Infusion-Related Reactions in the Phase III Double-Blind, Placebo-Controlled ORATORIO Study of Ocrelizumab in Primary Progressive Multiple Sclerosis
Objectives: To evaluate the occurrence and associated symptom profile of IRRs in a Phase III, randomized, double-blind, placebo-controlled study in PPMS (ORATORIO).
Methods: Patients were randomized (2:1) to receive OCR 600 mg via intravenous (IV) as two 300 mg infusions 14 days apart or placebo (PBO) infusions every 24 weeks for ≥120 weeks until a pre-specified number of 12-week confirmed disability progression events occurred. IRRs were defined as events that occurred during or within 24 hours of infusion. All patients were pretreated with IV infusion of methylprednisolone 100 mg 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: A total of 725 patients were included in the ORATORIO safety analysis: 239 in the PBO group and 486 in the OCR group. Throughout a mean treatment duration of approximately 3 years, the proportion of patients with at least 1 IRR was 25.5% (n=61) with PBO and 39.9% (n=194) with OCR; most were mild-to-moderate in severity (93.4% [n=57] and 96.9% [n=188], respectively). The most common IRR symptoms included skin and subcutaneous tissue disorders (45.9% [n=89] with OCR and 13.1% [n=8] with PBO). There were no life-threatening or fatal IRRs. The incidence of IRRs in the OCR group was highest with the first infusion (27.4%) and decreased markedly with subsequent dosing (11.6% at first infusion of dose 2). Overall, IRRs mostly occurred during infusion in the OCR group (61.3% compared with 37.7% in the PBO group). One patient (0.2%) withdrew from OCR treatment due to an IRR during the first infusion.
Conclusions: In a Phase III study of OCR in PPMS, 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.