Primary comparison immediately post intervention (T2) based on ABILHAND-KIDS and GMFM scores will be between treatment groups using linear regression with treatment group (HABIT-ILE/waitlist control) included as the main effect and baseline ABILHAND-KIDS as the covariable. Effect estimates will be presented as mean difference and 95% confidence interval. Secondary analyses will use similar methods to compare outcomes between groups immediately post intervention (T2) for brain structural integrity and structural connectivity (dMRI and fMRI guided tractography), and at T2 and 26 weeks (T3) for clinical outcomes: walking speed, self-care and performance of and satisfaction with individualised goals. Comparisons of the extent of anatomical change in between T1 and T2 will be made between each group to quantify the relative effect of HABIT-ILE versus usual care. In cases where interval data are not able to be transformed appropriately for regression analyses, non-parametric methods (Mann-Whitney U) will be used for between-treatment comparisons. Possible differential attrition will be assessed by comparing baseline characteristics of drop-outs and continuing participants using t-tests (or Mann-Whitney U) for continuous variables and chi-squared tests for categorical variables. Sensitivity analyses of all outcomes will be conducted using multiple imputation techniques, to investigate the effect of non-ignorable missing data during follow up.

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)
NSW,QLD,WA
Recruitment hospital [1] 9754 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [2] 9755 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [3] 9756 0
Perth Children's Hospital - Nedlands
Recruitment hospital [4] 9863 0
Cerebral Palsy Alliance - Allambie Heights
Recruitment postcode(s) [1] 18532 0
4101 - South Brisbane
Recruitment postcode(s) [2] 18533 0
6008 - Subiaco
Recruitment postcode(s) [3] 18534 0
6009 - Nedlands
Recruitment postcode(s) [4] 18648 0
2100 - Allambie Heights

Funding & Sponsors
Funding source category [1] 298393 0
Government body
Name [1] 298393 0
National Health and Medical Research Council
Address [1] 298393 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 298393 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
The University of Queensland
St Lucia QLD 4072
Country
Australia
Secondary sponsor category [1] 297522 0
None
Name [1] 297522 0
Address [1] 297522 0
Country [1] 297522 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299384 0
Children's Health Queensland Human Research Ethics Committee
Ethics committee address [1] 299384 0
Level 7, Centre for Children's Health Research
Lady Cilento Children's Hospital Precinct
62 Graham Street South Brisbane QLD 4101
Ethics committee country [1] 299384 0
Australia
Date submitted for ethics approval [1] 299384 0
18/12/2017
Approval date [1] 299384 0
20/12/2017
Ethics approval number [1] 299384 0
HREC/17/QRCH/282
Ethics committee name [2] 299386 0
The University of Queensland's Human Research Ethics Committee
Ethics committee address [2] 299386 0
Cumbrae-Stewart Building #72
The University of Queensland
St Lucia QLD 4072
Ethics committee country [2] 299386 0
Australia
Date submitted for ethics approval [2] 299386 0
09/01/2018
Approval date [2] 299386 0
12/01/2018
Ethics approval number [2] 299386 0
2018000017/HREC/17/QRCH/282

Summary
Brief summary
In Australia, 35,000 people have cerebral palsy (CP), and between 60-70% of these have difficulties with movement on both sides of their body. There are currently no effective interventions for children with CP that affects both sides of their body to improve their ability to use their hands, walk and perform daily life tasks. We will test the efficacy of Hand Arm Bimanual Intensive Training Including Lower Extremity (HABIT-ILE), in 126 children with cerebral palsy and compare results to usual care.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2350 2350 0 0
Attachments [2] 2351 2351 0 0
Attachments [3] 2352 2352 0 0
Attachments [4] 2353 2353 0 0
/AnzctrAttachments/374297-Parent-guardianIS_v2_11122017.docx (Participant information/consent)
Attachments [5] 2356 2356 0 0
/AnzctrAttachments/374297-Child Adolescent Information Sheet.docx (Participant information/consent)
Attachments [6] 2357 2357 0 0
/AnzctrAttachments/374297-CHQ_Pariticpant Concent Form.docx (Participant information/consent)

Contacts
Principal investigator
Name 80246 0
Dr Leanne Sakzewski
Address 80246 0
Queensland Cerebral Palsy and Rehabilitation Research Centre
Level 6 Centre for Children's Health Research
62 Graham Street
South Brisbane QLD 4101
Country 80246 0
Australia
Phone 80246 0
+61 7 3069 7345
Fax 80246 0
Email 80246 0
l.sakzewski1@uq.edu.au
Contact person for public queries
Name 80247 0
Ms Natalie Dos Santos
Address 80247 0
Queensland Cerebral Palsy and Rehabilitation Research Centre
Level 6 Centre for Children's Health Research
62 Graham Street
South Brisbane QLD 4101
Country 80247 0
Australia
Phone 80247 0
+61 7 3069 7356
Fax 80247 0
Email 80247 0
n.dossantos@uq.edu.au
Contact person for scientific queries
Name 80248 0
Dr Leanne Sakzewski
Address 80248 0
Queensland Cerebral Palsy and Rehabilitation Research Centre
Level 6 Centre for Children's Health Research
62 Graham Street
South Brisbane QLD 4101
Country 80248 0
Australia
Phone 80248 0
+61 7 3069 7345
Fax 80248 0
Email 80248 0
l.sakzewski1@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All information collected from participants will be coded, and stored securely at the Research Centre. No individual data will be available at any time during the study to ensure participants' and their families' confidentiality and privacy.
What supporting documents are/will be available?
Study protocol
Informed consent form
How or where can supporting documents be obtained?
Type [1] 6083 0
Study protocol
Citation [1] 6083 0
Sakzewski L, Bleyenheuft Y, Boyd RN, Novak I, Elliott C, Reedman S, Morgan C, Pannek K, Fripp J, Golland P, Rowell D, Chatfield M, Ware R. A Multi-site Randomised Trial of Hand Arm Bimanual Intensive Training Including Lower Extremity Training for Children with Bilateral Cerebral Palsy: HABIT-ILE Australia. BMJ Open 2019, Aug 27;9(8):e029587. doi: 10.1136/bmjopen-2019-032194.
Link [1] 6083 0
Email [1] 6083 0
Other [1] 6083 0
Type [2] 6084 0
Informed consent form
Citation [2] 6084 0
Link [2] 6084 0
Email [2] 6084 0
Other [2] 6084 0
Summary results
No Results