Prednisolone Trial in Children Younger Than 4 Years

NCT ID: NCT03141970

Last Updated: 2024-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 170 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-07-01
• Study Completion Date: 2021-10-31

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.

Conditions

Nephrotic Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Prednisolone

Intervention Type: DRUG

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

No intervention

Subjects will NOT receive 12-weeks of additional Prednisolone therapy following randomization

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Prednisone

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,

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 4 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

NephCure Accelerating Cures Institute

UNKNOWN

Sponsor Role: collaborator

University of Michigan

OTHER

Sponsor Role: collaborator

Department of Biotechnology, Government of India (funding agency)

UNKNOWN

Sponsor Role: collaborator

All India Institute of Medical Sciences

OTHER

Sponsor Role: lead

Responsible Party

Arvind Bagga

Professor, Department of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Arvind Bagga, MD

Role: PRINCIPAL_INVESTIGATOR

All India Institute of Medical Sciences, New Delhi, India

Debbie Gipson, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

Cedars-Sinai Medical Center, Pediatric IBD & Pediatric Nephrology

Los Angeles, California, United States

Stanford University Medical Center, Department of Pediatrics, Division of Nephrology

Stanford, California, United States

University of Michigan Department of Pedatric Nephrology

Ann Arbor, Michigan, United States

Levine's Children/Carolinas HealthCare System

Charlotte, North Carolina, United States

All India Institute of Medical Sciences

New Delhi, National Capital Territory of Delhi, India

Countries

United States; India

References

Hahn D, Samuel SM, Willis NS, Craig JC, Hodson EM. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2024 Aug 22;8(8):CD001533. doi: 10.1002/14651858.CD001533.pub7.

Reference Type: DERIVED

PMID: 39171624 (View on PubMed)

Study Documents

Document Type: Study Protocol

Contains details of registration of clinical trial prior to recruiting patients in India, at website of Clinical Trials Registry of India

View Document

Other Identifiers

CTRI/2015/06/005939

Identifier Type: REGISTRY

Identifier Source: secondary_id

v1.0

Identifier Type: -

Identifier Source: org_study_id