Clinical trial NCT06635720: REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
Official title: REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE): a Pilot Open-label Randomized, Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Nephrotic Syndrome in Children
Nephrotic Syndrome, Minimal Change
Nephrotic Syndrome
Nephrotic Syndrome，Idiopathic
Keywords: Nephrotic syndrome
Idiopathic nephrotic syndrome
Childhood nephrotic syndrome
Minimal change disease
Focal segmental glomerulosclerosis
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2024-10-10
Enrollment: 50
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a pilot feasibility study for a proposed full-scale randomized controlled trial to evaluate the effectiveness and safety of a reduced-dose oral prednisone (steroids) regimen to treat childhood steroid-sensitive nephrotic syndrome relapses versus standard-dose prednisone (i.e., usual standard of care).

This internal pilot study is a single-center, open-label, randomized controlled trial at The Hospital for Sick Children (Toronto, ON, Canada). The primary objective of this pilot study is to determine the feasibility, safety, and resources needed to conduct the future full-scale randomized controlled trial.

Detailed description: Study design:

This is a pilot study for a planned multi-center, Bayesian adaptive, non-inferiority RCT (Figure 1). This planned multi-center RCT will require additional funding, which we will apply for if feasibility is shown by this pilot. This pilot is a single-center (SickKids) open-label RCT comparing reduced vs. standard-dose steroids to treat nephrotic syndrome relapses.

Study population:

We will include children (1-18 years) from Ontario, Canada that are diagnosed with idiopathic SSNS and present in relapse (≥3+ dipstick protein or protein:creatinine ratio ≥200mg /mmol for ≥3 consecutive days). We will exclude children that have received \&gt;2 days of standard-dose prednisone; are on maintenance high-dose prednisone (\&gt;0.3mg/kg per day or \&gt;0.6mg/kg alternate days); have relapsed within the past 6 weeks; have grade 3+ peripheral edema (i.e., moderate-severe); are hospitalized; have stage 2+ acute kidney injury; or have thromboembolism. Children receiving other steroid-sparing immunosuppressives are eligible, but target drug levels will remain constant until the 2-week visit. No additional laboratory or imaging tests are needed, to maximize recruitment.

Interventions:

Reduced-dose steroids (intervention): oral prednisone 30mg/m2 (1mg/kg; max 40mg) daily until remission, then 20mg/m2 (0.66mg/kg; max 25mg) on alternate days for four weeks.

Standard-dose steroids (control): oral prednisone 60mg/m2 (2mg/kg; max 60mg) daily until remission, then 40mg/m2 (1.5mg/kg; max 50mg) on alternate days for four weeks.

Randomization 1:1 using permuted blocks. If a participant does not achieve remission by 2-weeks, develops symptomatic edema, stage 2+ acute kidney injury, or thromboembolism, they will be escalated to standard-dose steroids.

Outcomes:

The primary outcome is recruitment rate (number enrolled per month), since it is the greatest anticipated barrier to RCT feasibility. Other feasibility, tolerability, and safety outcomes are listed in Table 1. The pilot study will test case report forms, data management, quality control, and training systems. We will estimate treatment effect for the full-scale RCT's primary outcome (complete remission without steroid dose escalation by 2-weeks), to re-estimate sample size and evaluate full-scale RCT feasibility.

Sample size:

For this pilot study, we will recruit 50 children (25 per arm), which is 15% of the estimated sample size of the full-scale RCT. Sample size for this pilot must be adequate to assess RCT feasibility.

Eligibility criteria: Inclusion Criteria:

1. Provide informed consent ± assent
2. Participant age 1-18 years
3. Diagnosis of idiopathic nephrotic syndrome (defined as nephrotic-range proteinuria \[first morning or 24-hour urine protein/creatinine ratio ≥200mg/mmol or ≥3+ protein on dipstick\] and either hypoalbuminemia \[serum albumin \&lt;30g/L\] or edema)
4. Active nephrotic syndrome relapse at time of enrolment (defined as recurrence of nephrotic-range proteinuria \[≥3+ protein on dipstick for ≥3 consecutive days18 OR first morning or 24-hour urine protein/creatinine ratio ≥200mg/mmol AND ≥1+ protein on dipstick for ≥3 consecutive days\])
5. Ability to take oral medication and willingness to adhere to either study prednisone regimen
6. Ability and willingness to adhere to home urine and symptom monitoring during the initial two-week period after assigned treatment initiation
7. Have not been previously included in the RESPONSE trial
8. Participant located in Ontario, Canada at the time of study enrolment

Exclusion Criteria:

1. Prednisone treatment (at any dose) for the active relapse episode for \&gt;2-days prior to study enrolment
2. Relapse episode within the past 6-weeks (i.e., date of relapse onset within 6-weeks prior to date of enrolment)
3. Current receipt of high-dose maintenance prednisone therapy (dose \&gt;0.6mg/kg on alternate days or \&gt;0.3mg/kg daily)
4. Steroid-resistant nephrotic syndrome classification (defined as lack of complete remission within 6-weeks after initiating daily steroid treatment at a standard dose for the initial episode of nephrotic syndrome)
5. Congenital or monogenic cause of nephrotic syndrome (defined as age at diagnosis \&lt;1-year or known/suspected monogenic cause of nephrotic syndrome)
6. Secondary cause of nephrotic syndrome (includes membranous nephropathy, post-infectious glomerulonephritis \[GN\], complement-mediated GN \[e.g., C3 glomerulopathy and immune complex-GN\], IgA nephropathy, IgA vasculitis, lupus nephritis, medication-induced nephrotic syndrome, malignancy-induced nephrotic syndrome, active hepatitis B or C infection, or active HIV infection)
7. Presence of moderate-to-severe peripheral edema (grade 3+; indentation depth ≥5mm and rebound time \&gt;15 seconds)
8. Hospitalization since the onset of the active relapse episode
9. Acute kidney injury (KDIGO stage ≥1) since the onset of the active relapse episode
10. Active or prior known or suspected venous thromboembolism during a relapse episode
11. Active pregnancy or lactation
12. Any condition or diagnosis, that could in the opinion of the Principal Investigator or delegate interfere with the participant's ability to comply with study instructions, might confound the interpretation of the study results, or put the participant at risk

Primary outcomes:
measure: Study recruitment rate
timeFrame: 1 year
Secondary outcomes:
measure: Treatment effect - treatment failure
timeFrame: From enrolment to 2-week study visit
measure: Number of eligible participants
timeFrame: 1 year
measure: Number of participants that initiate assigned treatment
timeFrame: 1 year
measure: Participant drop-out rate
timeFrame: 1 year
measure: Treatment preference
timeFrame: 1 year
measure: Hospitalizations
timeFrame: From enrolment to 1 year
measure: Cumulative steroid dose
timeFrame: From enrolment to 1 year
measure: Adverse events
timeFrame: From enrolment to 1 year
measure: Treatment adherence
timeFrame: From enrolment to 1 year
measure: Number of participants that complete 2-week study visit
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Rulan Parekh, MD MS
role: PRINCIPAL_INVESTIGATOR
References: