ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12622000788774p

Ethics application status

Not yet submitted

Date submitted

11/05/2022

Date registered

2/06/2022

Date last updated

2/06/2022

Date data sharing statement initially provided

2/06/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

Australian Cerebral Palsy Musculoskeletal Health Network: assessment of hip, spine and fracture complications in children with Cerebral Palsy.

Scientific title

Australian Cerebral Palsy Musculoskeletal Health Network: Longitudinal cohort study to evaluate hip displacement, scoliosis and skeletal fragility in children with cerebral palsy Gross Motor Function Classification System (GMFCS) III-V

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1278-1702

Trial acronym

CPMSK

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cerebral Palsy

Scoliosis

Hip displacement

Osteoporosis

Condition category

Condition code

Neurological

Other neurological disorders

Musculoskeletal

Other muscular and skeletal disorders

Musculoskeletal

Osteoporosis

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

Prospective cohort study (n=500, Gross Motor Function Classification System (GMFCS) III-V, aged 4-8 years) for 4 years longitudinal evaluation of hip, spine and skeletal fragility onset, progression, biomarkers and risk factors for outcomes at 8-12 years;
Annual Pelvic x-ray, anterior-posterior (AP) spine x-ray, duel energy x-ray absorptiometry (DXA), peripheral quantitative computer tomography (pQCT)- Delivered by paediatric radiographer, nuclear medicine technician or clinical researcher accredited to perform DXA and pQCT. It is anticipated that these assessments will take a total of 2 hours to perform. Undertaken annually for 4 years of the study.
Annual questionnaires completed by parents and participants: Child Health Utility instrument (CHU9D), CPCHILD - delivered by clinical researchers. It is anticipated that it will take up to 60 minutes to complete these questionnaires. Undertaken annually for 4 years of the study.
Physical activity: ActiGraph GT3X+ for 7 consecutive days Annual. Delivered by exercise physiologists. This is not a physical activity intervention, but rather a measure of physical activity that the child undertakes spontaneously. Undertaken annually for 4 years of the study.
Blood tests: Calcium, Magnesium, Phosphate, (CMP) 25 Hydroxy vitamin D (25OHD). Annual. Blood collected by paediatric phlebotomist. A numbing cream will be applied prior to the collection of blood. It is anticipated blood collection will take 5 minutes. Undertaken annually for 4 years of the study.

Intervention code [1]

Early Detection / Screening

Intervention code [2]

Diagnosis / Prognosis

Comparator / control treatment

Published reference data for DXA and pQCT be comparing the results of your study with the aggregated results in these published papers
DXA:
1. Lu PW, Briody JN, Ogle GD, et al. Bone mineral density of total body, spine, and
femoral neck in children and young adults: a cross-sectional and longitudinal
study. J Bone Miner Res 1994;9:1451–8.
2. Ogle GD, Allen JR, Humphries IR, et al. Body-composition assessment by dual energy
x-ray absorptiometry in subjects aged 4–26 y. Am J Clin Nutr 1995;61:
746–53.
3. Hogler W, Briody J, Woodhead HJ, et al. Importance of lean mass in the
interpretation of total body densitometry in children and adolescents. J Pediatr
2003;143:81–8.
pQCT:
1. Rauch F, Schoenau E. Peripheral quantitative computed
tomography of the distal radius in young subjects – New
reference data and interpretation of results. Journal of
Musculoskeletal and Neuronal Interactions 2005;5(2):
119–126.
2. Moyer-Mileur LJ, Quick JL, Murray MA. Peripheral quantitative
computed tomography of the tibia: Pediatric reference
values. Journal of Clinical Densitometry 2008;11(2):
283–294.

Published data on functional status:
1. Jackman, M., Sakzewski, L., Morgan, C., Boyd, R.N., Brennan, S.E., Langdon, K., Toovey, R.A.M., Greaves, S., Thorley, M. and Novak, I. (2022), Interventions to improve physical function for children and young people with cerebral palsy: international clinical practice guideline. Dev Med Child Neurol, 64: 536-549

Control group

Historical

Outcomes

Primary outcome [1]

Hip radiological measure from anterior-posterior (AP) pelvis x-ray. Migration percentage (MP) is the gold standard of femoral head displacement.

Timepoint [1]

Assessed annually for 4 years post-enrolment

Primary outcome [2]

Hip radiological measure from AP pelvis x-ray. Acetabular index (AI), assesses acetabular dysplasia.

Timepoint [2]

Measured annually with final measurement at 4 years post-enrolment

Primary outcome [3]

Hip radiological measure from AP pelvis x-ray. Hilgreneiner’s Epiphyseal Angle (HEA) and femoral neck-shaft angle (NSA) describe the proximal femoral epiphysis and with cerebral palsy surveillance program (CPUP) score offer prognosis for bony surgery.

Timepoint [3]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [1]

Primary outcome:
Hip: Dual energy x-ray absorptiometry (DXA), age/height matched areal bone mineral density (aBMD; g/cm2), bone mineral content (BMC; grams)

Timepoint [1]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [2]

Primary outcome:
Lumbar spine: Dual energy x-ray absorptiometry (DXA), age/height matched areal bone mineral density (aBMD; g/cm2), bone mineral content (BMC; grams)

Timepoint [2]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [3]

Primary outcome:
Total body: Dual energy x-ray absorptiometry (DXA), age/height matched areal bone mineral density (aBMD; g/cm2), bone mineral content (BMC; grams)

Timepoint [3]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [4]

Primary outcome:
Lateral distal femur: Dual energy x-ray absorptiometry (DXA), age/height matched areal bone mineral density (aBMD; g/cm2), bone mineral content (BMC; grams)

Timepoint [4]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [5]

Primary outcome:
Posterior-Anterior (PA) spine radiograph. Measured by two investigators following intra-observer calculations.
Major/compensatory structural curve (Cobb)

Timepoint [5]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [6]

Primary Outcome:
Posterior-Anterior (PA) spine radiograph. Measured by two investigators following intra-observer calculations.
Thoracic kyphosis angle

Timepoint [6]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [7]

Parent Reported Secondary outcomes: CHU9D is a generic instrument for children aged 7-11 gives preference-based utility index for economic evaluations

Timepoint [7]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [8]

Primary outcome:
Posterior-Anterior (PA) spine radiograph. Measured by two investigators following intra-observer calculations.
Rotational spinal deformity

Timepoint [8]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [9]

Posterior-Anterior (PA) spine radiograph. Measured by two investigators following intra-observer calculations.
Sagittal balance (sagittal vertical axis)

Timepoint [9]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [10]

Posterior-Anterior (PA) spine radiograph. Measured by two investigators following intra-observer calculations.
Sacral shift (central sacral vertical line)

Timepoint [10]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [11]

Posterior-Anterior (PA) spine radiograph. Measured by two investigators following intra-observer calculations.
Shoulder asymmetry (vertical height acromion)

Timepoint [11]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [12]

Posterior-Anterior (PA) spine radiograph. Measured by two investigators following intra-observer calculations.
Spinal deformity severity by CPUP

Timepoint [12]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [13]

Rib hump (Adams Forward Bend Test). Evaluated by trained physiotherapist

Timepoint [13]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [14]

Lateral spine flexibility test (in lying/sit), Outcome: distance (cm) finger-feet left and right. Evaluated by trained physiotherapist

Timepoint [14]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [15]

Functional reach test left and right in sitting/stand. Evaluated by trained physiotherapist

Timepoint [15]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [16]

Musculoskeletal Examination Surveillance in Europe and Australian Spasticity Assessment Scales.
Lower limb muscle length/contracture

Timepoint [16]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [17]

Musculoskeletal Examination Surveillance in Europe and Australian Spasticity Assessment Scales.
Range of motion

Timepoint [17]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [18]

Motor type/distribution using Musculoskeletal Examination Surveillance in Europe and Australian Spasticity Assessment Scales.

