Infusion-Related Reactions With Ocrelizumab: Risk Factors, Symptom Management and Patient Choices in the ENSEMBLE PLUS Study
Robert Bermel1, Joep Killestein2, Thomas Berger3, Bruno Brochet4, William Carroll5, Mark Freedman6, Trygve Holmoy7, Rana Karabudak8, Carlos Nos9, Francesco Patti10, Amy Perrin Ross11, Ludo Vanopdenbosch12, Timothy Vollmer13, Regine Buffels14, Karen Kadner14, Oscar Bortolami14, Hans-Peter Hartung15
1Mellen Center for MS, Department of Neurology, Cleveland Clinic, Cleveland, OH, USA, 2Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands, 3Department of Neurology, Medical University of Vienna, Vienna, Austria, 4University of Bordeaux, Bordeaux, France, 5Department of Neurology, Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, Australia, 6University of Ottawa, Department of Medicine and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 7Department of Neurology, Akershus University Hospital, Lørenskog, Norway, 8Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey, 9Centre d’Esclerosi Mútiple de Catalunya (Cemcat), Vall d’Hebron Hospital Universitari, Barcelona, Spain, 10Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Catania, Italy, 11Loyola University Chicago, Chicago, IL, USA, 12Department of Neurology, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium, 13Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA, 14F. Hoffmann-La Roche Ltd, Basel, Switzerland, 15Department of Neurology, UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
Objective:
To assess patient preference for conventional (CON) or shorter (SHORT) infusion post unblinding of the ENSEMBLE PLUS study.
Background:
Shortening the infusion duration of ocrelizumab to 2 hours reduces total site stay. Previous infusion-related reactions (IRRs) are a risk factor for future IRRs. Identification of specific symptoms, potential risk factors during infusions, was investigated in ENSEMBLE PLUS.
Design/Methods:
ENSEMBLE PLUS was a randomized, double-blind substudy to ENSEMBLE (NCT03085810). Ocrelizumab (600 mg) administered over the approved 3.5-hour infusion time (CON) was compared with a 2-hour infusion (SHORT). The primary endpoint was the proportion of patients with IRRs at first randomized dose (RD). Risk factors were assessed for development of IRRs. Patients could switch between CON/SHORT infusion post unblinding.
Results:
Within 24 hours of first RD, 27.1% (CON: n=101/373) versus 28.8% (SHORT: n=107/372) of patients had IRRs. Most IRRs (CON 100%; SHORT 97.2%) were mild or moderate (Grade 1 or 2);none were Grade 4 or 5 IRRs. No IRR-related discontinuations occurred. The proportion of patients with throat irritation as an IRR symptom was 23.1% (CON) and 33.0% (SHORT) in patients with ≥1 throat irritation before first RD; in patients with no throat irritation before first RD, the proportion was 5.3% (CON) and 5.4% (SHORT). Patient migraine/headache history did not correlate with IRR development. Post unblinding, 79.7% patients switched to SHORT infusion from CON, and 94.6% patients stayed on SHORT infusion. Treating neurologists frequently attempted minor adaptations of pre-medication timing/regimen without substantially affecting IRR incidence.
Conclusions:
Previous IRRs may be a risk factor for future IRRs but are not influenced by shorter infusion time. Pre-randomization throat irritation was predictive of developing throat irritation as an IRR symptom, however migraines were not. Most patients remained on/moved to SHORT infusion after unblinding. Overall, IRRs did not strongly influence patient decisions. Most pre-medication changes had no impact on IRR incidence.