Trial Review

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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.
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.
Secondary ID [1] 312999 0
Incidence of adverse events
Universal Trial Number (UTN)
Trial acronym
OPEN Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Kidney disease 334080 0
Condition category
Condition code
Inflammatory and Immune System 330871 330871 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
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.

Intervention code [1] 328901 0
Treatment: Drugs
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.
Control group
Dose comparison

Outcomes
Primary outcome [1] 338629 0
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).
Timepoint [1] 338629 0
Time in days from onset of relapse to remission up to one year post-enrolment
Primary outcome [2] 339333 0
Consolidation Phase – Time in days from remission to next relapse, defined in the same manner as the primary relapse.
Timepoint [2] 339333 0
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.
Secondary outcome [1] 438613 0
Health economic evaluation
Timepoint [1] 438613 0
12 months post intervention commencement
Secondary outcome [2] 439800 0
Incidence of adverse events
Timepoint [2] 439800 0
Until cessation of the study medication or end of the consolidation phase.

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
Minimum age
1 Years
Maximum age
15 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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.

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)
central randomisation by computer generated sequence.
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.
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/01/2025
Actual
Date of last participant enrolment
Anticipated
6/01/2028
Actual
Date of last data collection
Anticipated
29/12/2028
Actual
Sample size
Target
350
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 26512 0
New Zealand
State/province [1] 26512 0
Auckland

Funding & Sponsors
Funding source category [1] 316721 0
Government body
Name [1] 316721 0
Australian Government’s Medical Research Future Fund
Country [1] 316721 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
Country
Australia
Secondary sponsor category [1] 319458 0
None
Name [1] 319458 0
Address [1] 319458 0
Country [1] 319458 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315496 0
Women's and Children's Health Network Human Research Ethics Committee
Ethics committee address [1] 315496 0
Ethics committee country [1] 315496 0
Australia
Date submitted for ethics approval [1] 315496 0
05/06/2024
Approval date [1] 315496 0
Ethics approval number [1] 315496 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134878 0
Prof Jonathan Craig
Address 134878 0
College of Medicine and Public Health, Health and Medical Research Building, Flinders University, Bedford Park, SA 5042
Country 134878 0
Australia
Phone 134878 0
+61 8 82015817
Fax 134878 0
Email 134878 0
[email protected]
Contact person for public queries
Name 134879 0
Jonathan Craig
Address 134879 0
College of Medicine and Public Health, Health and Medical Research Building, Flinders University, Bedford Park, SA 5042
Country 134879 0
Australia
Phone 134879 0
+61 8 82015817
Fax 134879 0
Email 134879 0
[email protected]
Contact person for scientific queries
Name 134880 0
Jonathan Craig
Address 134880 0
College of Medicine and Public Health, Health and Medical Research Building, Flinders University, Bedford Park, SA 5042
Country 134880 0
Australia
Phone 134880 0
+61 8 82015817
Fax 134880 0
Email 134880 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers who submit a scientifically feasible and ethically sound proposal.

Conditions for requesting access:
• -

What individual participant data might 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.

What types of analyses could be done with individual participant data?
• 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.

When can requests for individual participant data be made (start and end dates)?
From:
After publication of study outcomes
Start date n/a
End date n/a

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?
• 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.

Are there extra considerations when requesting access to individual participant data?
No


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.