Ocrelizumab shorter infusion: Primary results from the ENSEMBLE PLUS substudy in patients with MS

Abstract

Objective: To assess the safety of ocrelizumab (OCR) shorter duration infusion in patients with MS.

Methods: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early stage relapsing-remitting MS received OCR 600 mg initially as two 300 mg IV infusions 2 weeks apart and subsequently as a single 3.5-hour 600 mg infusion every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration). The primary end point was the proportion of patients with infusion-related reactions (IRRs) after the first randomized dose (assessed during and up to 24 hours postinfusion).

Results: From November 1, 2018, to September 27, 2019, 580 patients were randomized 1:1 to the conventional or shorter infusion group. After the first randomized dose, 67 of 291 patients (23.1%) in the conventional and 71 of 289 patients (24.6%) in the shorter infusion group experienced IRRs. Most IRRs were mild or moderate in both groups; one patient in each group experienced a severe IRR, and in both groups, 98.6% (136 of 138) of all IRRs resolved without sequelae. No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuation occurred. During the first randomized dose, 14 of 291 (4.8%) and 25 of 289 (8.7%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption.

Conclusion: The frequency and severity of IRRs were similar between conventional and shorter OCR infusions. Shortening the infusion time to 2 hours reduces the total infusion site stay time and lessens the overall patient and site staff burden.

Classification of evidence: This interventional study provides Class I evidence that the frequency and severity of IRRs were similar at the first randomized dose using OCR (600 mg) infusions of conventional and shorter duration in patients with relapsing-remitting MS.

Clinical trial identifier number: NCT03085810.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. ENSEMBLE PLUS (A) study design and (B) infusion schedule

The ENSEMBLE PLUS primary end point is the proportion of patients with IRRs after the first randomized dose (frequency and severity assessed during and 24 hours postinfusion). aRandomization of new patients at week 24. AH = antihistamine; IRR = infusion-related reaction; IVMP = methylprednisolone; PK = pharmacokinetic assessment.

Figure 2. Patient disposition and analysis of population

One patient disclosed that they were pregnant after randomization but before receiving any study treatment. Per protocol, treatment is withheld from patients who become pregnant during the study. There was also one withdrawal from the conventional infusion group because of an adverse event (depressive symptom) that was considered unrelated to the study treatment but because of concurrent illness of depression. A discontinuation visit had not been scheduled or undertaken for the patient at the time of CCOD; hence, this patient could not be included in any of the tables which display discontinuation. Other: accidental unblinding. CCOD = clinical cutoff date.