Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies

Lori Mayer, Ludwig Kappos, Michael K. Racke, Kottil W Rammohan, Anthony Traboulsee, Stephen L. Hauser, Laura Julian, Harold Köndgen, Carrie Li, Julie Napieralski, Hanzhe Zheng, Jerry S. Wolinsky

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)236-243
Number of pages8
JournalMultiple Sclerosis and Related Disorders
Volume30
DOIs
StatePublished - May 1 2019

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ocrelizumab
Chronic Progressive Multiple Sclerosis
Placebos
Intravenous Infusions
Histamine Antagonists
Subcutaneous Injections

Keywords

  • Hypersensitivity
  • Infusion
  • Infusion reaction
  • Multiple sclerosis
  • Ocrelizumab

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis : Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies. / Mayer, Lori; Kappos, Ludwig; Racke, Michael K.; Rammohan, Kottil W; Traboulsee, Anthony; Hauser, Stephen L.; Julian, Laura; Köndgen, Harold; Li, Carrie; Napieralski, Julie; Zheng, Hanzhe; Wolinsky, Jerry S.

In: Multiple Sclerosis and Related Disorders, Vol. 30, 01.05.2019, p. 236-243.

Research output: Contribution to journalArticle

Mayer, Lori ; Kappos, Ludwig ; Racke, Michael K. ; Rammohan, Kottil W ; Traboulsee, Anthony ; Hauser, Stephen L. ; Julian, Laura ; Köndgen, Harold ; Li, Carrie ; Napieralski, Julie ; Zheng, Hanzhe ; Wolinsky, Jerry S. / Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis : Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies. In: Multiple Sclerosis and Related Disorders. 2019 ; Vol. 30. pp. 236-243.
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abstract = "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.",
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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 W

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.

PY - 2019/5/1

Y1 - 2019/5/1

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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