Prednisolone Trial in Children Younger Than 4 Years

• ClinicalTrials.gov Identifier: NCT03141970
• Recruitment Status: Active, not recruiting
• First Posted: May 5, 2017
• Last Update Posted: September 9, 2020
• Sponsor: All India Institute of Medical Sciences, New Delhi
• Collaborators: NephCure Accelerating Cures Institute; University of Michigan; Department of Biotechnology, Government of India (funding agency)
• Information provided by (Responsible Party): Arvind Bagga, All India Institute of Medical Sciences, New Delhi

Tracking Information

• First Submitted Date: March 17, 2017
• First Posted Date: May 5, 2017
• Last Update Posted Date: September 9, 2020
• Actual Study Start Date: July 1, 2015
• Estimated Primary Completion Date: October 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 3, 2017)

Relapse of nephrotic syndrome during 12 months after randomization [ Time Frame: 12 month period following randomization ]

Proportion of patients with one or more relapse(s) of nephrotic syndrome

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 3, 2017)

• Number of relapses during 12 months follow up [ Time Frame: 12 month period following randomization ]
  Number of nephrotic syndrome relapses per patient year during the 12-month period following randomization
• Time to first relapse (days) [ Time Frame: 12 month period following randomization ]
  Number of days from randomization to occurrence of first relapse
• Occurrence of frequent relapses of nephrotic syndrome during 12 months from randomization [ Time Frame: 12 month period following randomization ]
  Proportion of patients with frequent relapses during the 12 months post randomization
• Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period from randomization [ 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
• The use of steroid-sparing medications [ Time Frame: 12 month period following randomization ]
  The proportion of patients in each study arm treated with steroid-sparing strategies or medications, e.g., levamisole, cyclophosphamide, mycophenolate mofetil and calcineurin inhibitors
• Adverse events during 12-month period after randomization [ Time Frame: 12 month period following randomization ]
  Number and types of adverse events experienced, related or unrelated to corticosteroid use
• Change in anthropometry and growth velocity during 12-month period after randomization [ Time Frame: 12 month period following randomization ]
  Changes in standard deviation scores (SDS) for weight, height and body mass index during 12-month period following randomization

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: May 3, 2017)

• 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 ]
  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
• Relapse of nephrotic syndrome during 24 months after randomization [ Time Frame: 24 month period following randomization ]
  Proportion of patients with one or more relapse(s) of nephrotic syndrome
• Number of relapses during 24 months follow up [ Time Frame: 24 month period following randomization ]
  Number of nephrotic syndrome relapses per patient year during the 24-month period
• Time to first relapse (days) [ Time Frame: 24 month period following randomization ]
  Number of days from randomization to occurrence of first relapse
• Occurrence of frequent relapses of nephrotic syndrome during 24 months from randomization [ Time Frame: 24 month period following randomization ]
  Proportion of patients with frequent relapses during the 24 months post randomization
• Cumulative prednisolone [or corticosteroid equivalent] received during 24 month period [ Time Frame: 24 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 24 months from randomization
• Relapse of nephrotic syndrome during 12 months after randomization in boys compared to girls [ Time Frame: 12 month period following randomization ]
  Proportion of patients with one or more relapse(s) of nephrotic syndrome in boys compared to girls
• 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 ]
  Proportion of patients with one or more relapse(s) of nephrotic syndrome in patients <2-yr-old at randomization compared to older patients
• 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 ]
  Proportion of patients with one or more relapse(s) of nephrotic syndrome in Indian patients compared to those in the USA
• Number of relapses during 12 months follow up in boys compared to girls [ Time Frame: 12 month period following randomization ]
  Number of nephrotic syndrome relapses per patient year during the 12-month period in boys compared to girls
• 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 ]
  Number of nephrotic syndrome relapses per patient year during the 12-month period in patients <2-yr-old at randomization compared to older patients
• Number of relapses during 12 months follow up in Indian patients compared to those in the USA [ Time Frame: 12 month period following randomization ]
  Number of nephrotic syndrome relapses per patient year during the 12-month period in Indian patients compared to those in the USA
• Time to first relapse (days) in boys compared to girls [ Time Frame: 12 month period following randomization ]
  Number of days from randomization to occurrence of first relapse in boys compared to girls
• 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
• 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
• 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
• 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
• 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
• Cumulative prednisolone [or corticosteroid equivalent] received during 12 month period in boys compared to girls [ 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 boys compared to girls
• 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
• 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

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Multicentric, Parallel group, Open label randomized controlled trial

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Nephrotic Syndrome

Intervention

Drug: Prednisolone

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 Name: Prednisone

Study Arms

• 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
  Intervention: Drug: Prednisolone
• No Intervention: No intervention
  Subjects will NOT receive 12-weeks of additional Prednisolone therapy following randomization

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 6, 2020): 170
• Original Estimated Enrollment (submitted: May 3, 2017): 156
• Estimated Study Completion Date: October 31, 2021
• Estimated Primary Completion Date: October 31, 2020 (Final data collection date for primary outcome measure)

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,

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 4 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: India, United States

Administrative Information

• NCT Number: NCT03141970
• Other Study ID Numbers: v1.0; CTRI/2015/06/005939 ( Registry Identifier: Clinical Trials Registry-India )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Following anonymisation to protect patient identity, data from patients in USA will be pooled and analyzed with that from Indian patients. Data will be available once all subjects have completed the study and data has been analyzed. No interim data analysis will be conducted
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)

• Responsible Party: Arvind Bagga, All India Institute of Medical Sciences, New Delhi
• Study Sponsor: All India Institute of Medical Sciences, New Delhi

Collaborators

• NephCure Accelerating Cures Institute
• University of Michigan
• Department of Biotechnology, Government of India (funding agency)

Investigators

• Principal Investigator: Arvind Bagga, MD; All India Institute of Medical Sciences, New Delhi, India
• Principal Investigator: Debbie Gipson, MD; University of Michigan

• PRS Account: All India Institute of Medical Sciences, New Delhi
• Verification Date: September 2020