Clinical trial NCT05834855: Non-inferiority Study of Rituximab Compared to Ocrelizumab in Relapsing MS
Official title: Non-inferiority Study of Rituximab Compared to Ocrelizumab in Relapsing Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Keywords: ocrelizumab
rituximab
non-inferiority
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: Stichting Treatmeds
First posted: 2023-04-28
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter randomized controlled double-blind non-inferiority trial in The Netherlands
Primary purpose: TREATMENT

Brief summary: Rationale: Ocrelizumab is widely and effectively used to treat relapsing multiple sclerosis (RMS). Phase II studies and data from large patient cohorts indicate that rituximab, another anti-CD20 monoclonal antibody, is probably equally effective and safe as ocrelizumab in the treatment of RMS. An advantage of rituximab is a considerably lower price. Therefore we will start a study aimed at demonstrating non-inferiority of rituximab compared to ocrelizumab in RMS. If non-inferiority of rituximab can be shown, important reductions in the cost of treatment of RMS will be possible, without loss of efficacy.

Objective: Evaluating the efficacy and safety of ritixumab compared to ocrelizumab in the treatmens of RMS.

Study design: Randomized double blind multi-centre non-inferiority study of rituximab compared to ocrelizumab in 200 patients with RMS. The trial duration will be 30 months

Study population: The study population consists of 200 adult RMS patiens with an indication to start anti-CD20 monoclonal antibody treatment.

Intervention: Patients will be randomized 1:1 into the standard group (ocrelizumab treatment) or the experimental group (rituximab treatment).

Main study parameters: To conclude non-inferiority of rituximab there will be one primary endpoint: the proportion of patients free of inflammatory disease activity (defined as: new or enlarged T2 lesions) between week 24 (M6) and week 96 (M24) of treatment in each arm. Secondary trial endpoints are presence and number of clinical relapses,T2 and contrast enhancing lesion volumes, brain volume and brain volume changes, disease progression (defined as clinically relevant change on any of the measures: EDSS, T25FW, 9HPT, SDMT), biochemical parameters such as lipidomics and neurofilament light (NfL), immunological parameters, safety as measured by the number of (serious) adverse events ((S)AE), quality of life (EQ-5D-L) and treatment satisfaction (TSQM) and patient reported measures of MS impact (MSIS-29) and well-being (questionnaire on physical complaints)

Nature and extent of the burden and risk: Patients included in this study will be treated and monitored by MRI, clinical tests and laboratory tests according to existing protocols and will not be exposed to extra or unknown risks. They will have extra annual questionnaires and larger blood samples at some time points. There is extensive experience with both rituximab and ocrelizumab as efficacious and safe treatments of RMS.


Eligibility criteria: Inclusion Criteria:

1. Men and women aged 18 years and older
2. A diagnosis of relapsing MS according to the 2017 revised diagnostic criteria
3. Indication to start treatment with anti-CD20 therapy according to the treating neurologist and the relevant label in the Netherlands for treatment of relapsing MS
4. Able to understand written and spoken Dutch or English
5. Capable of giving signed informed consent including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
6. Screening EDSS score ≤ 6.5 .

Exclusion Criteria:

Medical Conditions

1. A known allergy or other intolerability to RTX, OCR, gadolinium-based MRI contrast agents, or corticosteroids.
2. A diagnosis of primary progressive MS according to the diagnostic criteria.
3. A diagnosis of not-active secondary progressive MS.
4. Chronic infectious diseases such as tuberculosis, VZV, hepatitis virus or HIV, as well as hepatitis B surface antigen positivity and/or hepatitis C PCR positivity verified at screening visit.
5. A history of proven inflammatory bowel disease such as M. Crohn or ulcerative colitis
6. Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol.
7. Cardiac disease that makes treatment with OCR or RTX contra-indicated as stated by the most recent SmPC
8. Active malignancy or prior history of malignancy that makes treatment with OCR or RTX contra-indicated as stated by the most recent SmPC.
9. WBC \< 1.5 x 109/L if not caused by a reversible effect of documented ongoing medication. If caused by a reversible effect of documented ongoing medication the WBC count must be \> 1,5 x 109/L before start of study treatment.
10. Platelet (thrombocyte) count \< 100 x 109/L
11. ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)
12. Serum creatinine \> 200 μmol/L
13. Serum bilirubin \> ULN
14. Serum IgG \< LLN
15. Pregnant or breast-feeding women
16. Women of childbearing potential (WOCBP) not able or willing to use highly effective methods of birth control per ICH M3 (R2) that result in failure rate of ≤ 1% per year when used consistently and correctly for the duration of the study OR until 3 months after last dose administered.
17. History of serious or life-threatening infusion reaction to OCR or RTX
18. Treatment with glucocorticoids or ACTH within one month prior to start of study treatment

    Prior/Concomitant Therapy
19. Previous use of second line MS-therapies cladribine, RTX, alemtuzumab, OCR, ofatumumab, hematopoietic stem cell therapy (HSCT) or other immunosuppression therapies with long lasting effects. Mitoxantrone is allowed if used \> 1 year before enrolment. If any of these medications have been used for indications other than MS, patients can be included if the medications have not been used the year before enrolment. Previous treatment with natalizumab is allowed if the reason to switch was disease activity (so not allowed in for example cases that switch from natalizumab to anti-CD20 therapy because of JCV positivity).
20. Concomitant use of systemic immunosuppressive medication (except corticosteroids for symptomatic treatment of relapses).

    Prior/Concurrent Clinical Study Experience
21. Currently enrolled in another investigational device or drug study, or less than 30 days since ending of another investigational device or drug study (s), or receiving other investigational treatment(s). Patients participating in a purely observational studies will be allowed to participate.

    Lifestyle
22. Current alcohol or drug dependencies.

    Diagnostic assessments
23. Presence of metallic objects implanted in the body, that would preclude the ability of the patient to safely have MRI exams.
24. Not willing to undergo MRI scans with i.v. gadolinium injections

Primary outcomes:
measure: Proportion of patients free of inflammatory disease activity
timeFrame: between month 6 and month 24
Secondary outcomes:
measure: Presence and number of clinical relapses
timeFrame: Baseline, month 6, month 24
measure: Contrast enhancing lesions
timeFrame: Baseline, month 6, month 24
measure: Average number of T2 lesions on brain MRI
timeFrame: Baseline, month 6, month 24
measure: Disability progression during follow-up
timeFrame: Baseline, month 6, month 24
measure: Disability progression during follow-up
timeFrame: Baseline, month 6, month 24
measure: Disability progression during follow-up
timeFrame: Baseline, month 6, month 24
measure: Disability progression during follow-up
timeFrame: Baseline, month 6, month 24
Other outcomes:
measure: Anti-drug antibodies
timeFrame: 30 months
measure: Infusion reactions
timeFrame: 30 months
measure: Infections
timeFrame: 30 months
measure: Malignancies
timeFrame: 30 months
measure: Adverse events
timeFrame: 30 months
measure: Burden of physical senstations during treatment
timeFrame: Baseline, month 6, month 12, month 18, month 24, month 30
measure: Quality of life questionnaires
timeFrame: Baseline, month 6, month 12, month 18, month 24, month 30
measure: Quality of life questionnaires
timeFrame: Baseline, month 6, month 12, month 18, month 24, month 30
measure: Treatment satisfaction
timeFrame: Baseline, month 6, month 12, month 18, month 24, month 30
measure: Lymphocytes
timeFrame: 30 months
measure: Neurofilament
timeFrame: 30 months
measure: Dynamics of B-cell depletion
timeFrame: Baseline, week 2, month 6, month 12, month 18, month 24, month 30
measure: Dynamics of B-cell repopulation
timeFrame: Baseline, week 2, month 6, month 12, month 18, month 24, month 30
measure: Dynamics of ocrelizumab drug concentrations
timeFrame: Baseline, week 2, month 6, month 12, month 18, month 24, month 30
measure: Immunoglobulins
timeFrame: Baseline, week 2, month 6, month 12, month 18, month 24, month 30
measure: Serum levels
timeFrame: 30 months
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VUmc
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Bob van Oosten, Dr
role: PRINCIPAL_INVESTIGATOR
References: