Clinical trial NCT04578639: Ocrelizumab VErsus Rituximab Off-Label at the Onset of Relapsing MS Disease
Official title: Ocrelizumab VErsus Rituximab Off-Label at the Onset of Relapsing
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: RRMS
MS
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: University Hospital, Akershus
name: Oslo University Hospital
name: Helse Stavanger HF
name: St. Olavs Hospital
name: University Hospital of North Norway
First posted: 2020-10-08
Enrollment: 214
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: A prospective randomized double blinded multicenter non-inferiority study designed to establish non-inferiority of the study treatment rituximab compared with the comparator ocrelizumab for consecutively included patients (male or female) with active relapsing-remitting multiple sclerosis aged 18-60 years.
Primary purpose: TREATMENT

Brief summary: This is a multicenter non-inferiority study, designed to establish non-inferiority of the study treatment rituximab compared with the comparator ocrelizumab for consecutively included patients (male or female) with active relapsing-remitting multiple sclerosis aged 18-60 years.

Detailed description: The objective of the study is to demonstrate if rituximab is non-inferior to ocrelizumab with regards to efficacy and safety in treatment naïve RRMS patients, diagnosed within the last 12 months.

To test this hypothesis, the investigators aim to perform a 30-months (24 + 6 months) prospective randomized double blinded multicenter non-inferiority study to compare rituximab to ocrelizumab in RRMS.

MS disease activity as measured by brain MRI is more sensitive as compared to clinical disease activity as measured by number of relapses or disability progression. New or enlarging MRI T2 lesions is regarded an acceptable marker of disease activity, and is routinely used in clinical practice by annual examinations (Thompson, Baranzini et al. 2018) (Thompson, Banwell et al. 2018). The investigators will therefore use the proportion of patients with no new or enlarging T2-weighted brain MRI lesions from month 6 to month 24 as the primary endpoint of this study.

Secondary objectives are included to further evaluate potential the difference or similarities in effectiveness between the treatments (disability progression, relapse rate, T25FW, 9-HPT, SDMT), to evaluate the difference in safety issues (most notably hematological complications, infections, malignancies, infusion reactions and other serious adverse events) and to evaluate the difference in patient reported outcomes by evaluation of working status, fatigue, anxiety and depressive symptoms, quality of life and treatment satisfaction (EQ-5D, MSIS-29, FSMC, and SDMT). The exploratory outcomes are included to evaluate specific blood samples and plasma biomarkers for treatment response (sNFL and CD19+ cell counts) and side effects (hypogammaglobulinemia and neutropenia) of the two treatments, differences in vaccination status (pneumococcus and/or influenza) and to determine the predictive value of BICAMS for the individual patient.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients, treatment naïve, and aged between 18 and 60 years included
2. Women of childbearing potential1 (WOCBP) able and willing to use highly effective methods of birth control2 per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly for the duration of the study OR until 3 months after last dose administered.
3. A diagnosis of RRMS according to the 2017 revised diagnostic criteria of McDonald (Thompson, Banwell et al. 2018) within the last 12 months.
4. Disease activity defined as ≥ 1 relapse3 or ≥ 1 new MRI lesion during the last 12 months
5. EDSS score ≤ 4.0
6. Absence of comorbidity or drug abuse that preclude study participation
7. Able to complete treatment or follow-up visits in the study (e.g. no contraindications for MRI or plans of moving)
8. Able to understand written and spoken Norwegian or English
9. Capable of giving signed informed consent as described in Appendix 1.2 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

1. Known hypersensitivity or other known side effects for any of the study medications, including co-medications such as high glucocorticosteroids
2. A diagnosis of primary progressive MS according to the revised diagnostic criteria of McDonald (Thompson, Banwell et al. 2018)
3. A disease course of secondary progressive MS (Lublin, Reingold et al. 2014)
4. Any ongoing infection, including tuberculosis, hepatitis virus or HIV, as well as hepatitis B surface antigen positivity and/or hepatitis C PCR positivity verified at screening visit.
5. 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.
6. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhythmia, unstable or advanced ischemic heart disease (NYHA III or IV)
7. Active malignancy or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
8. WBC \< 1.5 x 109/L if not caused by a reversible effect of documented ongoing medication. If WBC \< 1.5 x 109/L is caused by a reversible effect of documented ongoing medication the WBC count must be \> 1,5 x 109/L before start of study treatment.
9. Platelet (thrombocyte) count \< 100 x 109/L
10. ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)
11. Serum creatinine \> 200 µmol/L
12. Serum bilirubin \> ULN
13. Pregnancy or lactating female patients
14. Any disease that can influence the patient safety and compliance, or the evaluation of disability
15. History of serious or life-threatening infusion reaction to ocrelizumab or rituximab, if previously treated with these medications for other diseases than MS
16. Previous use of MS-therapies such as natalizumab, fingolimod, interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, cladribine, rituximab, alemtuzumab, ocrelizumab, hematopoietic stem cell therapy (HSCT) or other immunosuppression therapies with long lasting effects, or any other disease modifying therapy (DMT) for MS. If any of these medications have been used against other diseases than MS, patients can be included if the medications have not been used the previous year before enrollment.
17. Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study (s), or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded.
18. Presence of metallic objects implanted in the body, or allergy to MRI contrast that would preclude the ability of the patient to safely have MRI exams
19. Current alcohol or drug dependencies

