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Trial registered on ANZCTR


Registration number
ACTRN12618001875291
Ethics application status
Approved
Date submitted
21/10/2018
Date registered
16/11/2018
Date last updated
16/11/2018
Date data sharing statement initially provided
16/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Child-parent screening for familial hypercholesterolaemia
Scientific title
Child-parent screening for familial hypercholesterolaemia: screening children aged 1-2 years at the time of a scheduled immunisation
Secondary ID [1] 295685 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
familial hypercholesterolaemia 309050 0
Condition category
Condition code
Human Genetics and Inherited Disorders 307941 307941 0 0
Other human genetics and inherited disorders
Metabolic and Endocrine 308932 308932 0 0
Other metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a prospective, two-stage biochemical and “reflex” genetic testing strategy study to identify children with familial hypercholesterolaemia. The study population will be children aged 1-2 years receiving their scheduled 12- or 18-month immunisations, or an influenza immunisation, in a general practice or child health centre.
At the same time as the immunisation is administered by the practice nurse or general practitioner (GP), a heel-prick sample of blood (400 µL) will be collected by a second health professional (nurse or GP) into two separate capillary tubes, one for point of care testing for total cholesterol (100 µL) and one retained and frozen for “reflex” genetic testing (next generation sequencing, NGS) (300 µL). Capillary blood collected for NGS will be decanted into an EDTA tube which is then shaken, labelled and placed on ice prior prior to the sample being stored at -80°C.
Intervention code [1] 302002 0
Early detection / Screening
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307849 0
Number of children and parents finally diagnosed with FH (both genotypic and phenotypic) - composite primary outcome.
This will be assesses by the results of the FH mutational analysis
Timepoint [1] 307849 0
FH mutational analysis will be completed within 2 months of the patient having their initial point of care cholesterol test. Only those children with total cholesterol level greater than or equal to the 95th percentile (5.3mmol/L) will proceed to have FH mutational analysis.
Secondary outcome [1] 353148 0
Number and % of children recalled for further testing, who do not have FH (ie false positives).
Timepoint [1] 353148 0
Following results of FH mutational analysis, approximately 2 months after initial screening. If a child had a cholesterol level above the 95th percentile threshold but has a negative FH mutational analysis, they will be considered a false positive (i.e. initially thought to possibly have FH, but further testing confirm they do not have the condition)
Secondary outcome [2] 353856 0
Acceptability of screening test to parents. The questionnaire was designed specifically for this study and is entitled "parent satisfaction survey".
Timepoint [2] 353856 0
Immediately after the blood sample
Secondary outcome [3] 353857 0
Cost effectiveness of the screening program.
Timepoint [3] 353857 0
The cost-effectiveness of screening will be determined through the development of a lifetime Markov model based on both the number of children and parents diagnosed with FH and published estimates of longer-term outcomes from early detection of FH. We will collect costs associated with screening (initial screening plus immediate sequelae associated with positive test results) and the cost of treatment such as statin therapy. We will then project the occurrence of heart disease into the future and attach costs to coronary events at later time points. Finally we will attach utility weights to health states to generate a cost-utility analysis, which is the standard form of analysis used in national decision-making around health technology.
Secondary outcome [4] 353948 0
Acceptability of screening test to health professionals. The questionnaire was designed specifically for this study and is entitled "health professional satisfaction survey".
Timepoint [4] 353948 0
Immediately after the blood test. This will be assessed with a questionnaire.

Eligibility
Key inclusion criteria
Children 1-2 years presenting to a general practice or child health centre for an immunisation.
Only those parents whose child is found to have FH will be assessed with a total cholesterol level and FH mutational analysis, as one parent will also have FH.
Minimum age
12 Months
Maximum age
24 Months
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Children with a known family history of familial hypercholesterolaemia

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Assuming a FH prevalence of 1 in 250 (0.4%), we estimate that by recruiting 1,000 subjects we will identify 4 children with FH (minimum 2 and maximum 10, based on 95% confidence intervals 0.16% - 1.0%). In addition, we estimate that through family cascade screening, for each child diagnosed with FH we will diagnose a further parent with FH (i.e. expect to identify a total of 8 individuals with FH, minimum 4 and maximum 20). We expect 50 children will have a total cholesterol level > 5.3 mmol/L and require “reflex” genetic testing. 47/50 will not have a FH mutation identified and will require a further blood sample to be collected. One additional child will be diagnosed with phenotypic FH and the remaining 46/50 will be considered to not have FH and will have no further follow-up.
We will assess the acceptability of the screening approach by both parents and health professionals.
The cost-effectiveness of screening will be determined through the development of a lifetime Markov model based on both the clinical outcomes of the trial and published estimates of longer-term outcomes from early detection of FH. Co-Investigators Professor Watts and A/Professor Norman have been involved in international work modelling the longer-term impacts of early FH detection, and this work can be adapted for the analysis proposed here.20 We will collect costs associated with screening (initial screening plus immediate sequelae associated with positive test results) and the cost of treatment such as statin therapy. We will then project the occurrence of heart disease into the future and attach costs to CAD events at later time points. Finally we will attach utility weights to health states to generate a cost-utility analysis, which is the standard form of analysis used in national decision-making around health technology.

Recruitment
Recruitment status
Not yet 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)
WA
Recruitment hospital [1] 12227 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 24406 0
6008 - Subiaco
Recruitment postcode(s) [2] 24407 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 300268 0
Charities/Societies/Foundations
Name [1] 300268 0
Perth Children's Hospital Foundation
Address [1] 300268 0
15 Hospital Avenue, Nedlands, WA 6009, Australia
Country [1] 300268 0
Australia
Primary sponsor type
Individual
Name
Dr Andrew Martin
Address
Department of General Paediatrics
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 299694 0
None
Name [1] 299694 0
Address [1] 299694 0
Country [1] 299694 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301084 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 301084 0
15 Hospital Avenue
Nedlands
WA 6009
Ethics committee country [1] 301084 0
Australia
Date submitted for ethics approval [1] 301084 0
09/02/2018
Approval date [1] 301084 0
23/05/2018
Ethics approval number [1] 301084 0
RGS0795

Summary
Brief summary
Familial hypercholesterolaemia (FH) is the most common and serious cause of inherited high cholesterol and untreated leads to 50% of male and 20% of female patients suffering a fatal or non-fatal heart attack by age 50 years. Most individuals with FH are unaware they have the condition.
The high prevalence of FH (1 in 250), high rates of undiagnosed children and fact that heart attacks in early adult life can now be prevented with appropriate management in childhood, means that new approaches to detection are required.
Universal screening of children for FH at age 1-2 years, by measuring a total cholesterol level at the same time as a routine immunisation has been proposed. We hypothesise that screening children aged 1-2 years with a total cholesterol level, taken at the time of a routine immunisation will be feasible, cost effective and acceptable to parents.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85826 0
Dr Andrew Martin
Address 85826 0
Department of General Paediatrics
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 85826 0
Australia
Phone 85826 0
+61 8 64562222
Fax 85826 0
Email 85826 0
andrew.martin@health.wa.gov.au
Contact person for public queries
Name 85827 0
Dr Andrew Martin
Address 85827 0
Department of General Paediatrics
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 85827 0
Australia
Phone 85827 0
+61 8 64562222
Fax 85827 0
Email 85827 0
andrew.martin@health.wa.gov.au
Contact person for scientific queries
Name 85828 0
Dr Andrew Martin
Address 85828 0
Department of General Paediatrics
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 85828 0
Australia
Phone 85828 0
+61 8 64562222
Fax 85828 0
Email 85828 0
andrew.martin@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results