Prednisolone Trial in Children Younger Than 4 Years
Condition: Nephrotic Syndrome
MeSH terms: Nephrotic Syndrome; Nephrosis; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      This study is a multicentric, randomized, parallel group, open label controlled trial of
      children age 1 year up to 4 years with new onset, idiopathic nephrotic syndrome. It is
      designed to test the initial duration of steroid therapy of either 3 month or 6 month total
      duration. Participants will be randomized to either extend their pre-trial 3 months (12
      weeks) of standard of care corticosteroid therapy to add an additional 12 weeks of therapy or
      to stop therapy. Pre-trial standard of care corticosteroids will include 60 mg/m2/day for 6
      weeks followed by 40 mg/m2/day every other day for 6 weeks of prednisolone or equivalent. The
      trial intervention will therefore be an additional 12 vs 0 weeks of corticosteroids in these
      children with idiopathic nephrotic syndrome.
    

Detailed description: 
      Trial Registration Note:This trial was initially registered in the Indian Registry (list the
      number) on (date) prior to enrolling participants. The present listing shows this status of
      currently enrolling. New sites in the United States are expected to open within the coming
      year. At that time the answers to some questions, such as "Studies FDA regulated drug" will
      change because the basis for FDA regulation will reside on the presence of US sites and the
      use of US manufactured drug, whereas at this time the drug is not of US manufacture, and the
      trial is not currently conducted in the United States. This registration is being posted at
      this time to prepare to meet United States FDAAAA registration requirements.

      Nephrotic syndrome is a common renal disorder in children characterized by proteinuria,
      hypoalbuminemia and edema. The long-term prognosis for steroid-sensitive nephrotic syndrome
      is excellent for resolution of disease and maintenance of renal function. About 80% patients
      with steroid-sensitive nephrotic syndrome will relapse one or more times, requiring repeated
      treatment with corticosteroids. Of these, 50-60% show frequent relapses or steroid dependence
      and require therapy with long-term corticosteroids and other medications. Patients with
      multiple relapses are at risk for life-threatening infections, malnutrition and thrombotic
      episodes. They are also likely to show serious side effects of long-term steroid therapy and
      those related to use of other medications, including toxicity to bone marrow, gonads, central
      nervous system and kidneys. Repeated relapses also result in multiple hospitalizations and
      school absence. Strategies effective in reducing relapse rates and proportion of patients
      with frequent relapses or steroid dependence shall therefore be extremely valuable in
      improving the long-term management of nephrotic syndrome.

      Based on information from multiple studies that prolonged duration of initial therapy beyond
      8-weeks reduced the risk of an early relapse and lowered frequency of subsequent relapses, it
      is agreed upon that the initial therapy with prednisolone should continue for 12 weeks (3
      months), administered daily for a duration of 6 weeks, and then on alternate days for another
      6 weeks. However, the optimal dose and duration of corticosteroid therapy remains to be
      determined. Data from various prospective studies, systematically reviewed in the Cochrane
      Registry, suggests the beneficial effects of prolongation of treatment beyond 3 months, with
      benefit seen up to 6-months. However, the advantages of extending therapy from 3- to 6-months
      are not unambiguous; there are also concerns of the corticosteroid toxicity with the latter
      regimens. Recent placebo controlled trials reported in 2013, including from this center,
      suggest that extending initial prednisolone treatment from 3 months to 6 months, with or
      without an increase in cumulative dose, does not influence the course of disease in children
      with nephrotic syndrome. However, in the study conducted in India, we found that prolonged
      therapy was useful in postponing the first relapse, and was associated with an
      insignificantly decreased risk of frequent relapses, in the subgroup of children younger than
      4 years. Since the subgroups were not defined a priori, a prospective study is required to
      clarify the efficacy of this intervention in young patients.

      Further, the lack of clarity regarding disease pathogenesis makes the administration of
      corticosteroid therapies largely empirical. While clear insight into the pathogenic pathways
      targeted by prednisolone is lacking, there is some evidence that disease remission is
      associated with down regulation of T cell activation, altered B-T cell crosstalk,
      upregulation of T helper type 1(Th1) and/or T regulatory compartments.

      This present study proposes to examine the benefits of prolongation of initial therapy of
      idiopathic nephrotic syndrome from the current standard of 3 to 6 months among children
      younger than 4-yr-old an onset of disease. Prolongation of treatment at the first episode
      would have considerable promise, if found effective in reducing future relapses and without
      concomitant risks of corticosteroid toxicity. The proposal also aims to examine the
      proportions of T and B lymphocyte subsets in 20 patients with the initial episode of
      nephrotic syndrome. The evaluation shall be conducted at onset of disease, following
      prednisolone induced disease remission, and at one year from randomization or at first
      relapse of the disease to determine differences in the immune profiles at different stages of
      the disease. Apart from improving our knowledge of pathogenesis of nephrotic syndrome, this
      approach shall enhance our understanding of the immunological alterations influenced by
      therapy.
    

Intervention name(s): Prednisolone
Intervention type(s): Drug
Intervention description(s): Prednisolone for 12 weeks as follows 30 mg/m2 on alternate days for 4 weeks 20 mg/m2 on alternate days for 4 weeks 10 mg/m2 on alternate days for 4 weeks
Other intervention name(s): Prednisone
Intervention MeSH terms: Prednisone; Prednisolone
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Multicentric, Parallel group, Open label randomized controlled trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Proteinuria Hypoproteinemia Edema Hypoalbuminemia Prednisone