Clinical trial NCT03141970: Prednisolone Trial in Children Younger Than 4 Years
Official title: Randomized, Multicentric, Open Label, Parallel Group Trial to Compare the Efficacy of 6-months Versus 3-months Therapy With Prednisolone for the First Episode of Idiopathic Nephrotic Syndrome in Children Younger Than 4 Years
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Nephrotic Syndrome
Keywords: Proteinuria Hypoproteinemia Edema Hypoalbuminemia Prednisone
Lead sponsor: All India Institute of Medical Sciences
Sponsor class: OTHER
Collaborators: name: NephCure Accelerating Cures Institute
name: University of Michigan
name: Department of Biotechnology, Government of India (funding agency)
First posted: 2017-05-05
Enrollment: 170
Sex: ALL
Minimum age (years): 1
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentric, Parallel group, Open label randomized controlled trial
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

1. Idiopathic, steroid-sensitive, first episode of nephrotic syndrome
2. Age 12 months up to 48 months
3. Written informed consent

Exclusion Criteria

1. Nephrotic syndrome known to be secondary to a systemic disorder, e.g., Immunoglobulin A (IgA) nephropathy, systemic lupus erythematosus, Henoch Schonlein purpura, vasculitis, , hepatitis B or Alport syndrome.
2. Persistent estimated glomerular filtration rate (GFR) \<75 ml/min/1.73 m2,
3. Therapy with prednisolone for prior episodes of nephrotic syndrome,
4. Therapy with corticosteroids in the past 3 months, in a dose more than 1 mg/kg for \>14 days for any other reason,
5. Corticosteroid therapy for initial episode of nephrotic syndrome prior to randomization varying from pre-specified protocol on more than 14 days,
6. Patients who show relapse during the first 3 months of pre-randomization corticosteroid therapy for nephrotic syndrome,
7. Unclear treatment history,
8. Gross hematuria,
9. Patients with initial steroid resistance,
10. Participation in any other drug study during the course of this study.
11. Participation in more than one study without approval from the researchers involved in each study,

Primary outcomes:
measure: Relapse of nephrotic syndrome during 12 months after randomization
timeFrame: 12 month period following randomization
Secondary outcomes:
measure: Number of relapses during 12 months follow up
timeFrame: 12 month period following randomization
measure: Time to first relapse (days)
timeFrame: 12 month period following randomization
measure: Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization
timeFrame: 12 month period following randomization
measure: Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period from randomization
timeFrame: 12 month period following randomization
measure: The use of steroid-sparing medications
timeFrame: 12 month period following randomization
measure: Adverse events during 12-month period after randomization
timeFrame: 12 month period following randomization
measure: Change in anthropometry and growth velocity during 12-month period after randomization
timeFrame: 12 month period following randomization
Other outcomes:
measure: In a subgroup of 20 patients, the proportions of the following cell subsets, at baseline and at 6 and 12 months after randomization and at first relapse
timeFrame: 12 month period following randomization
measure: Relapse of nephrotic syndrome during 24 months after randomization
timeFrame: 24 month period following randomization
measure: Number of relapses during 24 months follow up
timeFrame: 24 month period following randomization
measure: Time to first relapse (days)
timeFrame: 24 month period following randomization
measure: Occurrence of frequent relapses of nephrotic syndrome during 24 months from randomization
timeFrame: 24 month period following randomization
measure: Cumulative prednisolone [or corticosteroid equivalent] received during 24 month period
timeFrame: 24 month period following randomization
measure: Relapse of nephrotic syndrome during 12 months after randomization in boys compared to girls
timeFrame: 12 month period following randomization
measure: Relapse of nephrotic syndrome during 12 months after randomization in patients <2-yr-old at randomization compared to older patients
timeFrame: 12 month period following randomization
measure: Relapse of nephrotic syndrome during 12 months after randomization in Indian patients compared to those in the USA
timeFrame: 12 month period following randomization
measure: Number of relapses during 12 months follow up in boys compared to girls
timeFrame: 12 month period following randomization
measure: Number of relapses during 12 months follow up in patients <2-yr-old at randomization compared to older patients
timeFrame: 12 month period following randomization
measure: Number of relapses during 12 months follow up in Indian patients compared to those in the USA
timeFrame: 12 month period following randomization
measure: Time to first relapse (days) in boys compared to girls
timeFrame: 12 month period following randomization
measure: Time to first relapse (days) in patients <2-yr-old at randomization compared to older patients
timeFrame: 12 month period following randomization
measure: Time to first relapse (days) in Indian patients compared to those in the USA
timeFrame: 12 month period following randomization
measure: Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization in boys compared to girls
timeFrame: 12 month period following randomization
measure: Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization in patients <2-yr-old at randomization compared to older patients
timeFrame: 12 month period following randomization
measure: Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization in Indian patients compared to those in the USA
timeFrame: 12 month period following randomization
measure: Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period in boys compared to girls
timeFrame: 12 month period following randomization
measure: Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period in patients <2-yr-old at randomization compared to older patients
timeFrame: 12 month period following randomization
measure: Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period in Indian patients compared to those in the USA
timeFrame: 12 month period following randomization
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, Pediatric IBD & Pediatric Nephrology
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center, Department of Pediatrics, Division of Nephrology
state: California
city: Ann Arbor
country: United States
facility: University of Michigan Department of Pedatric Nephrology
state: Michigan
city: Charlotte
country: United States
facility: Levine's Children/Carolinas HealthCare System
state: North Carolina
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
state: Delhi
Study officials:
affiliation: All India Institute of Medical Sciences, New Delhi, India
name: Arvind Bagga, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Debbie Gipson, MD
role: PRINCIPAL_INVESTIGATOR
References: