TY - JOUR
T1 - Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis
T2 - Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies
AU - Mayer, Lori
AU - Kappos, Ludwig
AU - Racke, Michael K.
AU - Rammohan, Kottil
AU - Traboulsee, Anthony
AU - Hauser, Stephen L.
AU - Julian, Laura
AU - Köndgen, Harold
AU - Li, Carrie
AU - Napieralski, Julie
AU - Zheng, Hanzhe
AU - Wolinsky, Jerry S.
N1 - Funding Information:
L Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards for trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CLC Behring, F. Hoffmann-La Roche Ltd and Genentech, Inc., GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharmaceutical, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB and XenoPort; has received license fees for Neurostatus products; and has received research grants from the European Union, Gianni Rubatto Foundation, Novartis Research Foundation, Roche Research Foundation, Swiss Multiple Sclerosis Society and Swiss National Research Foundation.
Funding Information:
This work was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Funding Information:
K Rammohan has received honoraria for serving on advisory boards and consulting for Acorda, Biogen, EMD Serono, F. Hoffmann-La Roche Ltd and Genentech, Inc., Genzyme and Teva and has received grants from Accera, Novartis and the US Department of Defense.
Publisher Copyright:
© 2019
PY - 2019/5
Y1 - 2019/5
N2 - Background: Ocrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20 + B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS). Methods: OPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of ocrelizumab or placebo. Results: Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs. Conclusion: Findings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.
AB - Background: Ocrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20 + B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS). Methods: OPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of ocrelizumab or placebo. Results: Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs. Conclusion: Findings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.
KW - Hypersensitivity
KW - Infusion
KW - Infusion reaction
KW - Multiple sclerosis
KW - Ocrelizumab
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U2 - 10.1016/j.msard.2019.01.044
DO - 10.1016/j.msard.2019.01.044
M3 - Article
C2 - 30844611
AN - SCOPUS:85062283848
VL - 30
SP - 236
EP - 243
JO - Multiple Sclerosis and Related Disorders
JF - Multiple Sclerosis and Related Disorders
SN - 2211-0348
ER -