A study to examine whether giving steroids in low dose daily is more effective than if given on alternate days, in controlling disease activity in patients with frequently relapsing nephrotic syndrome

Phase 3

Recruiting

Conditions: Nephrotic syndrome with minor glomerular abnormality,

Registration Number: CTRI/2019/01/017091

Lead Sponsor: Indian Council of Medical Research

Brief Summary: The management of patients with frequently relapsing nephrotic syndrome, a common morbidity of childhood, is difficult and requires close monitoring for adverse effects of disease and therapies. Therapy with prednisolone and alternative immunosuppressive agents is empirical without a clear understanding of the pathogenic pathways targeted by any of these interventions. While most patients respond promptly to corticosteroid therapy with remission of proteinuria, more than 80% relapse subsequently, either infrequently (20-25%) or frequently (50-60%). Relapses of nephrotic syndrome may be triggered by minor respiratory infections, allergic reactions or vaccination. Disease relapses are often associated with serious acute complications *e.g*., those related to anasarca, hypertension, life threatening infections (peritonitis, pneumonia, meningitis), thrombosis and malnutrition. Repeated courses of steroids lead to considerable medication related toxicity and morbidity. Reduction of relapse rates is therefore a major aim of long-term therapy of subjects with nephrotic syndrome.

Some preliminary studies have shown benefit of small daily dose prednisolone over standard alternate day regimen, but adequately powered randomized controlled trials are lacking. In a previous study performed in this institute, authors compared twenty one patients given daily low dose prednisolone (LDP) with fourteen historic controls who were given standard alternate day therapy. They found that long term therapy with a small daily dose of prednisolone can significantly reduce the number of relapses in patients with frequently relapsing nephrotic syndrome, and that the beneficial effect may continue even after its stoppage. The relapse rate in the LDP group during the treatment period was significantly lower than that observed during the preceding year when they were on standard alternate day therapy as well as that noted in the historical control group during the observation period of 18 months. In their study they found no side effects related to LDP [22]. Moreover, continued suppression of relapses after stoppage of treatment in some patients was a surprising observation, since other corticosteroid regimens do not affect the relapse rate once the drug is discontinued [23]. The side effects of glucocorticoids are numerous, well recognized and of great concern to the patients and their family. When unacceptable glucocorticoid related adverse events occur, these patients are considered for glucocorticoid sparing therapy [13, 14]. The assessment of glucocorticoid related adverse events is mostly based upon clinical observation rather than objective assessment [13].

With this background, we propose to compare the safety and efficacy of therapy with daily prednisone in low doses (0.15-0.2 mg/kg) *versus* standard therapy (0.5-0.6 mg/kg) with prednisolone on alternate days (given daily for 5-7 days during episodes of infections) in maintaining disease remission over 24 months in patients with frequently relapsing nephrotic syndrome. If therapy with low dose prednisolone is found to be associated with sustained remission, fewer relapses and less significant adverse effects than therapy with prednisolone on alternate days, it would mark a paradigm shift in clinical practice recommendations of standard case management for patients with frequent relapses. This would have implications in terms of improved strategies for prevention of relapses and avoidance of serious adverse events including reduced growth rates, hypertension, cataracts, glaucoma, and psychological disorders, which would ultimately affect the outcome of children with FRNS*.* If the two are comparable in efficacy and safety, either agent may be offered, with parents being counseled regarding the relative efficacy and safety of each strategy.

During the study period of 24 months, patients are followed up regularly in the two limbs, at 3-monthly intervals, with clinical and laboratory monitoring as specified in the protocol, to monitor for various outcomes, including adverse effects of therapy, as well as control of disease. In view of the ongoing COVID-19 pandemic, as required by the circumstances, some of these visits may be replaced by (i) teleconsultations for history and compliance; (ii) review of urine protein diary and other relevant records over mobile apps; (iii) laboratory evaluations performed at standard local laboratories; (iii) physical examination, including anthropometry and blood pressure, by local pediatrician; and (iv) ophthalmological evaluation for cataract and intraocular pressure by local ophthalmologist.

Detailed Description: Not available

Recruitment & Eligibility

Status: Open to Recruitment

Sex: All

Target Recruitment: 160

Inclusion Criteria

Children aged 2-18 yr with frequently relapsing or steroid dependent nephrotic syndrome Written informed consent from parents.

Exclusion Criteria

Steroid resistant nephrotic syndrome Congenital nephrotic syndrome Nephrotic syndrome secondary to systemic disease (systemic lupus erythematosus, IgA nephropathy, infection with HIV or hepatitis B or C) Estimated glomerular filtration rate below 60 ml/min/1.73 sq.
m Recent (during the last 6-months) therapy with long term alternate day prednisolone for >3-months, levamisole, cyclophosphamide or mycophenolate mofetil History of therapy with cyclosporine, tacrolimus or rituximab Significant steroid toxicity, as defined by BMI >2 SDS; stage 2 hypertension; cataract, glaucoma; fasting glucose levels >100 mg/dl; history of steroid psychosis.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
The proportions of patients with infrequent relapses	18 months

Secondary Outcome Measures

Name	Time	Method
Time to first relapse	18 months
Time to frequent relapses	18 months
Frequency of relapses	18 months
Proportion of patients with sustained remission	18 months
Proportion of patients with frequent relapses	18 months
Frequency and types of infections	18 months
Patients with corticosteroid related adverse events, including reduced growth velocity, obesity, cushingoid features, hirsutism, hypertension, cataract and glaucoma	18 months

Trial Locations

Locations (1): All India Institute of Medical Sciences
🇮🇳
South, DELHI, India
All India Institute of Medical Sciences
🇮🇳South, DELHI, India
Aditi Sinha
Principal investigator
9899145489
aditisinhaaiims@gmail.com