Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000006347
Ethics application status
Approved
Date submitted
15/12/2016
Date registered
3/01/2017
Date last updated
7/06/2021
Date data sharing statement initially provided
7/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effectiveness of GAME (Goals Activity Motor Enrichment) for infants at high risk of cerebral palsy
Scientific title
Harnessing Neuroplasticity to Improve Motor Performance in Infants with Cerebral Palsy: a Pragmatic Randomized Controlled Trial
Secondary ID [1] 290770 0
1120031 (NHMRC)
Universal Trial Number (UTN)
Trial acronym
GAME trial
Linked study record
ANZCTRN: 12611000572965

This study was the pilot work for the current study

Health condition
Health condition(s) or problem(s) studied:
cerebral palsy 301296 0
Condition category
Condition code
Neurological 301046 301046 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: GAME (Goals Activity Motor enrichment) has 3 key elements
1. Motor training. Motor goals are first identified by parents and then the therapist identifies and explains to families the factors limiting performance. Training is then designed to target goal achievement. Training is goal-oriented, relevant, task specific, providing the necessary repetition required to learn to perform the new goal behaviours independently.
2. Parent coaching in motor training. During the dace to face sessions, parents are coached in how to provide motor training and cognitive stimulation within their child’s natural playtime. They are educated about usual developmental trajectories and how to advance progress.
3. Environmental enrichment. GAME is provided in the natural home environment where training is personalised to the infant’s enjoyment – translating to more intense, specific and relevant practice. GAME intervention enriches the: (a) physical environment by setting up the home with activities and materials entice infant-generated motor practice at the appropriate level of challenge; (b) cognitive environment by encouraging infant problem solving and self-correction of errors; (c) sensory environment by providing evidence-based interventions that improve backdrop capacity for learning; and (d) social environment by coaching parents to be sensitive, responsive and communicative to infant cues.
This intervention is designed to be individualised to the child and family
DOSE: intervention sessions will be offered weekly from enrolment until age 2 years (corrected for prematurity). A maximum of 91 sessions (depending on age at enrolment) will be provided.
Each session will be about 1 hour. Parents will carry out a home programme to increase the dose but it will be up to the parents how much they do based on family ecology and preferences.
WHO: GAME intervention will be provided by a physiotherapist and/or occupational therapist. The therapists will design the home program in collaboration with the family and it will be provided in written format.
FIDELITY: Intervention fidelity will be assessed by the chief investigators using a fidelity checklist, appraisal of home programs and site visits
Intervention code [1] 296646 0
Rehabilitation
Comparator / control treatment
STANDARD CARE INTERVENTION: "Standard care” (SC) describes the current follow-up and/or therapeutic interventions used when an infant at high risk of CP is discharged from hospital. It is not possible to standardise the frequency, intensity or type of interventions received in the SC group. Therapeutic approaches used and modes and intensity of delivery are varied. All SC providers tend to use a combination of centre based visits and home programs. Some infants in SC will receive home visits as well as clinic based appointments. Intervention approaches vary and are typically “eclectic” borrowing from a variety of therapy intervention paradigms including neurodevelopmental therapy and the developmental skills approach.
Control group
Active

Outcomes
Primary outcome [1] 300495 0
Peabody Developmental Motor Scales - second edition
Timepoint [1] 300495 0
Primary end point is 24 months, interim measures will be taken at 12 months
Secondary outcome [1] 330119 0
Gross Motor Function Measure-66
Timepoint [1] 330119 0
Primary end point is 24 months, interim measures will be taken at 12 months
Secondary outcome [2] 330219 0
PEDI-CAT
Timepoint [2] 330219 0
Primary end point is 24 months, interim measures will be taken at 12 months
Secondary outcome [3] 330220 0
Bayley Scales of Infant and Toddler Development -III (cognition)
Timepoint [3] 330220 0
Primary end point is 24 months, interim measures will be taken at 12 months
Secondary outcome [4] 330221 0
Infant Toddler Quality of Life Questionnaire
Timepoint [4] 330221 0
Primary end point is 24 months, interim measures will be taken at 12 months
Secondary outcome [5] 330222 0
Magnetic Resonance Imaging (MRI) will be acquired on 3T scanners. Along with standard radiological images, we will acquire high-resolution structural images and multi-shell high angular resolution diffusion weighted images (HARDI; R1,R2). Structural images will be used to investigate cortical thickness and folding, sulcal depth, deep gray matter volumes, and ventricular shape and their relationship to motor skills. Diffusion images will be used to assess structural connectivity (connectome) using an approach adapted from that described by us previously. Structural integrity of connections will be assessed using quantitative metrics, including corrected streamline number (R3) and neurite orientation dispersion index (R2), as well as standard diffusion tensor metrics (fractional anisotropy, mean diffusivity). The relationship between structural integrity of connections and motor skills will be investigated
Timepoint [5] 330222 0
24 months
Secondary outcome [6] 396567 0
A within-trial economic evaluation will be conducted from a societal perspective assessing resource use and costs, and cost-effectiveness of intervention to achieve an improvement in gross and fine motor skills and an improvement in infant toddler quality of life.
The economic outcomes include improvement in fine and gross motor skills as measured by the Total Motor Quotient of the PDMS-2 scale; and improvement in the ITQOL for overall health, and for each domain separately.
Consistent with a societal perspective, all relevant resource use and costs will be identified, measured and valued. This includes health system costs, disability costs (to the NDIS and other providers like Better Start), Social Services, as well as out of pocket costs to families. These will be tabulated separately. Examples of relevant costs include the cost of delivering the intervention and cost of standard care; outpatient costs (e.g. doctor and allied health visits); inpatient hospitalisations and emergency department presentations; prescribed medicines; costs borne by the NDIS and other disability providers; Social Services (e.g. carer’s allowances); and out of pocket costs e.g. specialised toys or home modifications purchased by families. Resource use will be measured using linked Medicare data (MBS and PBS), and additionally by participant questionnaires in study case report forms. Unit pricing will be obtained from Medicare records, Australian-Refined Diagnosis Related Groups (AR-DRGs) and/or the Net Efficient Price where activity based funding models are used, and presented in the most recent reference year (e.g. 2020), Australian dollars. Costs and outcomes will be discounted by 5% in year 2, consistent with Australian Government recommendations.
For each outcome, the incremental cost effectiveness ratio (ICER) of the GAME intervention versus standard care will be calculated, and reported with 95% confidence intervals, obtained through non-parametric bootstrapping. Scenario analyses for the cost-effectiveness of GAME will be undertaken for each of the pre-defined stratification factors: i.e. state (NSW, VIC, QLD, WA) due to differences in CP service provision and costs; and severity, dichotomised by the HINE score at baseline (<40 vs >=40).
Timepoint [6] 396567 0
24 months

Eligibility
Key inclusion criteria
(a) Aged 3-6.5 months corrected for prematurity;
(b) Discharged home from hospital; and
(c) Diagnosis of cerebral palsy OR (d) diagnosis of “high risk of cerebral palsy” via: (i) General Movements “Absent fidgety” score + abnormal brain MRI/CUS indicating cerebral palsy; OR (ii) General Movements “Absent fidgety” score + Hammersmith Infant Neurological Examination score <57@ 3 months / <59 6 months; OR (iii) Abnormal brain MRI/CUS indicating cerebral palsy + Hammersmith Infant Neurological Examination score <57@ 3 months / <59@ 6 months of age.; OR (iv) imaging evidence of a unilateral brain injury on MRI/CUS + clinical signs of asymmetry + Hammersmith Infant Neurological Examination score in optimal range
Minimum age
3 Months
Maximum age
6 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) Drug resistant epilepsy meeting the International League Against Epilepsy (ILAE) criteria;
(b) Severe vision impairment (unable to fix and follow in good light);
(c) medically fragile preventing safe child-active participation in training; and
(d) living in remote location inaccessible by study personnel for home visits.

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)
After consent and baseline measures, infants will be centrally randomised to GAME or control intervention from concealed opaque envelopes obtained by the site investigator over the phone from independent personnel at a non-study site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be computer generated at the Clinical Trials Centre. Participants will be stratified by site and by severity of neonatal brain injury score to ensure treatment balance across groups.
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 employ the Full Analysis Set comprising all randomised patients, by intention to treat. Primary outcome and other continuous variables will be compared by t-tests and general linear models when normally distributed and with equivalent non-parametric tests when they are not. The primary analysis will assess the effect of the intervention unadjusted for any baseline factors. Secondary analysis will assess the effect of the intervention adjusted for baseline patient characteristics including, neonatal MRI motor severity scores, age at enrolment, parent’s socioeconomic status, and total dose of therapy.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/04/2017
Actual
8/05/2017
Date of last participant enrolment
Anticipated
30/09/2021
Actual
Date of last data collection
Anticipated
31/07/2023
Actual
Sample size
Target
300
Accrual to date
282
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 7137 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 7138 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 7139 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 7140 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [5] 7141 0
Royal Hospital for Women - Randwick
Recruitment hospital [6] 7142 0
Nepean Hospital - Kingswood
Recruitment hospital [7] 7143 0
Liverpool Hospital - Liverpool
Recruitment hospital [8] 7144 0
Campbelltown Hospital - Campbelltown
Recruitment hospital [9] 7145 0
Westmead Hospital - Westmead
Recruitment hospital [10] 7146 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [11] 7147 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [12] 7148 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [13] 7149 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [14] 7150 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [15] 7151 0
Casey Hospital - Berwick
Recruitment hospital [16] 7152 0
Sunshine Hospital - St Albans
Recruitment hospital [17] 7153 0
Gold Coast University Hospital - Southport
Recruitment hospital [18] 7154 0
The Northern Hospital - Epping
Recruitment hospital [19] 7155 0
The Royal Women's Hospital - Parkville
Recruitment hospital [20] 7156 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [21] 7157 0
Frankston Hospital - Frankston
Recruitment hospital [22] 19650 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 14899 0
2145 - Westmead
Recruitment postcode(s) [2] 14900 0
2031 - Randwick
Recruitment postcode(s) [3] 14901 0
2065 - St Leonards
Recruitment postcode(s) [4] 14902 0
2050 - Camperdown
Recruitment postcode(s) [5] 14903 0
2747 - Kingswood
Recruitment postcode(s) [6] 14904 0
2170 - Liverpool
Recruitment postcode(s) [7] 14905 0
2560 - Campbelltown
Recruitment postcode(s) [8] 14906 0
4029 - Herston
Recruitment postcode(s) [9] 14907 0
3052 - Parkville
Recruitment postcode(s) [10] 14908 0
4101 - South Brisbane
Recruitment postcode(s) [11] 14909 0
3168 - Clayton
Recruitment postcode(s) [12] 14910 0
3806 - Berwick
Recruitment postcode(s) [13] 14911 0
3021 - St Albans
Recruitment postcode(s) [14] 14912 0
4215 - Southport
Recruitment postcode(s) [15] 14913 0
3076 - Epping
Recruitment postcode(s) [16] 14914 0
3084 - Heidelberg
Recruitment postcode(s) [17] 14915 0
3199 - Frankston
Recruitment postcode(s) [18] 34282 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 295191 0
Government body
Name [1] 295191 0
NHMRC
Country [1] 295191 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Camperdown, Sydney 2006
Country
Australia
Secondary sponsor category [1] 294019 0
None
Name [1] 294019 0
Address [1] 294019 0
Country [1] 294019 0
Other collaborator category [1] 279625 0
Charities/Societies/Foundations
Name [1] 279625 0
Cerebral Palsy Alliance
Address [1] 279625 0
PO Box 6427, Frenchs Forest, NSW 2086
Country [1] 279625 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296543 0
Cerebral Palsy Alliance HREC
Ethics committee address [1] 296543 0
PO Box 6427, Frenchs Forest NSW 2086
Ethics committee country [1] 296543 0
Australia
Date submitted for ethics approval [1] 296543 0
30/11/2016
Approval date [1] 296543 0
14/02/2017
Ethics approval number [1] 296543 0
2016-11-03
Ethics committee name [2] 300732 0
Sydney CHildren's Hospital Network HREC
Ethics committee address [2] 300732 0
Corner Hawkesbury Road
and Hainsworth Street
Locked Bag 4001
Westmead NSW 2145
Sydney Australia
Ethics committee country [2] 300732 0
Australia
Date submitted for ethics approval [2] 300732 0
17/02/2017
Approval date [2] 300732 0
19/04/2017
Ethics approval number [2] 300732 0
HREC/17/SCHN/37

Summary
Brief summary
Each year, 600 Australians are diagnosed with cerebral palsy with a $4 billion annual socioeconomic burden. One third never walk. The National Disability Insurance Scheme ranks early intervention to improve disability as its top priority.
We have developed an early training intervention ("GAME" Goals Activity Motor Enrichment) based on the key neuroscience principles of activity dependent plasticity and enriched environments and on successful training interventions known to work in older children with cerebral palsy and adults post stroke.
GAME is the only published protocol of an infant friendly early, intense, specific training intervention grounded in contemporary neuroscience, tested for safety and early efficacy, and is acceptable to parents.
This new pragmatic, single blind randomised controlled trial (RCT) in 300 infants with cerebral palsy or at high risk of cerebral palsy aims to evaluate the effects of “GAME” versus traditional passive early intervention on gross and fine motor skills at two years of age. We will also evaluate the secondary outcomes of neuroplasticity on MRI,
cognitive skills and quality of life. In this pragmatic trial, infants will receive experimental GAME training (once weekly therapist provided+ daily parent provided) versus control (traditional therapy alone). Both groups will be dose matched according to the standard
National Disability Insurance Scheme early intervention funding package. Experimental and control treatments will continue until the infant’s 2nd birthday.
Assessments will be carried out at baseline, prior to randomisation and at 1 and 2 years of age (corrected for prematurity).
The expected clinical outcomes of our trial are that infants who received our intervention will have significant and lasting motor and cognitive gains that lessen the severity of their cerebral palsy and improve their quality of life.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71074 0
Prof Iona Novak
Address 71074 0
Cerebral Palsy Alliance Research Institute
The University of Sydney
PO Box 6427, Frenchs Forest NSW 2086
Country 71074 0
Australia
Phone 71074 0
+ 61 409078917
Fax 71074 0
Email 71074 0
[email protected]
Contact person for public queries
Name 71075 0
Prof Iona Novak
Address 71075 0
Cerebral Palsy Alliance Research Institute
The University of Sydney
PO Box 6427, Frenchs Forest NSW 2086
Country 71075 0
Australia
Phone 71075 0
+ 61 409078917
Fax 71075 0
Email 71075 0
[email protected]
Contact person for scientific queries
Name 71076 0
Prof Iona Novak
Address 71076 0
Cerebral Palsy Alliance Research Institute
The University of Sydney
PO Box 6427, Frenchs Forest NSW 2086
Country 71076 0
Australia
Phone 71076 0
+ 61 409078917
Fax 71076 0
Email 71076 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseHarnessing neuroplasticity to improve motor performance in infants with cerebral palsy: A study protocol for the GAME randomised controlled trial.2023https://dx.doi.org/10.1136/bmjopen-2022-070649
N.B. These documents automatically identified may not have been verified by the study sponsor.