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Trial registered on ANZCTR
Registration number
ACTRN12624001201561p
Ethics application status
Submitted, not yet approved
Date submitted
28/08/2024
Date registered
1/10/2024
Date last updated
1/10/2024
Date data sharing statement initially provided
1/10/2024
Type of registration
Prospectively registered
Titles & IDs
Public title
Treatment of steroid-sensitive nephrotic syndrome in children – the OPtimising dosE in Nephrotic syndrome (OPEN) trial.
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Scientific title
A multicentre, randomised, controlled trial to evaluate treatment of steroid-sensitive nephrotic syndrome in children – the OPtimising dosE in Nephrotic syndrome (OPEN) trial.
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Secondary ID [1]
312999
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Incidence of adverse events
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Universal Trial Number (UTN)
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Trial acronym
OPEN Trial
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Kidney disease
334080
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Condition category
Condition code
Inflammatory and Immune System
330871
330871
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0
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Other inflammatory or immune system disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
This is a randomized, multicentre, controlled trial aimed to determine if equivalent outcomes can be achieved using half dose (low intensity) prednisolone compared to current standard of care (high intensity), to treat children at the time of relapse of steroid-sensitive idiopathic nephrotic syndrome (SSNS).
There are two phases to this study, the induction phase (at the time of relapse) and the consolidation phase (at the time of remission).
Relapse is defined as level of proteinuria of greater than or equal to 3+ on urinalysis for greater than or equal to 3 days, or greater than or equal to 3+ on urinalysis with oedema (greater than or equal to 3+ on urinalysis considered equivalent to a urine protein-to-creatinine of 200mg/mmol).
Remission is defined as trace or negative proteinuria on urinalysis for 3 consecutive days (trace or negative on urinalysis considered equivalent to a urine protein-to-creatinine of
less than or equal to 20mg/mmol).
At the time of relapse of SSNS, eligible study participants enter the induction phase and are randomized to receive either a low-intensity (intervention arm) or high-intensity (control arm).
The control arm will receive standard of care treatment per International Paediatric Nephrology Association (IPNA guidelines), which is 60mg/m2 prednisolone daily (administered in capsule form) until remission.
The intervention arm will receive the same duration of prednisolone, but at half of the dose-30mg/m2 daily until remission.
When participants meet the definition of remission, they enter the consolidation phase and randomised again to either low-intensity (intervention arm) or high-intensity (control arm).
The control arm will receive standard of care treatment per IPNA guidelines which is 40mg/m2 every other day for four weeks
The intervention arm will receive the same duration of prednisolone, but at half the dose- 20mg/m2 every other day for four weeks.
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Intervention code [1]
328901
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Treatment: Drugs
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Comparator / control treatment
Control arm: Induction phase (high-intensity) - Will receive standard of care treatment per IPNA guidelines, which is 60 mg/m2 prednisolone (maximum 60 mg) daily until remission.
Control arm: Consolidated phase (low-intensity) - Will receive standard of care treatment per IPNA guidelines, which is 40mg/m2 prednisolone (maximum 40mg) every other day for 4 weeks.
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Control group
Dose comparison
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Outcomes
Primary outcome [1]
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Induction Phase - Time in days from onset of relapse to remission.
• Relapse is defined as level of proteinuria of greater than or equal to 3+ on urinalysis for greater than or equal to 3 days, or greater than or equal to 3+ on urinalysis with oedema (greater than or equal to 3+ on urinalysis considered equivalent to a urine protein-to-creatinine of 200mg/mmol).
• Remission is defined as trace or negative proteinuria on urinalysis for 3 consecutive days (trace or negative on urinalysis considered equivalent to a urine protein-to-creatinine of less than or equal to 20mg/mmol).
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Assessment method [1]
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From the date of reported relapse participants and/or their caregivers will measure early morning urine protein at home, per standard of care and in conjunction with routine training provided by local units, using a standardised urine dipstick (Multistix; provided if participants do not have an existing clinical supply). A daily REDCap link will be provided via email each day during the induction phase, and then weekly for the 28 days of consolidation to record the result. At the end of induction, caregivers will be asked to upload a picture of the trace or negative dipstick for verification. If there is uncertainty about the measurement then a formal urine protein-to-creatinine will be ordered, again guided by standard of clinical care. This approach is consistent with previously completed clinical trials (Christian MT, 2021). Once the consolidation phase is completed, participants will check urine dipstick per standard of clinical care to detect the onset of next relapse; i.e. with observation of oedema, during intercurrent viral illness or known triggers, any parental concern. Participants will be asked to report next relapse to the study team, with confirmation from the site. In-lieu of reported relapse, participants will be contacted 3-monthly to confirm that none have occurred.
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Timepoint [1]
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Time in days from onset of relapse to remission up to one year post-enrolment
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Primary outcome [2]
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Consolidation Phase – Time in days from remission to next relapse, defined in the same manner as the primary relapse.
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Assessment method [2]
339333
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Once the consolidation phase is completed, participants will check urine dipstick every 2 weeks or per standard of clinical care (i.e with observation of oedema, during intercurrent viral illness or known triggers, any parental concern) to detect the onset of next relapse.
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Timepoint [2]
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If a test detects >2+ proteinuria, then participants will be asked to monitor the urine dipstick daily until the results confirm progression to relapse or remission, up to one year post- enrolment.
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Secondary outcome [1]
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Health economic evaluation
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Assessment method [1]
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A modelled cost utility analysis will be undertaken using trial data. This analysis will calculate the economic benefit in terms of quality-adjusted life years, incorporating both resource use and costs (e.g MBS and PBS data on healthcare services) and patient reported outcomes. Diaries maintained by participants or their caregivers will record additional economic and quality of life data, including days of school or child-care missed by the child, day of work missed by the caregiver and out-of pocket expenses related to care.
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Timepoint [1]
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12 months post intervention commencement
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Secondary outcome [2]
439800
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Incidence of adverse events
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Assessment method [2]
439800
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Incidence of adverse events including infection requiring antibiotic therapy (captured as type, requirement for hospital admission, requirement for intensive care admission), abdominal pain requiring analgesia or haematemesis, new diagnosis of glaucoma or cataract, new diagnosis of hypertension requiring antihypertensive therapy, and skin changes (new striae, acne, unexpected bruising). These will be monitored as self-reported through the REDCap links to participants/caregivers, or by the clinical care team. Both caregiver and the treating clinical team will be surveyed at the end of consolidation to ensure no events have been missed.
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Timepoint [2]
439800
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Until cessation of the study medication or end of the consolidation phase.
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Eligibility
Key inclusion criteria
• Children between 1 and 15 years of age, inclusive
• With a relapse of Idiopathic Nephrotic Syndrome (INS)
• Whose last relapse (or initial presentation if this is the first relapse since) responded to prednisolone within 4 weeks (i.e. are steroid-sensitive)
• Not taking > 15 mg/m2 daily prednisolone at the time of recruitment or in the prior 2 weeks
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Minimum age
1
Years
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Maximum age
15
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
• Familial nephrotic syndrome: another first-degree relative with INS
• For children who have undergone kidney biopsy, findings other than minimal change disease or focal segmental glomerulosclerosis
• Children with a documented history of significant non-adherence or inability to perform daily urine dipsticks at home
• Children unable to take prednisolone capsules, even in crushed form mixed with food
• Any other condition resulting in life expectancy less than one year or that in the opinion of the investigator would present a serious safety risk to the participant.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
central randomisation by computer generated sequence.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation),
Stratified by site.
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
The difference between groups for the primary outcome will be tested by restricted mean survival time. Between group comparisons that are not time to event (e.g. difference in PEDSQL) will be tested by paired t-test or Wilcoxon rank sum for continuous variables depending on the distribution. Statistical analyses will be performed by an experienced University of Sydney statisticians, blinded to treatment allocation. The primary and secondary outcomes will be assessed in a modified intention to treat format (exclusion of participants who are randomised but never initiate the study medication). An alpha threshold of <0.025 will be used to denote statistical significance.
Sensitivity analyses will include:
• Per protocol analysis (exclusion of participants who take fewer than 75% of study medication doses)
• Adjustment for any imbalances in relevant baseline covariates between trial arms (age, ethnicity, proportion of participants receiving concomitant non-corticosteroid immunosuppression)
• Testing for effect modification by relevant covariates (age, ethnicity, proportion of participants receiving concomitant non-corticosteroid immunosuppression).
A separate statistical analysis plan will be constructed by the statistics and project teams, for approval by the steering committee prior to publication with the final trial protocol.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
6/01/2025
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Actual
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Date of last participant enrolment
Anticipated
6/01/2028
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Actual
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Date of last data collection
Anticipated
29/12/2028
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Actual
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Sample size
Target
350
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
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Recruitment outside Australia
Country [1]
26512
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New Zealand
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State/province [1]
26512
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Auckland
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Funding & Sponsors
Funding source category [1]
316721
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Government body
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Name [1]
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Australian Government’s Medical Research Future Fund
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Address [1]
316721
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Country [1]
316721
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Australia
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Primary sponsor type
University
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Name
Flinders University
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Address
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Country
Australia
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Secondary sponsor category [1]
319458
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None
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Name [1]
319458
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Address [1]
319458
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Country [1]
319458
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Ethics approval
Ethics application status
Submitted, not yet approved
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Ethics committee name [1]
315496
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Women's and Children's Health Network Human Research Ethics Committee
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Ethics committee address [1]
315496
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https://www.wchn.sa.gov.au/research/human-research
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Ethics committee country [1]
315496
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Australia
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Date submitted for ethics approval [1]
315496
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05/06/2024
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Approval date [1]
315496
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Ethics approval number [1]
315496
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Summary
Brief summary
Nephrotic syndrome (NS) affects around 1 in 50,000 children. Nephrotic syndrome causes the kidneys to leak too much protein into the urine leading to a drop in protein levels in the blood. This causes swelling in the body, especially in the face, legs and feet. The treatment of NS is steroid therapy. Most children with NS get better with steroid therapy but for many children, the disease comes back (relapses). NS often continues to relapse for many years. Steroids can help in treating relapses but they come with many side effects like changes in behaviour and sleep, appetite, weight and growth.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Jonathan Craig
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Address
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College of Medicine and Public Health, Health and Medical Research Building, Flinders University, Bedford Park, SA 5042
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Country
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Australia
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Phone
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+61 8 82015817
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Fax
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Email
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[email protected]
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Contact person for public queries
Name
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Jonathan Craig
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Address
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College of Medicine and Public Health, Health and Medical Research Building, Flinders University, Bedford Park, SA 5042
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Country
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Australia
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Phone
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+61 8 82015817
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Fax
134879
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Email
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[email protected]
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Contact person for scientific queries
Name
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Jonathan Craig
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Address
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College of Medicine and Public Health, Health and Medical Research Building, Flinders University, Bedford Park, SA 5042
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Country
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Australia
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Phone
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+61 8 82015817
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Fax
134880
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Email
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Aggregate data and de-identified individual participant data (subject to approval), with the exception of linked data from Services Australia agreement from MBS and PBS usage that will NOT be shared under the terms of agreement.
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When will data be available (start and end dates)?
After publication of study outcomes
Start date n/a
End date n/a
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Available to whom?
Researchers who submit a scientifically feasible and ethically sound proposal.
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Available for what types of analyses?
For meta-analysis, individual participant meta-analysis, or other secondary research question deemed feasible and ethically sound in the judgement of the trial statisticians, data manager and management committee.
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How or where can data be obtained?
Interested parties may submit a request by email to
[email protected]
to be considered by the trial management committee in consultation with the data manager and trial statistician (s), detailing the proposed work to be undertaken, with scientific justification and evidence of ethical approval or notification of waiver. If approved, a Data Transfer Agreement will be executed.
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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
No additional documents have been identified.
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