Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial

Background Children with multidrug-resistant nephrotic syndrome (MRNS) are exposed to drug toxicity (steroids/calcineurin inhibitors (CNI)/mycophenolate mofetil (MMF)) and have an increased risk of kidney disease progression. In small case series, the fully humanized anti-CD20 antibody ofatumumab (O...

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Published in:Pediatric nephrology (Berlin, West) West), 2020-06, Vol.35 (6), p.997-1003
Main Authors: Ravani, Pietro, Pisani, Isabella, Bodria, Monica, Caridi, Gianluca, Degl’Innocenti, Maria Ludovica, Ghiggeri, Gian Marco
Format: Article
Language:English
Subjects:
Adolescent
Antibodies, Monoclonal, Humanized - administration & dosage
Calcineurin
Calcineurin inhibitors
Care and treatment
CD20 antigen
Child
Child, Preschool
Children
Clinical trials
Diseases
Double-Blind Method
Drug Resistance, Multiple - drug effects
End-stage renal disease
Epidermal growth factor receptors
Female
Humans
Infusions, Intravenous
Kidney diseases
Male
Medicine
Medicine & Public Health
Monoclonal antibodies
Multidrug resistance
Multidrug resistant organisms
Mycophenolate mofetil
Mycophenolic acid
Nephrology
Nephrotic syndrome
Nephrotic Syndrome - drug therapy
Ofatumumab
Original Article
Pediatrics
Proteinuria
Remission
Remission (Medicine)
Remission Induction - methods
Renal failure
Renal function
Rituximab
Steroid hormones
Testing
Toxicity
Treatment Failure
Urology
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Summary:Background Children with multidrug-resistant nephrotic syndrome (MRNS) are exposed to drug toxicity (steroids/calcineurin inhibitors (CNI)/mycophenolate mofetil (MMF)) and have an increased risk of kidney disease progression. In small case series, the fully humanized anti-CD20 antibody ofatumumab (OFA) induced remission in children with MRNS when at high dose (10,300 mg/1.73 m 2 ) and partial remission at standard dose (1000 mg/1.73 m 2 ). Methods This double-blind randomized placebo-controlled trial tested the efficacy of single infusion OFA in children with proven MRNS and initial chronic renal failure (eGFR [median/range] 119/38–155 ml/min/1.73 m 2 in Placebo arm vs. 65/19–103 ml/min/1.73 m 2 Intervention). Children who had been resistant to a combination of CNI and steroids, with or without MMF or rituximab, were randomized to receive single infusion OFA (1500 mg/1.73 m 2 ) (Intervention arm) or normal saline (Placebo arm). We assessed complete or partial remission of proteinuria after 3 months (primary outcome), and after 6 and 12 months (secondary outcomes), as well as progression to end-stage kidney disease. Results After 13 of the planned 50 children (25%) were randomized, the data safety and monitoring board recommended study termination for futility. All 13 children remained nephrotic. Renal function worsened in 5 children (2 in Intervention arm, 3 in Placebo arm) who required renal replacement therapy during the study period. Circulating CD20 was reduced following OFA infusion and remained low for > 3 months. Conclusions OFA given in one single infusion of 1500 mg/1.73 m 2 doses does not induce remission in MRNS. Regimens based on higher OFA doses should be tested in clinical trials. Trial registration https://clinicaltrials.gov : NCT02394106
ISSN:0931-041X
1432-198X
DOI:10.1007/s00467-020-04481-y