ABSTRACT
Background: Understanding outcomes of Coronavirus Disease 2019 (COVID-19) and the impact of COVID-19 vaccination deserve significant consideration for people with multiple sclerosis (MS) treated with ocrelizumab (OCR). Aim(s): To report the number, characteristics and outcomes of COVID-19 cases in all OCR-treated patients and in those with COVID-19 vaccination (i.e. breakthrough cases) in two realworld cohort studies. Method(s): We analysed data from OCR-treated patients enrolled in ongoing, prospective, noninterventional studies conducted in Germany (CONFIDENCE, EUPAS22951) and in 25 other countries (MuSicalE, NCT03593590). COVID-19 seriousness was assessed per ICH guidelines. Outcomes were captured as recovered, recovered with sequelae, recovering, not recovered or fatal. Vaccine breakthroughs were cases with COVID-19 onset >=14 days after completion of the primary immunisation schedule recommended for each COVID-19 vaccine platform. 'Unvaccinated' included patients without COVID-19 vaccination recorded (including the prevaccination era) or with incomplete immunisation scheme. Result(s): Analyses included 1,702 OCR-treated patients from MuSicalE (73.1% relapsing-remitting MS, 21.2% primary progressive MS [PPMS], 5.6% relapsing secondary progressive MS) and 2,784 from CONFIDENCE (81.7% relapsing MS, 18.3% PPMS). As of March 2022 (preliminary data), completion of primary immunisation schedule was recorded for 542 (31.8%) and 710 (25.5%) patients in each study, mainly with mRNA vaccines (72.3% and 93.8%). COVID-19 infection was reported in 189 and 122 patients in MuSicalE and CONFIDENCE (11.1% and 4.4% among all patients), mostly reported as nonserious (85.2% and 83.6%), including 71 and 31 vaccine breakthroughs (13.1% and 4.4% among fully vaccinated patients). The following rates were reported in vaccinated and unvaccinated patients in MuSicalE and CONFIDENCE, respectively: (a) hospitalisations, 8.5% (6/71) vs 16.0% (19/118) and 9.7% (3/31) vs 14.3% (13/91);(b) serious cases, 8.5% (6/71) vs 17.8% (21/118) and 9.7% (3/31) vs 18.7% (17/91);(c) fatalities, 1.4% (1/71) vs 2.5% (3/118) and 0 deaths vs 2.2% (2/91). In both studies, the majority of patients had fully recovered (79.9% and 74.6%) or were recovering (11.1% and 7.4%) at last follow-up. Updated vaccination rates will be presented. Conclusion(s): Most COVID-19 cases were nonserious in these OCR-treated patient cohorts. Initial data suggest more favourable clinical outcomes associated with COVID-19 vaccination.
ABSTRACT
Background: Whilst the introduction of disease modifying treatments (DMTs) has transformed the management of people with early/relapsing MS (pwRMS), the use of DMTs in people with MS who are largely or completely wheel chair-dependent (EDSS>6.5) remains controversial. Evidence suggests that slowing or stopping disease deterioration is possible even past this arbitrary (loss of ambulatory function) threshold. Pathology and anecdotal clinical data support the hypothesis that even at an advanced stage of MS (AMS) inflammatory activity is a key driver of functional decline and that effective immunotherapy may halt this process. Cladribine tablets are a highly effective and central nervous system (CNS) penetrant DMT for people with highly-active RMS. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control in MS. Evidence, suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limb functions and (ii) longer axons are more vulnerable to the effects of focal inflammatory demyelination than shorter ones, corroborate our hypothesis that upper limb function can be protected even beyond EDSS=6.5. Objectives: Primary Objective: To investigate whether cladribine tablets over 24 months is an effective DMT in people with AMS (pwAMS;EDSS=6.5-8.5) as measured using the 9-hole peg test (9HPT) peg speed. Secondary Objectives: To establish whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in (i) blood/serum biomarkers of inflammation (lymphocyte subsets) and/or neurodegeneration (neurofilament light chain), (ii) MRI loss of brain volume and spinal cord cross sectional area, (iii) T2 lesion burden, (iv) hypointense lesions on T1 weighted scans, (v) quality of life, and (vi) whether cladribine is a cost-effective treatment for pwAMS. Methods: Randomised, double-blind, placebo-controlled phase IIb trial. To detect a 15% treatment effect in 9HPT peg speed with 90% power at 5% significance and 20% drop-out over 104 weeks n=200 pwAMS will be recruited across 20 UK MS centres. Results: Protocol and ancillary documents have been submitted for ethics approval. So far 17 centres have agreed to recruit pwAMS for ChariotMS. Due to the COVID-19 pandemic start of recruitment has been deferred to 04 Jan 2021. Conclusions: ChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for add-on therapies.