Efficacy, safety and cost-effectiveness of B cell tailored ocrelizumab versus standard ocrelizumab in relapsing remitting multiple sclerosis: a randomized controlled trial

Multiple sclerosis (MS) is a devastating disease of the central nervous system
(CNS), most commonly affecting young adults in western society.
Over the last two decades, immunomodulating drugs for RRMS have exponentially
increased. One of the most effective drugs (introduced to the market in 2018)
is ocrelizumab which has shown to reduce 46-47% of relapses and 91-98% of
gadolinium enhancing MS lesions on MRI compared to first-line MS therapy.
Ocrelizumab is currently one of the most frequently described drugs in active
RRMS worldwide. In March 2020, approximately 1,450 MS (and 1,120 RRMS) patients
in the Netherlands and 160,000 patients worldwide received ocrelizumab.

Ocrelizumab is approved in a 600 mg dose every 24 weeks (the first infusion is
divided in two 300 mg infusions 2 weeks apart). However, B cell depletion is
long-lasting with a medium repopulation after 72 weeks (range 27-175) after the
last 600 mg dose. In 80% of patients, there is no sign of starting repopulation
after 24 weeks. These are strong indicators of an *over-treatment* in the large
majority of patients.

With this study we aim to prove that personalized B cell tailored ocrelizumab
treatment is non-inferior in the suppression of MS disease activity (clinically
and radiologically) compared to the standard (fixed 24 week interval)
treatment.

This is a national multicenter non-inferiority randomized controlled trial in
the Netherlands. Follow-up will be 96 weeks.

In this study, patients currently treated with ocrelizumab will be randomized
(1:1) to stay on the standard treatment or receive a personalized B cell
tailored ocrelizumab treatment.

In patients in the personalized group, starting at 24 weeks after the last
ocrelizumab infusion, blood will be drawn to test B cells. As ocrelizumab can
interfere with the flow cytometry analysis of CD20 cells, CD19 cells which
carry a similar expression profile, are used for establishing B-cell depletion
and repopulation. When CD19 B cells start to replete, with a cut-off of 10
cells/µL, patients will be scheduled for an ocrelizumab infusion in the next
two weeks

Patients in the personalized group will likely receive less ocrelizumab,
therefore there is a small chance of recurrence of disease activity.