Timepoint [18]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [19]

Peripheral quantitative computer tomography (pQCT) of tibia in GMFCS III and subset of GMFCS IV:
Volumetric bone mineral density (BMD) of cortical bone (65% site)

Timepoint [19]

Measured 2nd yearly with final measurement at 4 years post-enrolment

Secondary outcome [20]

Peripheral quantitative computer tomography (pQCT) of tibia in GMFCS III and subset of GMFCS IV:
Volumetric BMD of trabecular bone (4% site)

Timepoint [20]

Measured 2nd yearly with final measurement at 4 years post-enrolment

Secondary outcome [21]

Peripheral quantitative computer tomography (pQCT) of tibia in GMFCS III and subset of GMFCS IV:
65% site cortical size

Timepoint [21]

Measured 2nd yearly with final measurement at 4 years post-enrolment

Secondary outcome [22]

Peripheral quantitative computer tomography (pQCT) of tibia in GMFCS III and subset of GMFCS IV:
65% Strength Strain Index (SSI)

Timepoint [22]

Measured 2nd yearly with final measurement at 4 years post-enrolments

Secondary outcome [23]

Fracture rate: Fractures using radiological evidence. Parents will report occurrence <24 hours, bring X-ray films and management details. Annual fracture questionnaire will record fracture history will be developed specifically for this study

Timepoint [23]

Measured 2nd yearly with final measurement at 4 years post-enrolment

Secondary outcome [24]

Habitual Physical Activity: will be measured using triaxial accelerometers worn on the less-affected wrist (ActiGraph GT3X+) and less-affected thigh (Axivity AX3) for 7 days during free living. Raw accelerometer signal will be processed into HPA outcomes using CI Trost’s machine-learned PA classification algorithms specifically trained and validated for youth with CP who are ambulatory or use mobility aids for ambulation. The algorithms use statistical and frequency domain features in the raw acceleration signal to identify activity type and quantify time spent in sedentary activities (sitting or lying down, transfers); wheelchair propulsion, standing, walking, and cycling.

Timepoint [24]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [25]

Growth and nutritional status: Body Mass (kg) using chair scales.

Timepoint [25]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [26]

Growth and nutritional status:
Height (cm) with a stadiometer, or length using a supine measuring board, Knee height and upper-arm length to predict height.

Timepoint [26]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [27]

Growth and nutritional status:
Body mass index as per Cerebral Palsy (CP) growth protocol.
Calculated using Mass using chair scales and Height with a stadiometer, or length using a supine measuring board.

Timepoint [27]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [28]

Body composition: DXA measurements of fat mass

Timepoint [28]

Measured 2nd yearly with final measurement at 4 years post-enrolment

Secondary outcome [29]

Body composition: DXA measurements of fat free mass

Timepoint [29]

Measured 2nd yearly with final measurement at 4 years post-enrolment

Secondary outcome [30]

DXA measurements of bone mineral content (BMC).

Timepoint [30]

Measured 2nd yearly with final measurement at 4 years post-enrolment

Secondary outcome [31]

Dietary energy intakes through our validated food records.

Timepoint [31]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [32]

Feeding through our parent report questionnaire.

Timepoint [32]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [33]

Pain: Pediatric Pain Profile collects data on episodes of pain, treatment, physician contacts, medication use.

Timepoint [33]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [34]

Blood collected by phlebotomists or under GA (during procedures), for 25-hydroxy vitamin D,

Timepoint [34]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [35]

Blood collected by phlebotomists or under GA (during procedures), for calcium

Timepoint [35]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [36]

Blood collected by phlebotomists or under GA (during procedures), for iron,

Timepoint [36]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [37]

Parent Reported Secondary outcomes: The Caregiver Priorities & Child Health Index of Life with Disabilities (CPCHILD©) Q has 6 domains: ADL; Positioning, Transferring & Mobility; Comfort/Emotions; Communication/Social; Health; and QOL, distinguishes between GMFCS.

Timepoint [37]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [38]

Sexual Maturation: Legal guardians complete standardised Tanner stage puberty diagrams to evaluate the child’s pubertal stage. Data will be reviewed by a physician for precocious puberty

Timepoint [38]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [39]

Two separate outcomes measurers of a validated parent reported food frequency questionnaire, including gastrostomy feeds and Sun Exposure: Diary to measure daily UV performed during 7 day physical activity, within 2 weeks 25OHD levels.

