Dupilumab Therapy in Nephrotic Syndrome in Children

Официальное название

Singapore-Malaysian Renal Trials - Nephrotic Syndrome (SMART-NS): Dupilumab Maintenance Therapy for Steroid-dependent and Frequently Relapsing Nephrotic Syndrome

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат Dupilumab
  Subcutaneous injection of Dupilumab for 24 weeks (weight based dosing)
• Препарат Placebo
  Subcutaneous injection of normal saline placebo (matching dupilumab subcutaneous injection dosing) for 24 weeks
• Препарат Co-intervention of Prednisolone wean during randomised controlled phase
  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
• Биопрепарат Dupilumab open label extension phase
  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).
• Препарат Co-intervention of Prednisolone wean during open label extension phase
  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.

Первичные конечные точки

• Time to relapse [Срок оценки: From enrolment until date of relapse, assessed up to 24 weeks]

Вторичные конечные точки (4)

• Time-averaged Albustix quantitation of proteinuria during study period [Срок оценки: From enrolment until date of relapse, assessed up to 24 weeks]
• Minimum dose of prednisolone at the end of study [Срок оценки: From enrolment until date of relapse, assessed up to 24 weeks]
• Percentage reduction in prednisolone dose at the end of study compared to baseline [Срок оценки: 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 [Срок оценки: At baseline, 1 month, 3 months, 6 months (or at time of relapse, whichever comes first)]

Критерии участия

Критерии включения

• 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
• Steroid-dependent disease or frequently relapsing disease prior to commencement of maintenance immunosuppression
• 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
• 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
• In complete remission at the time of recruitment
• Competent with, and compliant to, daily urine protein monitoring with Albustix

Критерии исключения

• Pre-existing ophthalmological conditions except refractive errors, squint or mild cataract
• Current symptoms of helminth infection or travel to endemic areas, unless helminth infection is excluded
• eGFR (by Bedside Schwartz equation) <60 ml/min/1.73m2
• Received Rituximab or other B-cell depleting agents within the last 1 year
• Biopsy proven focal segmental glomerulosclerosis
• Known ongoing infection including HIV, Hepatitis B, Hepatitis C or tuberculosis, otherwise immunosuppressed or with frequent infections
• Known or suspected non-compliance to medication or follow-up
• Pregnancy or intention to become pregnant
• Major systemic conditions, i.e. ASA Physical Status III-IV.
• Known hypersensitivity to dupilumab or any of its excipients

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Сингапур · 2 центра

• National University Hospital — Singapore
• KK Women's and Children's Hospital — Singapore

Публикации

• Chan CY, Teo S, Lu L, Chan YH, Lau PY, Than M, Jordan SC, Lam KP, Ng KH, Yap HK. Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy. Transl Res. 2021 Sep;235:48-61. doi: 10.1016/j.trsl.2021.03.019. Epub 2021 Apr 1. PMID 33812063
• Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, Jordan SC, Yap HK. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol. 2007 May;18(5):1476-85. doi: 10.1681/ASN.2006070710. Epub 2007 Apr 11. PMID 17429054
• Yap HK, Cheung W, Murugasu B, Sim SK, Seah CC, Jordan SC. Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol. 1999 Mar;10(3):529-37. doi: 10.1681/ASN.V103529. PMID 10073603

Идентификаторы

NCT: NCT07091175 · SMART-NS 01 · 2024/00054

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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