- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03141970
Prednisolone Trial in Children Younger Than 4 Years
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 Overview
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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Delhi
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New Delhi, Delhi, India, 110029
- All India Institute of Medical Sciences
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California
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Los Angeles, California, United States, 90048
- Cedars-Sinai Medical Center, Pediatric IBD & Pediatric Nephrology
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Stanford, California, United States, 94305
- Stanford University Medical Center, Department of Pediatrics, Division of Nephrology
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Michigan
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Ann Arbor, Michigan, United States, 48109
- University of Michigan Department of Pedatric Nephrology
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North Carolina
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Charlotte, North Carolina, United States, 28207
- Levine's Children/Carolinas HealthCare System
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Idiopathic, steroid-sensitive, first episode of nephrotic syndrome
- Age 12 months up to 48 months
- Written informed consent
Exclusion Criteria
- 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.
- Persistent estimated glomerular filtration rate (GFR) <75 ml/min/1.73 m2,
- Therapy with prednisolone for prior episodes of nephrotic syndrome,
- Therapy with corticosteroids in the past 3 months, in a dose more than 1 mg/kg for >14 days for any other reason,
- Corticosteroid therapy for initial episode of nephrotic syndrome prior to randomization varying from pre-specified protocol on more than 14 days,
- Patients who show relapse during the first 3 months of pre-randomization corticosteroid therapy for nephrotic syndrome,
- Unclear treatment history,
- Gross hematuria,
- Patients with initial steroid resistance,
- Participation in any other drug study during the course of this study.
- Participation in more than one study without approval from the researchers involved in each study,
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Intervention: Prednisolone
Drug: 12- Weeks of Prednisolone Therapy Subjects will add an additional 12 weeks of Prednisolone to follow pre-randomization standard of care prednisolone.
Post randomization Prednisolone therapy of 30 mg/m2 on alternate days for 4 weeks, 20 mg/m2 on alternate days for 4 weeks, and 10 mg/m2 on alternate days for 4 weeks
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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 Names:
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No Intervention: No intervention
Subjects will NOT receive 12-weeks of additional Prednisolone therapy following randomization
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Relapse of nephrotic syndrome during 12 months after randomization
Time Frame: 12 month period following randomization
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Proportion of patients with one or more relapse(s) of nephrotic syndrome
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12 month period following randomization
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of relapses during 12 months follow up
Time Frame: 12 month period following randomization
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Number of nephrotic syndrome relapses per patient year during the 12-month period following randomization
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12 month period following randomization
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Time to first relapse (days)
Time Frame: 12 month period following randomization
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Number of days from randomization to occurrence of first relapse
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12 month period following randomization
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Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization
Time Frame: 12 month period following randomization
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Proportion of patients with frequent relapses during the 12 months post randomization
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12 month period following randomization
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Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period from randomization
Time Frame: 12 month period following randomization
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Total amount of prednisolone [or corticosteroid equivalent] received, as mg/kg/day or mg/m2/day as intervention and for treatment of relapses, during 12 months from randomization
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12 month period following randomization
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The use of steroid-sparing medications
Time Frame: 12 month period following randomization
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The proportion of patients in each study arm treated with steroid-sparing strategies or medications, e.g., levamisole, cyclophosphamide, mycophenolate mofetil and calcineurin inhibitors
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12 month period following randomization
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Adverse events during 12-month period after randomization
Time Frame: 12 month period following randomization
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Number and types of adverse events experienced, related or unrelated to corticosteroid use
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12 month period following randomization
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Change in anthropometry and growth velocity during 12-month period after randomization
Time Frame: 12 month period following randomization
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Changes in standard deviation scores (SDS) for weight, height and body mass index during 12-month period following randomization
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12 month period following randomization
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
Time Frame: 12 month period following randomization
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Proportions of B (naive, memory, regulatory) and T (cytotoxic, helper 1, helper 2, helper 17, regulatory) cell subsets, as determined by flow cytometric staining for specific surface and intracellular markers
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12 month period following randomization
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Relapse of nephrotic syndrome during 24 months after randomization
Time Frame: 24 month period following randomization
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Proportion of patients with one or more relapse(s) of nephrotic syndrome
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24 month period following randomization
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Number of relapses during 24 months follow up
Time Frame: 24 month period following randomization
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Number of nephrotic syndrome relapses per patient year during the 24-month period
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24 month period following randomization
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Time to first relapse (days)
Time Frame: 24 month period following randomization
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Number of days from randomization to occurrence of first relapse
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24 month period following randomization
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Occurrence of frequent relapses of nephrotic syndrome during 24 months from randomization
Time Frame: 24 month period following randomization
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Proportion of patients with frequent relapses during the 24 months post randomization
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24 month period following randomization
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Cumulative prednisolone [or corticosteroid equivalent] received during 24 month period
Time Frame: 24 month period following randomization
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Total amount of prednisolone [or corticosteroid equivalent] received, as mg/kg/day or mg/m2/day as intervention and for treatment of relapses, during 24 months from randomization
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24 month period following randomization
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Relapse of nephrotic syndrome during 12 months after randomization in boys compared to girls
Time Frame: 12 month period following randomization
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Proportion of patients with one or more relapse(s) of nephrotic syndrome in boys compared to girls
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12 month period following randomization
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Relapse of nephrotic syndrome during 12 months after randomization in patients <2-yr-old at randomization compared to older patients
Time Frame: 12 month period following randomization
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Proportion of patients with one or more relapse(s) of nephrotic syndrome in patients <2-yr-old at randomization compared to older patients
|
12 month period following randomization
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Relapse of nephrotic syndrome during 12 months after randomization in Indian patients compared to those in the USA
Time Frame: 12 month period following randomization
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Proportion of patients with one or more relapse(s) of nephrotic syndrome in Indian patients compared to those in the USA
|
12 month period following randomization
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Number of relapses during 12 months follow up in boys compared to girls
Time Frame: 12 month period following randomization
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Number of nephrotic syndrome relapses per patient year during the 12-month period in boys compared to girls
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12 month period following randomization
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Number of relapses during 12 months follow up in patients <2-yr-old at randomization compared to older patients
Time Frame: 12 month period following randomization
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Number of nephrotic syndrome relapses per patient year during the 12-month period in patients <2-yr-old at randomization compared to older patients
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12 month period following randomization
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Number of relapses during 12 months follow up in Indian patients compared to those in the USA
Time Frame: 12 month period following randomization
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Number of nephrotic syndrome relapses per patient year during the 12-month period in Indian patients compared to those in the USA
|
12 month period following randomization
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Time to first relapse (days) in boys compared to girls
Time Frame: 12 month period following randomization
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Number of days from randomization to occurrence of first relapse in boys compared to girls
|
12 month period following randomization
|
Time to first relapse (days) in patients <2-yr-old at randomization compared to older patients
Time Frame: 12 month period following randomization
|
Number of days from randomization to occurrence of first relapse in patients <2-yr-old at randomization compared to older patients
|
12 month period following randomization
|
Time to first relapse (days) in Indian patients compared to those in the USA
Time Frame: 12 month period following randomization
|
Number of days from randomization to occurrence of first relapse in Indian patients compared to those in the USA
|
12 month period following randomization
|
Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization in boys compared to girls
Time Frame: 12 month period following randomization
|
Proportion of patients with frequent relapses during the 12 months post randomization in boys compared to girls
|
12 month period following randomization
|
Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization in patients <2-yr-old at randomization compared to older patients
Time Frame: 12 month period following randomization
|
Proportion of patients with frequent relapses during the 12 months post randomization in patients <2-yr-old at randomization compared to older patients
|
12 month period following randomization
|
Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization in Indian patients compared to those in the USA
Time Frame: 12 month period following randomization
|
Proportion of patients with frequent relapses during the 12 months post randomization in Indian patients compared to those in the USA
|
12 month period following randomization
|
Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period in boys compared to girls
Time Frame: 12 month period following randomization
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Total amount of prednisolone [or corticosteroid equivalent] received, as mg/kg/day or mg/m2/day as intervention and for treatment of relapses, during 12 months from randomization in boys compared to girls
|
12 month period following randomization
|
Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period in patients <2-yr-old at randomization compared to older patients
Time Frame: 12 month period following randomization
|
Total amount of prednisolone [or corticosteroid equivalent] received, as mg/kg/day or mg/m2/day as intervention and for treatment of relapses, during 12 months from randomization in patients <2-yr-old at randomization compared to older patients
|
12 month period following randomization
|
Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period in Indian patients compared to those in the USA
Time Frame: 12 month period following randomization
|
Total amount of prednisolone [or corticosteroid equivalent] received, as mg/kg/day or mg/m2/day as intervention and for treatment of relapses, during 12 months from randomization in Indian patients compared to those in the USA
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12 month period following randomization
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Arvind Bagga, MD, All India Institute of Medical Sciences, New Delhi, India
- Principal Investigator: Debbie Gipson, MD, University of Michigan
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Kidney Diseases
- Urologic Diseases
- Disease
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Syndrome
- Nephrotic Syndrome
- Nephrosis
- Physiological Effects of Drugs
- Anti-Inflammatory Agents
- Antineoplastic Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Prednisolone
- Prednisone
Other Study ID Numbers
- V1.0
- CTRI/2015/06/005939 (Registry Identifier: Clinical Trials Registry-India)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
Study Data/Documents
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Study Protocol
Information identifier: CTRI/2015/06/005939Information comments: Contains details of registration of clinical trial prior to recruiting patients in India, at website of Clinical Trials Registry of India
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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