A Prospective Randomized Trial of Non-inferiority Comparing RItuximab Versus Ocrelizumab in Relapsing-remitting Multiple Sclerosis
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 386
- 试验地点
- 23
- 主要终点
- To demonstrate the non-inferiority of rituximab versus ocrelizumab in active relapsing MS patients on the percentage of patients without disease activity at 2 years.
研究概览
简要总结
The goal of this randomized clinical trial is to compare relapse remitting multiple sclerosis (RRMS) patients treated by ocrelizumab or by rituximab followed for 2 years. The main question it aims to answer is : • to demonstrate the non-inferiority of rituximab versus ocrelizumab in active relapsing MS patients on the % of patients without disease activity at 2 years.
During the 2 years, the study includes 6 follow-up visits and the completion of various health and quality of life questionnaires. The protocol visits follow the usual schedule of treatment infusions for the disease (at initiation of treatment, 15 days after, and then every 6 months).
Two comparison groups: Researchers will compare rituximab treated patients versus ocrelizumab treated patients to see the % of patients without disease activity at 2 years.
详细描述
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). This disease is the leading cause of non-traumatic disability in young adults and France is characterized by a high prevalence (currently 1/1000 inhabitants) of MS.
Clinical trials with B cell depleting therapies have shown efficacy in relapsing-remitting MS (RRMS) and are increasingly perceived as an important addition to the existing panel of Disease-modifying treatments (DMTs). Rituximab, a mouse chimeric anti CD20, is approved for non-Hodgkin's lymphoma, chronic lymphocytic leukemia, certain forms of vasculitis and Rheumatoid Arthritis with first marketing approval in 1998. Rituximab has undergone clinical testing in RRMS in 2008 in a phase II placebo-controlled trial, demonstrating the clinico-radiological efficacy in 104 patients. Despite these promising results and the absence of adverse events, its clinical development was interrupted by the manufacturer (Roche). However, for several years, rituximab has been increasingly prescribed (off-label) in Europe and USA in patients refractory to first-line therapies, with a very good safety and efficacy. Thus, rituximab is prescribed for 40% of RRMS patients treated in Sweden. Roche has then developed a humanized anti-CD20 monoclonal antibody (Ocrelizumab). Two phase III clinical trials (OPERA I and II) have demonstrated its efficacy in active RRMS. Ocrelizumab has just been authorized in France in this indication: RRMS patients with active disease (clinical or radiological). So, it can be prescribed as a first line or second line therapy in active RRMS patients.
According to literature, there are no biological arguments to think that ocrelizumab could be more effective in active RRMS compared to rituximab. Moreover, regarding safety, rituximab has been used for other indications for almost two decades and no serious concern has arisen.
The high cost of this new antibody (x6 to 10) compared to rituximab) makes it wonder about its place inside the anti-CD20 therapeutic strategy compared to rituximab for treating relapsing MS patients.
Hypothesis
Researchers hypothesize that rituximab and ocrelizumab have the same efficacy in active RRMS patients. Indeed, if the non-inferiority of rituximab on the % of patients without disease activity is confirmed by the trial, the potential medico-economic benefit from a societal perspective will be a strong argument to ask for authorization of rituximab in active RRMS.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Randomisation code transmitted to the pharmacy preparing the treatment. Blind labelling of treatments
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients presenting a relapsing remitting MS according to Mac Donald 2017 criteria, with clinical or radiological criteria of activity (ie at least one relapse AND/OR one new T2 lesion in the last 12 months before inclusion);
- •Age between 18 and 55 years
- •Brain MRI within 6 months before inclusion
- •For women of childbearing potential*: effective contraception (effective contraception include oral contraception, intrauterine devices and other forms of contraception with failure rate <1%, for the duration of the study and until 12 months after last dose administered) * A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
- •A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
- •Having signed an informed consent form
- •Patients covered with social insurance
- •Non-Inclusion Criteria:
- •Secondary or primary progressive MS;
- •Previous treatment by mitoxantrone, cladribine, alemtuzumab and anti CD20 therapies in the last two years;
- •Previous treatment by fingolimod or natalizumab in the last 4 weeks;
- •Treatment with high dose corticosteroids during the 30 days preceding the inclusion;
- •Occurrence of a relapse less than 30 days before inclusion;
- •Pregnancy or breastfeeding;
- •Other neurologic or systemic disease;
- •Concomitant participation or Participation in another therapeutic trial in the last 6 months;
- •Incapacity to understand or sign the consent form;
- •Contraindication to MRI;
- •Contraindication to anti-CD20 therapies:
- •Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization
- •Active malignancy.
- •Any ongoing infection
- •Severe heart failure (New York Heart Association Class IV) or severe uncontrolled cardiac disease
- •Positive test for HIV, hepatitis B or C, or tuberculosis
- •Severe immune deficiency:
- •Lymphopenia grade 3 (0.2 to 0.5 × 10^9/L) or higher grades
- •Neutropenia grade 3 (0.5 to 1.0 × 10^9/L) or higher grades
- •Known hypersensitivity or other known side effects for any of the study medications, including co-medications such as high glucocorticosteroids
- •AST or ALT >=3ULN
- •Platelet (thrombocyte) count < 100 x 10^9/L
- •Adults legally protected (under judicial protection, guardianship, or supervision), persons deprived of their liberty.
排除标准
- 未提供
研究组 & 干预措施
Ocrelizumab
Day 0 (300mg), Day 15(300mg), and then 300 mg every 6 months (M6, M12, M18 and M24)
干预措施: Perfusion of treatment Ocrelizumab (Drug)
Rituximab
Day 0 (1000mg), Day 15 (1000 mg), and then 500 mg every 6 months (M6, M12, M18 and M24)
干预措施: Perfusion of treatment Rituximab (Drug)
结局指标
主要结局
To demonstrate the non-inferiority of rituximab versus ocrelizumab in active relapsing MS patients on the percentage of patients without disease activity at 2 years.
时间窗: at 2 years
Percentage of patients without disease activity at 2 years (Disease activity is defined as: * At least one relapse between baseline and M24 * OR MRI activity defined as Gd enhancing lesions at M6 or as the appearance of at least one new T2 lesion between M6 and M24)
次要结局
- To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Time of onset of the first relapse(at 2 years)
- Patients quality of life : MusiQOL (Multiple Sclerosis International Quality of Life questionnaire)(From baseline (Day 0) to Month 12)
- To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Annualized relapse rate(at 2 years)
- Medico-economic impact: cost-utility ratio, QALY(At 2 years)
- Safety: Number of each adverse event(At 2 years)
- Safety: Number of each severe adverse events(At 2 years)
- To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without disability progression(at 2 years)
- Patients experience : Musicare(From baseline (Day 0) to Month 24)
- To compare the two groups (ocrelizumab vs rituximab) for Clinical Criteria : o Percentage of patients without relapse(at 2 years)
- Patients quality of life : EQ-5D-5L(From baseline (Day 0) to every six month of follow up until Month 24)
- Patients quality of life : MusiQOL(From baseline (Day 0) to Month 24)
- MRI parameters : gadolinium (Gd) enhancing lesions(at 6 month)
- MRI parameters : Mean Number of new T2 lesions(From Month 6 to Month 24)
- MRI parameters : Percentage of patients with one or more new T2 lesions(From Month 6 to Month 24)
- Patients experience : Musicare(From baseline (Day 0) to Month 12)