Infusion-Related Reactions With Ocrelizumab in the Phase III Double-Blind, Double-Dummy, Interferon ß-1a-Controlled OPERA I and OPERA II Studies
Objectives: To evaluate the occurrence and associated symptom profile of IRRs in 2 identical, randomized, double-blind, double-dummy, IFNβ-1a–controlled Phase III trials in relapsing multiple sclerosis (RMS; OPERA I and OPERA II).
Methods: Patients were randomized (1:1) to receive OCR 600mg via intravenous (IV) infusion every 24 weeks as two 300mg infusions on Days 1 and 15 for Dose 1 and as a single 600mg infusion thereafter, or subcutaneous (SC) IFNβ-1a 44μg 3 times weekly over 96 weeks. Patients in the OCR and IFNβ-1a groups received matching SC and IV placebo treatments, respectively. IRRs were defined as events that occurred during or within 24 hours of infusion. All patients were pretreated with IV infusion of methylprednisolone 100mg or equivalent. Infusion rate adjustment and treatment with analgesics/antipyretics and antihistamines was permitted. IRRs were evaluated during infusion, shortly postinfusion (in clinic), and within 24 hours postinfusion.
Results: Pooled safety analysis of OPERA I and OPERA II consisted of 826 patients in the IFNβ-1a group and 825 in the OCR group. Over 96 weeks, 9.7% of IFNβ-1a patients (n=80) and 34.3% of OCR patients (n=283) had at least 1 IRR; most were mild to moderate in severity (99% [n=79] and 93% [n=262], respectively). The most frequent IRR symptoms with OCR included pruritus, rash, throat irritation and flushing. IRRs mostly occurred during infusion (IFNβ-1a, 46.3%; OCR, 80.6%) and were managed with infusion adjustments and symptomatic treatment (42.5% of patients that had IRRs in IFNβ-1a group and 65.4% in the OCR group received treatment). One OCR-treated patient had a serious IRR at first infusion, with life-threatening bronchospasm; despite event resolution, subsequent treatment was withdrawn per protocol. Withdrawal from treatment due to IRRs during the first infusion occurred in 11 patients (1.3%) in the OCR group only. IRR incidence with OCR was highest with the first infusion (27.5%) and markedly decreased with subsequent dosing (13.7% at Dose 2).
Conclusions: In 2 Phase III studies of OCR in RMS, IRRs were generally mild to moderate in severity, commonly occurred with the first infusion, and were manageable with premedication, infusion adjustments and symptomatic treatment.
Supported by F. Hoffmann-La Roche Ltd.