Dupilumab Therapy in Nephrotic Syndrome in Children

Phase 2RecruitingNCT07091175

National University Hospital, Singapore66 enrolled

Overview

The goal of this clinical trial is to learn if dupilumab works to treat severe nephrotic syndrome in children. It will also learn about the safety of dupilumab. The main questions it aims to answer are: * Does dupilumab reduce the time to relapse of nephrotic syndrome? * What medical problems do participants have when taking dupilumab? Researchers will compare dupilumab to a placebo (a look-alike substance that contains no drug) to see if dupilumab works to treat severe nephrotic syndrome. Participants will: * Receive an injection of dupilumab or placebo (just under the skin) every 2 weeks (if ≥30kg) or every 4 weeks (if \<30kg) for 24 weeks (6 months) * Wean down their prednisolone dose after starting the injections of dupilumab or placebo * Visit the clinic once every 2 weeks for checkups and tests * Keep a nephrotic diary to record down the urine dipstick result each day, together with the dose of prednisolone taken If protein returns in participant's urine, they will have completed the study at that point. However, if the participant is found to have received the placebo, they will be offered to receive dupilumab for up to 24 weeks.

This is a multi-centre phase II double blinded randomised controlled trial which aims to assess the safety and efficacy of dupilumab for the treatment of steroid dependent or frequently relapsing steroid sensitive nephrotic syndrome in children. Participants will be randomised to receive Dupilumab or placebo via subcutaneous injection for 24 weeks. The primary efficacy end point is time to relapse. Participants who relapse will be unmasked, and if found to have received placebo, will be eligible for the open label extension phase, in which they will receive dupilumab for the following 24 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Interventions

DupilumabBIOLOGICAL

Subcutaneous injection of Dupilumab for 24 weeks (weight based dosing)

PlaceboDRUG

Subcutaneous injection of normal saline placebo (matching dupilumab subcutaneous injection dosing) for 24 weeks

Co-intervention of Prednisolone wean during randomised controlled phaseDRUG

The Prednisolone wean will commence 2 weeks after receiving the loading dose of Dupilumab/placebo, with each weaning step 2 weeks apart. Prednisolone will be first weaned to the same dose every other day, if the current dosing is daily (or more frequent). The dose will subsequently weaned to 4 pre-determined levels of 30mg/m2, 15mg/m2, 10mg/m2 and 5mg/m2 every other day, rounding up to the nearest 5mg. For instance, if the current dose of prednisolone is 12mg/m2 every other day, the patient will decrease the dose to 10mg/m2 every other day for 2 weeks, followed by 5mg/m2 every other day for 2 weeks, before discontinuing the drug. If patients enter the trial on Mycophenolate or Levamisole, this will be continued for the duration of the trial at the same dose.

Dupilumab open label extension phaseBIOLOGICAL

Upon nephrotic relapse, participants will be unmasked. If they were given placebo, they will be invited to enrol in an open label extension phase to receive dupilumab for 24 weeks (with dosing identical to the experimental arm).

Co-intervention of Prednisolone wean during open label extension phaseDRUG

Patients will also receive prednisolone 60mg/m2/day as a single daily dose (max 60-80mg OD according to physician's discretion) until in remission for 3 days, before prednisolone is weaned to 40mg/m2 every other day for 2 weeks. Doses should be rounded up to nearest 5mg where possible. Prednisolone will then be weaned in steps as per the randomised controlled phase. If patients do not enter full remission after 2 weeks from enrolment into the extension phase, they will be removed from the study. Additional agents, e.g. Mycophenolate, Levamisole, Calcineurin inhibitors should not be started during this time unless there is strong clinical indication.

Eligibility

Sex: ALLMin age: 6 YearsMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age between 6 years old and 18 years old at the point of recruitment with idiopathic nephrotic syndrome with disease onset between 1-18 years old 2. Steroid-dependent disease or frequently relapsing disease prior to commencement of maintenance immunosuppression 3. On oral prednisolone +/- mycophenolate or levamisole only as maintenance therapy for 6 months or more, and with inadequate disease control or steroid toxicity on therapy 4. Nephrotic relapse or partial relapse (clinical or biochemical) within the last 1 year either unprovoked or during prednisolone wean, and which responded to increase in steroids 5. In complete remission at the time of recruitment 6. Competent with, and compliant to, daily urine protein monitoring with Albustix Exclusion Criteria: 1. Pre-existing ophthalmological conditions except refractive errors, squint or mild cataract 2. Current symptoms of helminth infection or travel to endemic areas, unless helminth infection is excluded 3. eGFR (by Bedside Schwartz equation) \<60 ml/min/1.73m2 4. Received Rituximab or other B-cell depleting agents within the last 1 year 5. Biopsy proven focal segmental glomerulosclerosis 6. Known ongoing infection including HIV, Hepatitis B, Hepatitis C or tuberculosis, otherwise immunosuppressed or with frequent infections 7. Known or suspected non-compliance to medication or follow-up 8. Pregnancy or intention to become pregnant 9. Major systemic conditions, i.e. ASA Physical Status III-IV. 10. Known hypersensitivity to dupilumab or any of its excipients

Outcomes

Primary Outcomes

Time to relapse

Relapse will be defined as either (a) urine dipstick ≥3+ on 3 consecutive days, with 1x urine protein creatinine ratio ≥200mg/mmol (2000mg/g), or (b) clinical edema in keeping with nephrotic syndrome accompanied by hypoalbuminaemia (serum albumin \<30g/L), with 1x urine protein creatinine ratio ≥200mg/mmol (2000mg/g). Participants will be expected to record down in a nephrotic diary the urine dipstick result each day, together with the dose of prednisolone taken. Participants are expected to inform the site principal investigator (or designate) if urine dipstick is ≥3+ on 3 consecutive days, and provisions will be made for an ad-hoc urine protein creatinine ratio measurement to determine if relapse has occurred. This should be done within 24 hours of notification by participants. Participants will also be routinely examined for signs of nephrotic syndrome, for example edema, at study visits, and urine protein creatinine ratio will be obtained at each study visit.

Time frame: From enrolment until date of relapse, assessed up to 24 weeks

Secondary Outcomes

Time-averaged Albustix quantitation of proteinuria during study period

Participants will be requested to record down in a nephrotic diary their urine dipstick result each day, together with the dose of prednisolone taken. The time-averaged albustix quantitation of proteinuria for the study period will then be calculated.

Time frame: From enrolment until date of relapse, assessed up to 24 weeks

Minimum dose of prednisolone at the end of study

Minimum dose of prednisolone at the end of study - at time of relapse or at 24 weeks, whichever comes first.

Time frame: From enrolment until date of relapse, assessed up to 24 weeks

Percentage reduction in prednisolone dose at the end of study compared to baseline

Percentage reduction in prednisolone dose at the end of study (at time of relapse or at 24 weeks, whichever comes first) compared to baseline

Time frame: At baseline and at time of relapse or at 24 weeks, whichever comes first

Change in health-related quality of life at the end of study compared to baseline

Health-related quality of life will be measured using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core scales short form. There are 15 questions, where each question is scored from 0 to 4. The total score ranges from 0 to 60, where a higher score represents a lower quality of life, with more problems associated with coping with health and activities, feelings, getting along with others and work/studies.

Time frame: At baseline, 1 month, 3 months, 6 months (or at time of relapse, whichever comes first)

Dupilumab Therapy in Nephrotic Syndrome in Children

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts