Non-Inferiority Trial of Ocrelizumab Versus Rituximab in Active Multiple Sclerosis Patients
- Trial ID
- 2024-514287-84-00
- Protocol
- DanNORMS
- Sponsor
- Region Hovedstaden
Trial statistics
Objectives
The primary objective of this study is to evaluate whether **rituximab** treatment is non-inferior to **ocrelizumab** treatment in patients with active forms of **multiple sclerosis**. This will be assessed by the primary endpoint, which is the percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24. This objective is clinically relevant as it aims to establish an alternative treatment option that may offer similar efficacy in managing disease progression in multiple sclerosis.
Secondary objectives include the evaluation of other standard efficacy and safety endpoints, as well as tertiary, explorative endpoints related to the assessment of efficacy and safety. These include blood flow cytometry, whole blood gene expression, genotyping of Fcγ-receptor or complement genes, serum neurofilament light chain (NFL), and immunoglobulin G (IgG) concentrations during the 24-month core study period. These secondary objectives are important for a comprehensive understanding of the treatment's impact on various biological markers and safety profiles.
Participants
The clinical trial involves participants diagnosed with **multiple sclerosis**, specifically targeting individuals aged between 18 and 65 years. The study population includes both male and female subjects, with no vulnerable populations being selected. Participants are required to have an Expanded Disability Status Scale (EDSS) score of 6.5 or less and must meet the criteria for active multiple sclerosis as defined by the 2017 McDonald criteria. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data. The selection process for the trial population is based on specific inclusion criteria, including treatment-naïve or previously treated relapsing-remitting multiple sclerosis (RRMS) patients and progressive multiple sclerosis patients with certain clinical or MRI criteria. Participants must have completed the first 24 months of the study to be eligible for the extended interval dosing sub-study, with no signs of active disease in the previous 18 months. The trial aims to evaluate the efficacy and safety of rituximab and ocrelizumab therapy over a long-term period.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the non-inferiority of **rituximab** compared to **ocrelizumab** in patients with active **multiple sclerosis**. The trial will span a total duration of 60 months, with an initial core study phase of 24 months followed by an extension phase of 36 months. The primary endpoint is the percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24. Secondary endpoints include the percentage of patients with 6-month confirmed disease worsening in the Expanded Disability Status Scale (EDSS) and other functional measures, as well as changes in lesion volume and serum neurofilament light chain levels.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis according to the 2017 McDonald criteria, and disease activity. The core study phase will include regular follow-up visits to monitor treatment efficacy and safety, with assessments conducted at baseline, month 6, and month 24. Upon completion of the core study, participants will be invited to continue in the extension phase, which will further evaluate long-term efficacy and safety, as well as the potential benefits of extended interval dosing.
The expected length of participant involvement is up to 60 months, contingent upon completion of both the core and extension phases. Conditions that may lead to early termination from the study include the development of significant adverse events, withdrawal of consent, or failure to adhere to study protocols. The trial aims to provide valuable insights into the comparative efficacy and safety of rituximab and ocrelizumab, potentially informing future treatment strategies for multiple sclerosis.
Treatment
The clinical trial involves the use of **Rituximab**, marketed under the name Rixathon 500 mg concentrate for solution for infusion, as an experimental treatment. This pharmaceutical form is a concentrate for solution for infusion, administered via **intravenous infusion**. The dosing regimen for Rituximab in this trial is 1000 mg every six months, with a maximum total dose of 12000 mg over a treatment period of 60 months. Rituximab is a protein-based therapeutic agent, specifically a biosimilar, and is not approved for the treatment of multiple sclerosis, which is the indication being investigated in this study. The trial aims to evaluate the efficacy of Rituximab as a monotherapy in comparison to the standard treatment.
Ocrevus, containing the active substance **Ocrelizumab**, is used as a comparator treatment in this study. It is also provided as a 300 mg concentrate for solution for infusion, administered through **intravenous infusion**. The maximum daily dose for Ocrelizumab is 600 mg, with a total maximum dose of 6600 mg over the same 60-month treatment period. Ocrelizumab is a protein-based therapeutic agent and is approved for the treatment of multiple sclerosis. The trial will compare the efficacy of Rituximab to Ocrelizumab in patients with active multiple sclerosis, focusing on the percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24.
Additionally, Ruxience, another formulation of **Rituximab**, is included in the study. Like Rixathon, Ruxience is a 500 mg concentrate for solution for infusion, administered via **intravenous infusion**. The dosing schedule mirrors that of Rixathon, with 1000 mg administered every six months and a maximum total dose of 12000 mg over 60 months. Ruxience is also a biosimilar and is not approved for the treatment of multiple sclerosis. The trial will assess the long-term efficacy and safety of Rituximab and Ocrelizumab, considering both standard dosing and extended interval dosing strategies.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24. This endpoint is crucial in determining the non-inferiority of **rituximab** treatment compared to **ocrelizumab** in patients with active multiple sclerosis. Secondary endpoints include the percentage of patients with 6-month confirmed disease worsening (CDW) in the Expanded Disability Status Scale (EDSS) from baseline to month 24, annualized relapse rate (ARR) based on the cumulative number of confirmed relapses from baseline to month 24, and the percentage of patients with 6-month CDW in the Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT) from baseline to month 24. Additional secondary endpoints involve changes in the Multiple Sclerosis Impact Scale (MSIS-29), Fatigue Scale for Motor and Cognitive Functions (FSMC), and EQ-5D from baseline to month 24, the percentage of patients without gadolinium-enhancing lesions (GdEL) on month 6 and month 24 scans, changes in T2 and T1 white matter lesion volume from month 6 to month 24, and differences in serum neurofilament light chain (NFL) from baseline to month 24.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Inclusion criteria for core study: • Age ≥18 and ≤65 years • MS diagnosis and definition of disease course according to the 2017 McDonald criteria • Expanded disability status scale (EDSS) ≤6.5 • Fulfilling criteria for active MS: o Treatment naïve RRMS patients (never treated, or no DMT the previous 3 months):≥2 relapse previous 12 months OR ≥1 relapse previous 12 months AND ≥9 T2 lesions on brain and/or spinal MRI AND ≥1 contrast-enhancing lesion or ≥1 new or enlarging T2 lesion on brain and/or spinal MRI previous 12 month o Previously treated RRMS patients: ≥1 relapse previous 12 months OR ≥1 contrast-enhancing lesion or ≥2 new/enlarging T2 lesions on brain MRI previous 12 months o Progressive MS patients: ≥1 relapse previous 12 months OR ≥1 contrast-enhancing lesion previous 12 months or ≥1new/enlarging T2 lesions on brain MRI previous 12 months or ≥2 new or enlarging T2 lesion on brain MRI previous 24 months OR Increased levels of neurofilament light chain in serum or cerebrospinal on sample collected previous 12 months Progressive MS patients not fulfilling the clinical/MRI criteria for active disease, may qualify for inclusion in the study if sNFL or CSF NFL levels is elevated: • Signed written informed consent long-term follow-up phase of the study: Inclusion criteria for extended interval dosing sub-study though randomisation • Completed the first 24 months of the study • No signs of active disease the previous 18 months • Signed written informed consent Inclusion criteria for extended interval dosing outside the randomisation process • Completed the first 24 months of the study • Recommended by physician to switch to extended interval dosing due to Low IgG (<6,1 g/L) or Frequent infections • No signs of active disease the previous 18 months • Signed written informed consent
Exclusion Criteria
- Pregnancy or breast feeding • Lack of effective contraception (failure rate <1%) for women of child-bearing potential • Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization • Active malignant disease in the previous 5 years • Positive test for HIV, hepatitis B or C, or tuberculosis • Negative test for varicella zoster • Lymphopenia grade 2 (0.5 to 0.8 × 109/L) or higher grades of lymphopenia (in case of switching from fingolimod, siponimod or ozanimod lymphopenia is accepted at screening visit (note that treatment with interferon-beta can induce transient lymphopenia) • Neutropenia grade 2 (1.0 to 1.5 × 109/L) or higher grades • Thrombocytopenia grade 2 (50 to 75 × 109/L) or higher grades • Previous treatment with alemtuzumab or hematopoietic stem-cell transplantation • Previous treatment with cladribine, CD20-depleting antibodies, daclizumab or other immune suppressive treatment which is judged to still exert immune suppressive effect by treating physician • Methylprednisolone treatment 4 weeks within baseline visit and baseline MRI scan • Findings on the screening MRI (for patients without MRI scan of the brain the previous 12 months the baseline MRI scan is also used as screening MRI) judged to preclude participation by the treating physician • Other diseases judged to be relevant by the treating physician • Contraindication to MRI • Known allergy or hypersensitivity to rituximab or ocrelizumab
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 28 Apr 2021 | 600 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Rixathon 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 60 | PRD6060692 |
Ocrevus 300 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 600 | 60 | PRD5771848 |
Ruxience 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 60 | PRD7980794 |