Journal of the American Society of Nephrology
Clinical Research
A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial
Ravani, Pietro*; Rossi, Roberta†; Bonanni, Alice†; Quinn, Robert R.*; Sica, Felice‡; Bodria, Monica†; Pasini, Andrea§; Montini, Giovanni§; Edefonti, Alberto‖; Belingheri, Mirco‖; De Giovanni, Donatella‡; Barbano, Giancarlo†; Degl’Innocenti, Ludovica†; Scolari, Francesco¶; Murer, Luisa**; Reiser, Jochen††; Fornoni, Alessia‡‡; Ghiggeri, Gian Marco†
*Division of Nephrology, University of Calgary, Calgary, Alberta, Canada;
†Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children’s Hospital, Genoa, Italy;
‡Division of Pediatrics, Hospital of Foggia, Foggia, Italy;
§Nephrology and Pediatric Dialysis, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant'Orsola, Bologna, Italy;
‖Pediatric Nephrology and Dialysis Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy;
¶Division of Nephrology and Dialysis, Ospedale di Montichiari Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy;
**Pediatric Nephrology, Dialysis and Transplant Unit, Department of Pediatrics, University Hospital of Padua, Padua, Italy;
††Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois; and
‡‡Miller School of Medicine, University of Miami, Miami, Florida
Correspondence: Dr. Pietro Ravani, University of Calgary, Faculty of Medicine, Foothills Medical Centre, 1403-29th Street NW, Calgary, AB T2N 2T9, Canada, or Dr. Gianmarco Ghiggeri, Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children’s Hospital, Via Gerolamo Gaslini 5, Genoa, 16148, Italy. Email: [email protected] or [email protected].
Received August 18, 2014
Accepted November 18, 2014
Abstract
Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1–16 years who had developed SDNS in the previous 6–12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m2; intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m2 per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6–13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.