B Cell Tailored Ocrelizumab Versus Standard Ocrelizumab in Relapsing Remitting Multiple Sclerosis (BLOOMS)

Efficacy, Safety and Cost-effectiveness of B Cell Tailored Ocrelizumab Versus Standard Ocrelizumab in Relapsing Remitting Multiple Sclerosis: a Randomized Controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Ocrelizumab

• Study Type: Interventional
• Enrollment (Anticipated): 296
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Laura Hogenboom, Msc; Phone Number: +31 01204440717; Email: l.hogenboom1@amsterdamumc.nl
• Study Contact Backup: Name: Zoé van Kempen, Dr.; Phone Number: +31 0204442182; Email: z.vankempen@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081 HV
      • Recruiting
      • Amsterdam UMC, location VU
      • Contact: Laura Hogenboom, Msc.; Phone Number: +31 0204440717; Email: l.hogenboom1@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard interval dosing; The standard group will receive ocrelizumab every 24 weeks following the current label.
Experimental: Personalized B cell tailored ocrelizumab treatment; The personalized group will start with B cell measurements 24 weeks after the last infusion (baseline). The infusion interval will never be shorter than 24 weeks. The personalized group will start the study with a possible extension of the interval. The infusion will be postponed as long as CD19 B cell count stays below 10 cells/µL (determined every 4 weeks). When CD19 B cell count exceeds or is equal to 10 cells/µL, ocrelizumab infusion will be scheduled within two weeks	Drug: Ocrelizumab; Personalized B cell tailored ocrelizumab treatment; Other Names: ocrevus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed relapse-free patients	Difference of percentage of confirmed relapse-free patients between the two treatment groups after 96 weeks follow-up.	96 weeks
Change of T2 lesions on brain MR	Difference of percentage of patients without new/enlarging T2 MRI lesions between the two treatment groups after 96 weeks follow-up.	96 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized relapse rate	Clinical relapses during B-cell tailored dosing	Baseline, year 1, year 2
Total number of active (new and/or enlarging) T2 lesions on brain MRI	In comparison to the baseline MRI and number of active MRI scans.	Baseline, year 1, year 2
Disability progression during follow-up	Disability progression measured on the Expanded Disability Status Scale (EDSS)	Baseline, 6 months,12 months, 18 months, 24 months
Disability progression during follow-up	Disability progression measured on the Expanded Disability Status Scale (EDSS)	Baseline, year 1, year 2
Brain atrophy	Rate of brain atrophy comparing baseline MRI and MRI at 96 weeks.	Baseline, year 1, year 2
NEDA (no evidence of disease activity)	NEDA is defined as absence of confirmed relapses, MRI disease activity (new/enlarging T2 lesions) and confirmed disability progression.	96 weeks
Change of neurofilament light	Measured in serum	96 weeks
Change of quality of life	Measured by the Multiple Sclerosis Impact Scale (MSIS-29)	Baseline, year 1, year 2
Change of burden of treatment	measured by the Treatment Satisfaction Questionnaire for Medication (TSQM)	Baseline, year 1, year 2
Ocrelizumab wearing-off effect	Presence of a possible wearing-off effect measured by a questionnaire developed by the Amsterdam MS Center	Baseline, year 1, year 2
IgG levels	Change of IgG levels	Baseline, year 1, year 2
Cost analysis	Cost-utility analysis using EuroQol 5D (EQ-5D)	96 weeks
Disability progression: decrease of hand mobility	Significant decrease of hand mobility measured by an app that analyses key stroke dynamics. The dynamics are measured continuously and analysed every 6 months.	Baseline, 6 months,12 months, 18 months, 24 months
Disability progression: two minute walking distance	Significant decrease of walking distance measured by an app that analyses distance using GPS signal. The test is taken monthly and analysed every 6 months.	Baseline, 6 months,12 months, 18 months, 24 months
Disability progression: cognitive impairment	Significant decrease of cognitive impairment measured by an app that is validated for a digital Symbol Digit Modalities Test (SDMT). The test is taken monthly and analysed every 6 months.	Baseline, 6 months,12 months, 18 months, 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough ocrelizumab concentration	in serum	24 weeks, 48 weeks, 72 weeks, 96 weeks
Intra-individual course and stability B-cell counts and subsets from whole blood	In a subgroup of patients cell subsets including CD4+ T cells, CD8+ T cells, CD20+ T cells, CD3-D56+ NK cells, and various B cell subsets (CD19+CD27- naive B cells, CD19+CD27+ memory B cells, CD19+CD27+IgD-IgM- switched memory B cells and CD19+CD27+IgD+ marginal zone B cells) will be tested.	24 weeks, 48 weeks, 72 weeks, 96 weeks

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Joep Killestein, Prof., Amsterdam UMC, location VU

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2022
• Primary Completion (Anticipated): April 1, 2024
• Study Completion (Anticipated): March 1, 2026

Study Registration Dates

• First Submitted: February 18, 2022
• First Submitted That Met QC Criteria: March 15, 2022
• First Posted (Actual): March 25, 2022

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 21, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: ocrelizumab; ocrevus; personalised dosing
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Immunologic Factors; Ocrelizumab
• Other Study ID Numbers: 2021.0639

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: After medical ethical commitee approved the study protocol.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No