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Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

ABSTRACT: Background: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS.

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 ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose.

Results: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab.

Conclusion: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5-6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

SUBMITTER: Hartung HP

PROVIDER: S-EPMC7513877 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

Hartung H-P HP Berger T T Bermel R A RA Brochet B B Carroll W M WM Holmøy T T Karabudak R R Killestein J J Nos C C Patti F F Ross A Perrin AP Vanopdenbosch L L Vollmer T T Buffels R R Garas M M Kadner K K Manfrini M M Wang Q Q Freedman M S MS

Multiple sclerosis and related disorders 20200924

<h4>Background</h4>Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS.<h4>Methods</h4>ENSEMBLE PLUS is a randomized, double-blind substudy to the ...[more]

PMID: 33039944

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Project description:To assess the safety of ocrelizumab (OCR) shorter duration infusion in patients with MS. 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). 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. 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. 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. NCT03085810.

Project description:Background and objectivesMultiple sclerosis (MS) is a chronic, progressive neurological disease characterized by early-stage neuroinflammation, neurodegeneration, and demyelination that involves a spectrum of heterogeneous clinical manifestations in terms of disease course and response to therapy. Even though several disease-modifying therapies (DMTs) are available to prevent MS-related brain damage-acting on the peripheral immune system with an indirect effect on MS lesions-individualizing therapy according to disease characteristics and prognostic factors is still an unmet need. Given that deregulated miRNAs have been proposed as diagnostic tools in neurodegenerative/neuroinflammatory diseases such as MS, we aimed to explore miRNA profiles as potential classifiers of the relapsing-remitting MS (RRMS) patients' prospects to gain a more effective DMT choice and achieve a preferential drug response.MethodsA total of 25 adult patients with RRMS were enrolled in a cohort study, according to the latest McDonald criteria before (pre-cladribine, pre-CLA; pre-ocrelizumab, pre-OCRE, time T0) and after high-efficacy DMTs, time T1, 6 months post-CLA (n = 10, 7 F and 3 M, age 39.0 ± 7.5) or post-OCRE (n = 15, 10 F and 5 M, age 40.5 ± 10.4) treatment. A total of 15 age- and sex-matched healthy control subjects (9 F and 6 M, age 36.3 ± 3.0) were also selected. By using Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells (PBMC). miRNA-target networks were obtained by miRTargetLink, and Pearson's correlation served to estimate the association between miRNAs and outcome clinical features.ResultsFirst, the miRNA profiles of pre-CLA or pre-OCRE RRMS patients compared to healthy controls identified modulated miRNA patterns (40 and seven miRNAs, respectively). A direct comparison of the two pre-treatment groups at T0 and T1 revealed more pro-inflammatory patterns in the pre-CLA miRNA profiles. Moreover, both DMTs emerged as being capable of reverting some dysregulated miRNAs toward a protective phenotype. Both drug-dependent miRNA profiles and specific miRNAs, such as miR-199a-3p, miR-29b-3p, and miR-151a-3p, emerged as potentially involved in these drug-induced mechanisms. This enabled the selection of miRNAs correlated to clinical features and the related miRNA-mRNA network.DiscussionThese data support the hypothesis of specific deregulated miRNAs as putative biomarkers in RRMS patients' stratification and DMT drug response.

Dataset Information

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

Publications

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

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