Clinical trial NCT05296161: B Cell Tailored Ocrelizumab Versus Standard Ocrelizumab in Relapsing Remitting Multiple Sclerosis
Official title: Efficacy, Safety and Cost-effectiveness of B Cell Tailored Ocrelizumab Versus Standard Ocrelizumab in Relapsing Remitting Multiple Sclerosis: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Multiple Sclerosis, Relapsing-Remitting
Keywords: ocrevus
ocrelizumab
personalised dosing
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2022-03-25
Enrollment: 296
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter randomized controlled non-inferiority trial in The Netherlands
Primary purpose: TREATMENT

Brief summary: Rationale: B-cell depleting therapies like ocrelizumab are very effective in the treatment of relapsing remitting multiple sclerosis (RRMS). As B cell repopulation varies extensively between individuals (ranging from 27-175 weeks), using a treatment scheme with a fixed infusion interval may be suboptimal. So far personalized adapted treatment of ocrelizumab in RRMS has not been studied in a prospective setting.

Objective: Evaluating the efficacy, safety and cost-effectiveness of ocrelizumab when administered in personalized B cell tailored intervals in RRMS patients.

Study design: This is a national multicenter randomized controlled trial with 96 week follow-up.

Study population: The study population consists of 296 adult RRMS patients who have received ocrelizumab treatment for a minimum of 12 months (2x 300 mg infusion and 1x 600mg infusion).

Intervention: Patients will be randomized into the standard interval group (600 mg infusions every 24 weeks) or the personalized interval group in which the infusions will be extended as long as the serum CD19 B cell count is below 10 CD19 cells/µL, determined every 4 weeks.

Main study parameters: To conclude non-inferiority of personalized B cell tailored ocrelizumab there will be two co-primary endpoints: 1. the difference of percentage of confirmed relapse-free patients between the two groups after 96 weeks and 2. the difference of percentage of patients free from new/enlarging T2 lesions on MRI between the two groups after 96 weeks. Secondary study parameters are number of confirmed relapses, annualized relapse rate, number of new T2 lesions and brain atrophy on MRI, disability progression, no evidence of disease activity (NEDA), MS disease biomarkers (serum neurofilament light), quality of life, burden of treatment, immunoglobulin levels and (serious) adverse events including occurrence of infections and COVID-19. Furthermore, various immune cell subsets will be studied in relation to ocrelizumab concentration in a subgroup.

Nature and extent of the burden and risks: All patients will be subjected to visits every 24 weeks including clinical scoring and questionnaires. Blood samples and MRI scans will be taken and performed every 48 weeks. Continuous assessment of key stroke dynamics on the patients smartphone and monthly digital cognitive test and walk test will be performed in most patients. As CD19 B cells are kept near complete depletion, the estimated risk of recurrence of disease activity is very low.


Eligibility criteria: Inclusion Criteria:

* A current diagnosis of relapsing remitting multiple sclerosis according to the 2017 McDonald criteria34
* EDSS score of 0 to 6.5
* Treatment with ocrelizumab for a minimum of 48 weeks (two 300 mg infusions and one 600 mg infusion)

Exclusion Criteria:

* Previous treatment with alemtuzumab, cladribine or stem cell transplantation
* Relapse in the past 3 months prior to inclusion
* Subsequent treatment with another DMT next to ocrelizumab in the past 6 months prior to inclusion
* Inability to undergo regular MRI scanning
* Women who are pregnant or expect to become pregnant during the study period

Primary outcomes:
measure: Confirmed relapse-free patients
timeFrame: 96 weeks
measure: Change of T2 lesions on brain MR
timeFrame: 96 weeks
Secondary outcomes:
measure: Annualized relapse rate
timeFrame: Baseline, year 1, year 2
measure: Total number of active (new and/or enlarging) T2 lesions on brain MRI
timeFrame: Baseline, year 1, year 2
measure: Disability progression during follow-up
timeFrame: Baseline, 6 months,12 months, 18 months, 24 months
measure: Disability progression during follow-up
timeFrame: Baseline, year 1, year 2
measure: Brain atrophy
timeFrame: Baseline, year 1, year 2
measure: NEDA (no evidence of disease activity)
timeFrame: 96 weeks
measure: Change of neurofilament light
timeFrame: 96 weeks
measure: Change of quality of life
timeFrame: Baseline, year 1, year 2
measure: Change of burden of treatment
timeFrame: Baseline, year 1, year 2
measure: Ocrelizumab wearing-off effect
timeFrame: Baseline, year 1, year 2
measure: IgG levels
timeFrame: Baseline, year 1, year 2
measure: Cost analysis
timeFrame: 96 weeks
measure: Disability progression: decrease of hand mobility
timeFrame: Baseline, 6 months,12 months, 18 months, 24 months
measure: Disability progression: two minute walking distance
timeFrame: Baseline, 6 months,12 months, 18 months, 24 months
measure: Disability progression: cognitive impairment
timeFrame: Baseline, 6 months,12 months, 18 months, 24 months
Other outcomes:
measure: Trough ocrelizumab concentration
timeFrame: 24 weeks, 48 weeks, 72 weeks, 96 weeks
measure: Intra-individual course and stability B-cell counts and subsets from whole blood
timeFrame: 24 weeks, 48 weeks, 72 weeks, 96 weeks
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VU
state: Noord-Holland
Study officials:
affiliation: Amsterdam UMC, location VU
name: Joep Killestein, Prof.
role: PRINCIPAL_INVESTIGATOR
References: