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| Name | Class |
|---|---|
| University Hospital, Akershus | OTHER |
| Oslo University Hospital | OTHER |
| Helse Stavanger HF | OTHER_GOV |
| St. Olavs Hospital |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rituximab | Experimental | Rituximab will be given as infusion at week 0, week 26, week 52, week 78, and week 104 unless there is a reason for schedule modifications (see Section 6.3). Each infusion is given over approximately 4 hours and follow local guidelines for infusion. Initial dose; 1000 mg Subsequent doses; 500 mg |
|
| Ocrelizumab | Active Comparator | Ocrelizumab will be given as infusion at week 0, week 26, week 52, week 78, and week 104 unless there is a reason for schedule modifications (see Section 6.3). Each infusion is given over approximately 4 hours and follow local guidelines for infusion. Initial and subsequent doses; 600 mg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Drug | 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. Active substance is biosimilar rituximab iv infusion and comparator is ocrelizumab (Ocrevus ®) iv infusion. Both treatments are given as infusion at month 0, month 6, month 12, month 18 and month 24. Randomization rituximab: ocrelizumab is 3:2. The primary end-point is proportion of patients with no new or enlarging T2-weighted brain MRI lesions between re-baselining at month 6 and month 24. |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion without new MRI activity | Proportion of patients with no new or enlarging T2-weighted brain MRI lesions | From month 6 (re-baseline) to month 24 |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of patients with 6-months confirmed disability progression (6M-CDP) | Proportion of patients with 6-months confirmed disability progression (6M-CDP) as measured by the Expanded disability status scale (EDSS) (Kurtzke 1983) from baseline to month 24. CDP-EDSS defined as an increase of one point in the EDSS score confirmed after 6 months, with an absence of relapse at the time of assessment. |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of patients with hypogammaglobinemia | The proportion of patients with hypogammaglobinemia during 24 months of treatment | From baseline to month 24 |
| The proportion of patients with neutropenia |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kjell-Morten Myhr, MD | Haukeland University Hospital | Study Director |
| Øivind Torkildsen, MD | Haukeland University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Haukeland University Hospital | Bergen | Norway | ||||
| Nordlandsykehuset HF |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42384870 | Derived | Torkildsen O, Brustad HK, Hogestol EA, Alstadhaug KB, Bhan A, Flemmen HO, Habbestad A, Hoglund RAA, LeBlanc M, Lopen P, Lorentzen AR, Morsund AH, Lossius A, Lundby R, Nygaard GO, Rod BE, Simonsen CS, Steffensen L, Torgauten H, Piehl F, Wergeland S, Myhr KM; OVERLORD-MS Investigators. Rituximab versus Ocrelizumab in Newly Diagnosed Relapsing Multiple Sclerosis. N Engl J Med. 2026 Jul 2;395(1):44-53. doi: 10.1056/NEJMoa2600993. |
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| ID | Term |
|---|---|
| D020529 | Multiple Sclerosis, Relapsing-Remitting |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| C533411 | ocrelizumab |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| OTHER |
| University Hospital of North Norway | OTHER |
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.
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The investigators as well as the study participants, are blinded to the treatment allocation status. To assure this double-blinding, a dedicated "treating nurse" will be appointed at each study centre. Information about randomization (treatment arm) will be given directly through electronic communication (automatic generated email) from Viedoc™ to the treating nurse as soon as the randomization procedure has been performed. Only the treating nurse will have access to information concerning which treatment arm the patient is allocated to.
The treating nurse will order the medicine from the pharmacy and perform the dilution in NaCl (in an infusion bag).
An evaluating nurse and evaluating neurologist (blinded to study drug) will perform the clinical evaluation of the patient while the patient receives the medication and as part of registration of study information. The evaluating neurologist and evaluating nurse will not be able to access the randomization procedure in Viedoc™.
|
|
| Ocrelizumab | Drug | 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. Active substance is biosimilar rituximab iv infusion and comparator is ocrelizumab (Ocrevus ®) iv infusion. Both treatments are given as infusion at month 0, month 6, month 12, month 18 and month 24. Randomization rituximab: ocrelizumab is 3:2. The primary end-point is proportion of patients with no new or enlarging T2-weighted brain MRI lesions between re-baselining at month 6 and month 24. |
|
|
| From baseline to month 24 |
| Proportion of patients with 6-months confirmed disability improvement (6M-CDI) | Proportion of patients with 6-months confirmed disability improvement (6M-CDI) as measured by the Expanded disability status scale (EDSS) (Kurtzke 1983) from baseline to month 24. CDI-EDSS is defined as a decrease of one point in the EDSS score, confirmed after 6 months, with an absence of relapse at the time of assessment. | From baseline to month 24 |
| Annual relapse rate | The annual relapse rate from baseline to month 24 | From baseline to month 24 |
| Proportion of patients without relapses | Proportion of patients without relapses from baseline to month 24 | From baseline to month 24 |
| Proportion of patients with 6M-CDP in T25FW | Proportion of patients with 6M-CDP in T25FW (Cutter, Baier et al. 1999) from baseline to month 24. 6M-CDP in T25FW is defined as patients experiencing an increase of ≥20% from baseline which is confirmed after 6 months (Bosma, Kragt et al. 2010, Motl, Cohen et al. 2017). | From baseline to month 24 |
| Proportion of patients with 6M-CDP in 9-HPT | Proportion of patients with 6M-CDP in 9-HPT (Cutter, Baier et al. 1999) 8.2.6) from baseline to month 24. 6M-CDP in 9HPT is defined as patients experiencing an increase of ≥20% from baseline which is confirmed after 6 months (Bosma, Kragt et al. 2010, Feys, Lamers et al. 2017). | From baseline to month 24 |
| Proportion of patients with 6M-CDP in SDMT | Proportion of patients with 6M-CDP in SDMT from baseline to month 24. SDMT is defined as patients experiencing a reduction of 15% from baseline which is confirmed after 6 months (Strober, DeLuca et al. 2019, Marstrand, Osterberg et al. 2020) | From baseline to month 24 |
| Proportion of patients with no new or enlarging T2-weighted brain MRI lesions | Proportion of patients with no new or enlarging T2-weighted brain MRI lesions from baseline to month 6, and from baseline to month 24 | From baseline to month 6, and from baseline to month 24 |
| Proportion of patients without new gadolinium enhancing T1-weighted brain MRI lesions | Proportion of patients without new gadolinium enhancing T1-weighted brain MRI lesions at month 6, month 12 and month 24 | At month 6, month 12 and month 24 |
| Change in brain volumes | Change in brain volumes from baseline to month 24 and from month 6 to month 24 | From baseline to month 24 and from month 6 to month 24 |
| Frequency of SAE/SAR and AESI during 24 months of treatment | Overall safety during 24 months of treatment | From baseline to month 24 |
| The frequency of immediate and delayed infusion reactions | The frequency of immediate and delayed infusion reactions during 24 months of treatment | From baseline to month 24 |
| Frequency of infections | The frequency of infections during 24 months of treatment | From baseline to month 24 |
| The frequency any malignancies | The frequency any malignancies during 24 months of treatment | From baseline to month 24 |
| Change in the quality of life (MSIS-29) | The Multiple Sclerosis Impact Scale (MSIS-29) is a 29-item self-report measure comprising 20 items associated with a physical scale and 9 items associated with a psychological scale, also translated and validated in Norwegian. Patients are asked about the impact of MS on day-to-day life in the last 2 weeks. All items have 5 response options from 1 (not at all) to 5 (extremely). Each of the 2 scales are scored by adding up the responses across items, then converting to a 0 to 100 scale, where 100 indicates greater impact of disease on daily function (worse health). | From baseline to month 24 |
| Change in Health related Anxiety and Depression as measured by HADS | The Hospital Anxiety and Depression Scale (HADS) is a questionnaire developed to screen anxiety and depression among patients in hospital settings. It consists of two subscales, one measuring anxiety, with seven items, and another measuring depression, with seven items. The two subscales are scored separately. The scale has been validated for use among MS patients as a screening instrument for symptoms of psychological distress. Higher scores indicate higher levels of anxiety and depression. | From baseline to month 24 |
| Change in the fatigue (FSMC) | The Fatigue scale for motor and cognitive functions (FSMC) is a method for evaluating fatigue in multiple sclerosis and other neurological conditions. The FSMC was developed and validated on a large sample of MS patients and healthy controls and includes subscales for both physical (motor) and mental (cognitive) aspects of fatigue. It was tested against 2 other validated fatigue scales (Fatigue Severity Scale and Modified Fatigue Impact Scale), and found to have better sensitivity and specificity than either of these instruments (Penner, Raselli et al. 2009). The FSMC has also undergone linguistic validation in over 20 languages, including Norwegian. | From baseline to month 24 |
| Change in EQ-5D score | The EQ-5D-5L self-report questionnaire essentially consists of 2 pages comprising:
| From baseline to month 24 |
| Change in employment status | Patients will be asked about employment status at each visit (according to the following criteria: employed, unemployed, part-time employed, disability pension). | From baseline to month 24 |
| The frequency of anti-drug-antibodies | The frequency of anti-drug-antibodies during 24 months of treatment | From baseline to month 24 |
The proportion of patients with neutropenia during 24 months of treatment
| From baseline to month 24 |
| Level and duration of B cell depletion | The level and duration of B cell depletion during 24 months of treatment | From baseline to month 24 |
| Level of CD27+ depletion | The level of CD27+ B memory cell depletion during 24 months of treatment | From baseline to month 24 |
| Change in serum levels of neurofilament (Nfl) | Change in serum levels of neurofilament (Nfl) during 24 months of treatment | From baseline to month 24 |
| Influence of different FcR genotypes | The influence of different FcR genotypes on B-cell depletion during 24 months of treatment | From baseline to month 24 |
| Influence of serum levels of vitamin D | The influence of serum levels of vitamin D on efficacy during 24 months of treatment | From baseline to month 24 |
| Change in cognition as measured by BICAMS | The BICAMS is a brief cognitive assessment that can be used also in study sites with staff members with no neuropsychological training (Walker, Osman et al. 2016) The tests address specific cognitive deficits that are common in MS patients, and the scales were chosen also for their psychometric qualities (reliability, validity and sensitivity) (Langdon, Amato et al. 2012). Tests must be administered during daytime, in a standardized manner, and in a quiet room. The order of tests will be fixed: the Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), and California Verbal Learning Test-II (CVLT-II). BICAMS has been validated for use in Norwegian MS-patients | From baseline to month 24 |
| Vaccination response | Vaccination response as measured by specific pneumococcus and/or influenza antibody titres in vaccinated patients during 24 months of treatment | From baseline to month 24 |
| Bodø |
| Norway |
| Vestre Viken sykehus | Drammen | Norway |
| Sørlandet Sykehus | Kristiansand | Norway |
| Molde sjukehus | Molde | Norway |
| Sykehuset Namsos | Namsos | Norway |
| Oslo University Hospital HF | Oslo | 0424 | Norway |
| Akershus University Hospital | Oslo | 1478 | Norway |
| Sykehuset Telemark | Skien | Norway |
| Stavanger University Hospital HF | Stavanger | 4068 | Norway |
| University Hospital North Norway | Tromsø | Norway |
| Karolinska Hospital | Stockholm | Sweden |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |