REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE) (RESPONSE)

REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE): a Pilot Open-label Randomized, Controlled Trial

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Nephrotic Syndrome; Nephrotic Syndrome in Children; Nephrotic Syndrome, Minimal Change; Nephrotic Syndrome，Idiopathic
• Intervention / Treatment: Drug: Prednisone

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 >2 days of standard-dose prednisone; are on maintenance high-dose prednisone (>0.3mg/kg per day or >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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1E8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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 <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 >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 >0.6mg/kg on alternate days or >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 <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 >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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reduced-dose steroids; Reduced-dose steroid protocol (intervention): oral prednisone or prednisolone 30mg/m2 (1mg/kg; max 40mg) daily until remission, then 20mg/m2 (0.66mg/kg; max 25mg) on alternate days for four weeks.	Drug: Prednisone; This study will compare two steroid dosing protocols for the treatment of childhood nephrotic syndrome relapses. The medications used for both intervention and control arms are oral prednisone 5mg tablets (DIN: 00312770) for children able to swallow or use crushed tablets, or oral prednisolone sodium phosphate 5mg base/5mL liquid (DIN: 02245532). Participants hospitalized after study enrollment will be permitted to switch to intravenous methylprednisolone sodium succinate (DIN: 02367955) at the same dose without being considered to have violated their treatment assignment.; Other Names: Prednisolone
Active Comparator: Standard-dose steroids; Standard-dose steroid protocol (control): oral prednisone or prednisolone 60mg/m2 (2mg/kg; max 60mg) daily until remission, then 40mg/m2 (1.5mg/kg; max 50mg) on alternate days for four weeks.	Drug: Prednisone; This study will compare two steroid dosing protocols for the treatment of childhood nephrotic syndrome relapses. The medications used for both intervention and control arms are oral prednisone 5mg tablets (DIN: 00312770) for children able to swallow or use crushed tablets, or oral prednisolone sodium phosphate 5mg base/5mL liquid (DIN: 02245532). Participants hospitalized after study enrollment will be permitted to switch to intravenous methylprednisolone sodium succinate (DIN: 02367955) at the same dose without being considered to have violated their treatment assignment.; Other Names: Prednisolone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study recruitment rate	Number of participants enrolled per study month	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment effect - treatment failure	Failure to achieve complete remission or steroid dose escalation by 2-weeks	From enrolment to 2-week study visit
Number of eligible participants	Number (%) of screen eligible participants	1 year
Number of participants that initiate assigned treatment	Number (%) of participants that initiate assigned treatment	1 year
Participant drop-out rate	Number (%) of study participants that drop out	1 year
Treatment preference	Treatment preference ratings	1 year
Hospitalizations	Number (%) of participants that are hospitalized	From enrolment to 1 year
Cumulative steroid dose	Cumulative steroid dose (mg/kg) prescribed	From enrolment to 1 year
Adverse events	Number (%) of participants that experience adverse events and serious adverse events	From enrolment to 1 year
Treatment adherence	Number (%) of participants that are adherent to assigned treatment and urine testing	From enrolment to 1 year
Number of participants that complete 2-week study visit	Number (%) of participants that complete 2-week study visit	2 weeks

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: Rulan Parekh, MD MS, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Actual): February 16, 2026
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: September 30, 2024
• First Submitted That Met QC Criteria: October 8, 2024
• First Posted (Actual): October 10, 2024

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Minimal change disease; Nephrotic syndrome; Focal segmental glomerulosclerosis; Idiopathic nephrotic syndrome; Childhood nephrotic syndrome
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Glomerulonephritis; Nephritis; Nephrosis; Nephrotic Syndrome; Glomerulosclerosis, Focal Segmental; Nephrosis, Lipoid; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienetriols; Pregnadienediols; Prednisone; Prednisolone
• Other Study ID Numbers: 1000081679

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No