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Randomized Controlled Trial
. 2024 Jul;271(7):4348-4360.
doi: 10.1007/s00415-024-12326-z. Epub 2024 Apr 22.

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial

Hans-Peter Hartung  1   2   3 , Thomas Berger  4   5 , Robert A Bermel  6 , Bruno Brochet  7 , William M Carroll  8 , Trygve Holmøy  9   10 , Rana Karabudak  11 , Joep Killestein  12 , Carlos Nos  13 , Francesco Patti  14 , Amy Perrin Ross  15 , Ludo Vanopdenbosch  16 , Timothy Vollmer  17 , Regine Buffels  18   19 , Monika Garas  18 , Karen Kadner  18 , Marianna Manfrini  18 , Qing Wang  18 , Mark S Freedman  20
Affiliations
Randomized Controlled Trial

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial

Hans-Peter Hartung et al. J Neurol. 2024 Jul.

Abstract

Introduction: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.

Methods: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.

Results: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.

Conclusion: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.

Clinical trials registration: Substudy of ENSEMBLE (NCT03085810).

Registration: March 21, 2017.

Keywords: ENSEMBLE PLUS; Infusion-related reaction; Ocrelizumab; Phase 3; Relapsing–remitting multiple sclerosis; Shorter infusion.

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Conflict of interest statement

H-P Hartung has received honoraria for serving on steering and data monitoring committees from Bayer, Biogen, GeNeuro, Merck, Novartis, Roche, Sanofi-Genzyme, and TG Therapeutics, with approval by the Rector of HHU. T Berger has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen, Biologix, Bionorica, Genzyme, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, TG Pharmaceuticals, Teva ratiopharm, and UCB. His institution has received financial support in the last 12 months by unrestricted research grants (Biogen, Bayer, Merck, Novartis, Sanofi/Genzyme, and Teva ratiopharm) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, and Teva. R.A. Bermel has received consultation fees from Biogen, EMD Serono, F. Hoffmann-La Roche Ltd/Genentech, Inc., Genzyme, Novartis, and Viela Bio; and has received institutional research support from Biogen, Genentech/Roche, and Novartis. B Brochet has received honoraria for consulting, speaking at scientific symposia, or serving on advisory boards from Biogen Idec., BMS-Celgene, Merck-Serono, Novartis, Roche, and Sanofi. W.M. Carroll has received honoraria for serving on steering committees and advisory boards; and for speaking at scientific meetings from Bayer, Biogen Idec., Merck, Novartis, Roche, and Sanofi-Genzyme. T Holmøy has received honoraria/consultation fees from Novartis, Biogen Idec., Sanofi-Genzyme, Merck, Bristol Myers Squibb, and Roche. R Karabudak received honoraria for consulting, lectures, and advisory boards from Sanofi-Genzyme, Roche, Novartis, Merck-Serono, Gen İlaç TR, and Teva. J Killestein has carried out contracted research for F. Hoffmann-La Roche Ltd, Biogen, Teva, Merck, Novartis, and Sanofi/Genzyme. C Nos or his institution has received honoraria/consultation fees from Roche and Sanofi. F Patti received personal compensation for speaking activities and serving on the advisory board by Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. He also received research grants by Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), RELOAD Onlus Association, and the University of Catania. A. Perrin Ross has received honoraria/consultation fees from Alexion, EMD Serono, Merck, Mallinckrodt, Novartis, Roche, Sanofi-Genzyme, Genentech, Inc., Horizon, TG Therapeutics, Janssen, Bristol Myers Squibb, UCB, and Sandoz and Cycle. L Vanopdenbosch has received compensation for lectures and consultancy from Biogen, F. Hoffmann-La Roche Ltd, Novartis, Merck-Serono, and Sanofi-Genzyme. T Vollmer has received compensation for lectures and consultancy from Biogen, Genentech/Roche, Siranax, Celgene, EMD Serono, and Novartis; and has received research support from Rocky Mountain Multiple Sclerosis Center, Biogen, Actelion, Roche/Genentech, F. Hoffmann-La Roche Ltd, and TG Therapeutics. R Buffels was an employee of F. Hoffmann-La Roche Ltd. M Garas is an employee of and a shareholder in F. Hoffmann-La Roche Ltd. K Kadner is an employee of F. Hoffmann-La Roche Ltd. M Manfrini is an employee of and a shareholder in F. Hoffmann-La Roche Ltd. Q Wang is an employee of F. Hoffmann-La Roche Ltd. M.S. Freedman has received a research grant from Genzyme Canada and honoraria/consultation fees from Actelion/Janssen, Alexion/AstraZeneca, Biogen Idec., BMS/Celgene, EMD Canada/Merck-Serono, Novartis, F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, and Teva Canada Innovation; is a member of a company advisory board, board of directors, or other similar group for Actelion/Janssen, Bayer HealthCare, Biogen Idec., F. Hoffmann-La Roche Ltd, Merck-Serono, Novartis, and Sanofi-Genzyme; and has served on a speakers’ bureau for Sanofi-Genzyme and EMD Serono.

Figures

Fig. 1
Fig. 1
Patient disposition and analysis population. Of the 754 patients enrolled, eight patients (all newly enrolled) consented to participate in the ENSEMBLE PLUS substudy but were never randomized and one patient (already enrolled) in the main ENSEMBLE study was never randomized into the ENSEMBLE PLUS substudy. Patients (N = 745) were randomized in a 1:1 ratio to the conventional infusion group (n = 373) or the shorter infusion group (n = 372). Of the 373 patients from the conventional infusion group who discontinued randomized treatment, six patients stopped the substudy and main study, and in turn, administration of OCR was stopped; two patients stopped the substudy and main study but continued on commercial OCR; and 365 patients stopped the substudy but continued in the main study. Of the 372 patients from the shorter infusion group who discontinued randomized treatment, six patients stopped the substudy and main study, and in turn, administration of OCR was stopped; one patient stopped the substudy and main study but continued on commercial OCR; and 363 patients stopped the substudy but continued in the main study. OCR ocrelizumab
Fig. 2
Fig. 2
IRRs by RD and severity (ITT). Percentages for the number of patients with an infusion are based on N, and percentages for the number of patients with any IRR are based on number of patients with an infusion. Percentages of patients with IRR grade are based on number of patients with any IRR. For summaries by grade, multiple IRRs in one patient are counted only once at the most extreme (highest) intensity observed. IRR infusion-related reaction, ITT intent-to-treat, RD randomized dose
Fig. 3
Fig. 3
IRRs at the first RD by OCR dose at which the patient was randomized. Percentages are based on N, number of patients that received the infusion at the OCR dose at which the patient was randomized. All IRRs are included in this graph, both serious and nonserious. Mild mild (Grade 1), Mod. moderate (Grade 2), Sev. severe (Grade 3), L-T life-threatening (Grade 4), Fatal fatal (Grade 5). IRR infusion-related reaction, OCR ocrelizumab, RD randomized dose
Fig. 4
Fig. 4
IRRs by RD and severity (patients without prefirst RD IRR, ITT). Percentages for the number of patients with an infusion are based on N, and percentages for a number of patients with any IRR are based on number of patients with an infusion. IRR infusion-related reaction, ITT intent-to-treat, RD randomized dose
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