Primary outcomes:
measure: Proportion without new MRI activity
timeFrame: From month 6 (re-baseline) to month 24
Secondary outcomes:
measure: Proportion of patients with 6-months confirmed disability progression (6M-CDP)
timeFrame: From baseline to month 24
measure: Proportion of patients with 6-months confirmed disability improvement (6M-CDI)
timeFrame: From baseline to month 24
measure: Annual relapse rate
timeFrame: From baseline to month 24
measure: Proportion of patients without relapses
timeFrame: From baseline to month 24
measure: Proportion of patients with 6M-CDP in T25FW
timeFrame: From baseline to month 24
measure: Proportion of patients with 6M-CDP in 9-HPT
timeFrame: From baseline to month 24
measure: Proportion of patients with 6M-CDP in SDMT
timeFrame: From baseline to month 24
measure: Proportion of patients with no new or enlarging T2-weighted brain MRI lesions
timeFrame: From baseline to month 6, and from baseline to month 24
measure: Proportion of patients without new gadolinium enhancing T1-weighted brain MRI lesions
timeFrame: At month 6, month 12 and month 24
measure: Change in brain volumes
timeFrame: From baseline to month 24 and from month 6 to month 24
measure: Frequency of SAE/SAR and AESI during 24 months of treatment
timeFrame: From baseline to month 24
measure: The frequency of immediate and delayed infusion reactions
timeFrame: From baseline to month 24
measure: Frequency of infections
timeFrame: From baseline to month 24
measure: The frequency any malignancies
timeFrame: From baseline to month 24
measure: Change in the quality of life (MSIS-29)
timeFrame: From baseline to month 24
measure: Change in Health related Anxiety and Depression as measured by HADS
timeFrame: From baseline to month 24
measure: Change in the fatigue (FSMC)
timeFrame: From baseline to month 24
measure: Change in EQ-5D score
timeFrame: From baseline to month 24
measure: Change in employment status
timeFrame: From baseline to month 24
measure: The frequency of anti-drug-antibodies
timeFrame: From baseline to month 24
Other outcomes:
measure: Proportion of patients with hypogammaglobinemia
timeFrame: From baseline to month 24
measure: The proportion of patients with neutropenia
timeFrame: From baseline to month 24
measure: Level and duration of B cell depletion
timeFrame: From baseline to month 24
measure: Level of CD27+ depletion
timeFrame: From baseline to month 24
measure: Change in serum levels of neurofilament (Nfl)
timeFrame: From baseline to month 24
measure: Influence of different FcR genotypes
timeFrame: From baseline to month 24
measure: Influence of serum levels of vitamin D
timeFrame: From baseline to month 24
measure: Change in cognition as measured by BICAMS
timeFrame: From baseline to month 24
measure: Vaccination response
timeFrame: From baseline to month 24
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Bodø
country: Norway
facility: Nordlandsykehuset HF
city: Drammen
country: Norway
facility: Vestre Viken syekhus
city: Kristiansand
country: Norway
facility: Sørlandet Sykehus
city: Molde
country: Norway
facility: Molde sjukehus
city: Namsos
country: Norway
facility: Sykehuset Namsos
city: Oslo
country: Norway
facility: Oslo University Hospital HF
city: Oslo
country: Norway
facility: Akershus University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Skien
country: Norway
facility: Sykehuset Telemark
city: Stavanger
country: Norway
facility: Stavanger University Hospital HF
city: Tromsø
country: Norway
facility: University Hospital North Norway HF
city: Tromsø
country: Norway
facility: University Hospital North Norway
city: Trondheim
country: Norway
facility: St. Olavs Hospital
city: Stockholm
country: Sweden
facility: Karolinska Hospital
Study officials:
affiliation: Haukeland University Hospital
name: Kjell-Morten Myhr, MD
role: STUDY_DIRECTOR
affiliation: Haukeland University Hospital
name: Øivind Torkildsen, MD
role: PRINCIPAL_INVESTIGATOR
References: