Ocrelizumab VErsus Rituximab Off-Label at the Onset of Relapsing
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 214
- 试验地点
- 12
- 主要终点
- Proportion without new MRI activity
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
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™.
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients, treatment naïve, and aged between 18 and 60 years included
- •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.
- •A diagnosis of RRMS according to the 2017 revised diagnostic criteria of McDonald (Thompson, Banwell et al. 2018) within the last 12 months.
- •Disease activity defined as ≥ 1 relapse3 or ≥ 1 new MRI lesion during the last 12 months
- •EDSS score ≤ 4.0
- •Absence of comorbidity or drug abuse that preclude study participation
- •Able to complete treatment or follow-up visits in the study (e.g. no contraindications for MRI or plans of moving)
- •Able to understand written and spoken Norwegian or English
- •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.
排除标准
- •Known hypersensitivity or other known side effects for any of the study medications, including co-medications such as high glucocorticosteroids
- •A diagnosis of primary progressive MS according to the revised diagnostic criteria of McDonald (Thompson, Banwell et al. 2018)
- •A disease course of secondary progressive MS (Lublin, Reingold et al. 2014)
- •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.
- •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.
- •Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhythmia, unstable or advanced ischemic heart disease (NYHA III or IV)
- •Active malignancy or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
- •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.
- •Platelet (thrombocyte) count < 100 x 109/L
- •ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)
- •Serum creatinine > 200 µmol/L
- •Serum bilirubin > ULN
- •Pregnancy or lactating female patients
- •Any disease that can influence the patient safety and compliance, or the evaluation of disability
- •History of serious or life-threatening infusion reaction to ocrelizumab or rituximab, if previously treated with these medications for other diseases than MS
- •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.
- •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.
- •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
- •Current alcohol or drug dependencies
研究组 & 干预措施
Rituximab
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
干预措施: Rituximab (Drug)
Ocrelizumab
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
干预措施: Ocrelizumab (Drug)
结局指标
主要结局
Proportion without new MRI activity
时间窗: From month 6 (re-baseline) to month 24
Proportion of patients with no new or enlarging T2-weighted brain MRI lesions
次要结局
- Proportion of patients without relapses(From baseline to month 24)
- Proportion of patients with 6M-CDP in 9-HPT(From baseline to month 24)
- Frequency of SAE/SAR and AESI during 24 months of treatment(From baseline to month 24)
- The frequency of immediate and delayed infusion reactions(From baseline to month 24)
- Proportion of patients with 6-months confirmed disability progression (6M-CDP)(From baseline to month 24)
- Annual relapse rate(From baseline to month 24)
- Proportion of patients with no new or enlarging T2-weighted brain MRI lesions(From baseline to month 6, and from baseline to month 24)
- Proportion of patients with 6-months confirmed disability improvement (6M-CDI)(From baseline to month 24)
- Proportion of patients with 6M-CDP in T25FW(From baseline to month 24)
- Proportion of patients with 6M-CDP in SDMT(From baseline to month 24)
- Proportion of patients without new gadolinium enhancing T1-weighted brain MRI lesions(At month 6, month 12 and month 24)
- Change in the fatigue (FSMC)(From baseline to month 24)
- Change in EQ-5D score(From baseline to month 24)
- Change in employment status(From baseline to month 24)
- Change in brain volumes(From baseline to month 24 and from month 6 to month 24)
- Change in the quality of life (MSIS-29)(From baseline to month 24)
- Frequency of infections(From baseline to month 24)
- The frequency any malignancies(From baseline to month 24)
- Change in Health related Anxiety and Depression as measured by HADS(From baseline to month 24)
- The frequency of anti-drug-antibodies(From baseline to month 24)