Timepoint [39]

Measured annually with final measurement at 4 years post-enrolment

Secondary outcome [40]

Economic Evaluation: A better understanding of the value and costs of a national approach would lead to better decision-making regarding hip, spine, and bone fragility complications in CP. We will perform an economic evaluation of surveillance/prevention programs for MSK problems in CP. A cost-consequence analysis (CCA) will be undertaken from the societal perspective to attain Aims 3 and 4. CCA provides a summary of varied health, non-health costs and multi-dimensional outcomes, is simple to understand and apply by decision-makers. CCA will capture direct medical costs (drug, physician visits, hospital stays, and home care), and direct non-medical costs (e.g. devices, transportation, and paid caregiver time). Resource use data and direct costs of treatments will be collected through Health Resource Use (HRU) Q supplemented by MBS and PBS data. HRU includes data on screening, therapy frequency/duration, hospital admissions, medical visits, operations, medications, equipment, and parent time for appointments. Standard cost sources (MBS, PBS, hospital, DRGs for IP/OP services) will be applied to resource use and total cost of care calculated per child aged 2-12 years. CCA will report health outcomes to demonstrate value for money, including best possible musculoskeletal health, physical function, greater QOL, non-health effects, and non-patient effects (carer wellbeing and QOL). CCA will report costs and outcomes in a simple and disaggregated format to help policymakers better understand the effects of prevention programs for MSK problems in CP across costs and outcomes. The analysis will be performed on a 4-years’ time horizon, with a 3% discount rate to account for time preference.

Timepoint [40]

Final measurement at 4 years post-enrolment

Eligibility

Key inclusion criteria

Prospective Study: Children aged 4-8 years with Cerebral Palsy GMFCS III-V

Minimum age

4 Years

Maximum age

8 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Unable or unwilling to undertake annual review for 4 years

Study design

Purpose

Natural history

Duration

Longitudinal

Selection

Defined population

Timing

Prospective

Statistical methods / analysis

Sample size and power: The total number of participants with data for the primary outcome (MP – Aim 1) is expected to be n=450 (assume 4- yr data from 90% of 500 enrolled participants based on attrition in previous NHMRC funded cohorts run by this team. If we assume approximately 70% of the cohort will have HD, then we will have 90% power (alpha=0.05) to detect differences between binary risk factor categories of 12% or greater, this is equivalent to identifying relative risks (RRs) of <0.80 or >1.18. Even when risk factors are unbalanced in a 4:1 ratio we will be able to identify RRs of <0.65 or >1.30. For Sc, if we assume overall cumulative incidence of 25%, we will be able to detect absolute between-group differences of >11%. Note that this is an underestimate of power due to the repeated annual measurements for each child.
Statistical analyses: CI Ware (Prof Biostatistics). To identify relationships between early biomarkers, early brain structure and clinical characteristics and bone quality with MSK complications we will build multivariable regression models according to our model. Association between risk factors and primary outcomes measured on the interval scale (eg MP%) will be investigated using mixed-effects linear regression models with child included as a random effect to account for repeated measures. Risk factor and time will be included as fixed effects, with an interaction term. Potentially confounding variables will be included. For binary outcomes mixed-effect logistic regression models will be constructed and mixed-effects Poisson models for count outcomes. When constructing predictive models, first important variables will be examined individually before the final multivariable model is selected using Bayesian Information Criteria. Model calibration will be tested graphically, and internal validation will use bootstrap resampling. Missing data will be treated case-by-case, i.e. multiple imputation methods if ‘missing at random’ and pattern-mixture models if ‘not missing at random’. Adjustment for multiple comparisons will be made for each separate analysis mindful of type I & II error rates, as is standard practice.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

2/01/2023

Actual

Date of last participant enrolment

Anticipated

31/12/2024

Actual

Date of last data collection

Anticipated

31/12/2027

Actual

Sample size

Target

500

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,WA,VIC

Recruitment hospital [1]

Queensland Children's Hospital - South Brisbane

Recruitment hospital [2]

The Royal Childrens Hospital - Parkville

Recruitment hospital [3]

Perth Children's Hospital - Nedlands

Recruitment hospital [4]

John Hunter Children's Hospital - New Lambton

Recruitment hospital [5]

Monash Children’s Hospital - Clayton

Recruitment hospital [6]

Sydney Children's Hospital - Randwick

Recruitment hospital [7]

The Children's Hospital at Westmead - Westmead

Recruitment postcode(s) [1]

4101 - South Brisbane

Recruitment postcode(s) [2]

3052 - Parkville

Recruitment postcode(s) [3]

6009 - Nedlands

Recruitment postcode(s) [4]

2305 - New Lambton

Recruitment postcode(s) [5]

3168 - Clayton

Recruitment postcode(s) [6]

2031 - Randwick

Recruitment postcode(s) [7]

2145 - Westmead

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Australian Government Department of Health (Medical Research Future Fund)

Address [1]

Department of Health
GPO Box 9848
Canberra ACT 2601
Australia

Country [1]

Australia

Primary sponsor type

University

Name

The University of Queensland

Address

St Lucia
Brisbane QLD 4072 Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

N/A

Address [1]

N/A

Country [1]

Ethics approval

Ethics application status

Not yet submitted

Ethics committee name [1]

The University of Queensland

Ethics committee address [1]

St Lucia
Brisbane QLD 4072 Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/06/2022

Approval date [1]

Ethics approval number [1]

Ethics committee name [2]

Children's Health Queensland

Ethics committee address [2]

501 Stanley Street
South Brisbane
Queensland 4101

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

01/06/2022

Approval date [2]

Ethics approval number [2]

Summary

Brief summary

Cerebral Palsy (CP) is the most common physical disability in childhood impacting 1 in 700 Australians. It is the 5th most costly condition at >AUD $5Billion p.a. CP is a disorder of movement and posture due to a static early brain lesion, however the musculoskeletal (MSK) sequelae are progressive. Major MSK complications are hip displacement, scoliosis and skeletal fragility, which lead to pain, disability and major orthopaedic surgery. Our Australian Cerebral Palsy Register has tracked the cause and severity of persons with CP. Our national Hip Surveillance Guidelines track progression of hip displacement which has shown a strong association with Gross Motor Function. Our Australasian Cerebral Palsy Clinical Trials network has implemented 3 international clinical practice guidelines on early detection, early intervention and efficacy of interventions to improve functional outcomes. Our team is well placed to develop a national program incorporating identification of hip displacement with scoliosis and fracture surveillance and to examine the inter-relationship between MSK complications.
In a prospective cohort of n=500 children with cerebral palsy, our Australian CP MSK Health Network aims to:
1. Identify novel clinical outcome assessments and biomarkers of onset and progression of hip displacement, scoliosis deformity and osteoporosis/bone fragility to identify therapeutic targets and prevent progression;
2. Develop and integrate national hip, spine and fracture registries to develop practice guidelines that will lead to improved MSK health and wellbeing of children with CP;
3. Examine the inter-relationships between hip, spine and bone health on progression of MSK deformity to clarify the natural history of MSK complications and identify novel therapeutic targets;
4. Develop a fracture risk assessment and decision tool for children with CP to allow for accurate prognosis and timely intervention to reduce impact of skeletal fragility.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Craig Munns

Address

Centre for Children’s Health Research (CCHR)
Room 603, UQ Child Health Research Centre
62 Graham Street
South Brisbane Qld 4101

Country

Australia

Phone

+61 7 3069 7362

Fax

[email protected]

Contact person for public queries

Name

Craig Munns

Address

Centre for Children’s Health Research (CCHR)
Room 603, UQ Child Health Research Centre
62 Graham Street
South Brisbane Qld 4101

Country

Australia

Phone

+61 7 3069 7362

Fax

[email protected]

Contact person for scientific queries

Name

Craig Munns

Address

Centre for Children’s Health Research (CCHR)
Room 603, UQ Child Health Research Centre
62 Graham Street
South Brisbane Qld 4101

Country

Australia

Phone

+61 7 3069 7362

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
15863	Study protocol			[email protected]	Contacting the PI
15864	Ethical approval			[email protected]

Results publications and other study-related documents

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Documents added automatically

No additional documents have been identified.

Trial Review

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