Lead Investigator: David Baker, Queen Mary University of London
Title of Proposal Research: Exploring possibilities to improve the risk:benefit balance through analysis of the ocrelizumab phase II extension study
Vivli Data Request: 5984
Funding Source: None
Potential Conflicts of Interest: In last 3 years consultancy or speaker honoraria from Novartis, Merck, Roche, Lundbeck InMune Bio, Canbex
No competitor company is aware we have access to this data yet and the information we seek is in the public domain. Confidential information is kept confidential and the data analysis plan is based on ideas from within our academic group.
Summary of the Proposed Research:
Multiple sclerosis is the major demyelinating disease of the central nervous system. Although considered to be a T cell-mediated autoimmune disease it has been shown that CD20 B cell– depleting antibodies exhibit high efficacy in the control of relapsing MS. We have recently suggested that all current MS drugs act because they target memory B cells, a subset of B cells within the CD20 population. Although the B cell subset depletion potential of ocrelizumab has not been reported, we know that other similar agents deplete memory B cells for months to years.
However, ocrelizumab treatment is given every six months to ensure that all B cells are depleted at a time when there may not be any CD20 positive memory B cells present in the circulation.
Memory B cell depletion can last for years and suggests that treatment effects may therefore last for years also, as found with other multiple sclerosis drugs that similarly deplete memory B cells. Therefore, it may be possible to achieve similar benefit with less frequent drug administration and thus avoiding or reducing potential drug-related side-effects, particularly as it is known that total B cell elimination leaves one susceptible to serious infection.
This study examines the long-term effect, at least 18 months, of a short-term treatment cycle and may provide information on the duration of efficacy and information of the durability of the lymphocyte depletion. Although the study was done many years ago it has not been reported fully, yet based on scientific meetings reports found in the public domain, there may be durability of efficacy offering the possibility of a drug-free pregnancy, and provides insight on how ocrelizumab may be working.
The objective of the study is to examine whether ocrelizumab has a durability of action longer than 6 months and to obtain data that will help to justify future studies that can may make ocrelizumab even safer.
Statistical Analysis Plan:
We aim to replicate studies published in meeting reports. The data analysis plan is contained within the clinical study reports 2012, 2016
The statistical analysis for efficacy has been reported in internet publications and it is clear that for efficacy measures, there is essential no difference between relapse rates following 3 or 4 cycles. During the 18 month treatment free period they are likewise comparably low and consistent with the adjusted annualised relapse rate of repeated fix dosing over 6 cycles (Hauser et al. 2018 Mult scler 24:S2):285).
We aim to replicate the Kaplan Meirer curves in the public domain (3/6 month disease progression) We aim to replicate the lymphocyte repletion curves in the public domain
Data will be reported with mean/median and 95% confidence intervals (Baker et al. 2020).
Chi-squared analysis will be used to compare adverse events and infections during the drug free period and effects during treatment. Based on available data these adverse events are reduced by about 50% which will be statistically significant.
At present we do not intend to perform sub group analysis.
Phase II, Multicenter, Randomized, Parallel-Group, Partially Blinded, Placebo and Avonex Controlled Dose Finding Study to Evaluate the Efficacy As Measured by Brain MRI Lesions, and Safety of 2 Dose Regimens of Ocrelizumab in Patients With RRMS
Study ID: NCT00676715
Sponsor ID: ACT4422g
- David Baker, Amy MacDougall, Angray S Kang, Klaus Schmierer, Gavin Giovannoni, Ruth Dobson. Seroconversion following COVID-19 vaccination: Can we optimize protective response in CD20-treated individuals?. Clinical and Experimental Immunology, 2021; uxab015. doi: 10.1093/cei/uxab015
- Baker, D., MacDougall, A., Kang, A. S., Schmierer, K., Giovannoni, G., & Dobson, R. (2022). CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis. Multiple Sclerosis and Related Disorders, 57, 103448. doi: 10.1016/j.msard.2021.103448