B-lymphocyte Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Multicentre, Randomized, Double-blind and Placebo Controlled Phase-III Study With Rituximab Induction and Maintenance Treatment.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 151
- 试验地点
- 5
- 主要终点
- Fatigue score, selfreported.
研究概览
简要总结
The hypothesis is that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system and may benefit from B-lymphocyte treatment using the monoclonal anti-CD20 antibody rituximab with induction and maintenance treatment.
详细描述
We have published a case series of pilot patient observations with B-cell depletion in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) (Fluge and Mella, BMC Neurol, 2009). Subsequently, we published a small randomized and double-blind phase II study using rituximab induction two infusions two weeks apart (Fluge et al, Plos One, 2011).
We have completed an open label phase II study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished).
We hypothesize that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system involving B-lymphocytes, possibly a variant of an autoimmune disease, and that patients may benefit from B-cell depletion therapy.
Three substudies will be performed:
Endothelial function: assessment of Flow-Mediated Dilation and skin microcirculation at baseline and repeated during the time interval 17-21 months.
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)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) according to Canadian diagnostic criteria (Carruthers, 2003)
- •Duration of CFS/ME disease 2-15 years. For patients with mild CFS/ME duration of disease must be 5-15 years.
- •Mild, Mild/Moderate, Moderate, Moderate/Severe and Severe CFS/ME may be included
- •Signed informed consent
排除标准
- •Patients with fatigue, who do not comply with Canadian diagnostic criteria (2003)
- •Duration of CFS/ME < 2 years or >15 years
- •Patients with very severe CFS/ME
- •Pregnancy or lactation.
- •Previous malignant disease (except basal cell carcinoma in skin or uterine cervical dysplasia)
- •Previous treatment with B-lymphocyte depleting therapeutic monoclonal antibodies, such as rituximab
- •Previous long-term systemic immunosuppressive treatment, including drugs such as cyclosporine, azathioprine, mycophenolate mofetil, but except steroid treatment e.g. for obstructive lung disease or for other autoimmune diseases such as ulcerative colitis
- •Severe endogenous depression
- •Lack of ability to adhere to protocol
- •Known multi-allergy with clinically assessed risk from rituximab infusion
- •Reduced kidney function (serum creatinine > 1,5x upper normal level)
- •Reduced liver function (serum bilirubin or transaminases > 1,5x upper normal level)
- •Known HIV positivity, previous hepatitis B or hepatitis C
- •Evidence of ongoing, active and clinically relevant infection
- •Known immunodeficiency with risk from therapeutic B-cell depletion, such as hypogammaglobulinemia
研究组 & 干预措施
Rituximab
Rituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months)
干预措施: Rituximab (Drug)
Placebo
Saline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months.
干预措施: Placebo (Drug)
结局指标
主要结局
Fatigue score, selfreported.
时间窗: Course of Fatigue score during 24 months follow-up.
Selfreported Fatigue score is registered every second week, as the mean score for the four symptoms: "Post-exertional malaise", "Fatigue", "Need for rest", "Daily functioning" (scale 0-6). Mean Fatigue scores for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are recorded for each patient. These data are used for statistical analysis. The difference in course of Fatigue score during 24 months follow-up, between the rituximab and placebo groups, will constitute the primary endpoint. Overall response is recorded as the effect on CFS/ME symptoms during 24 months follow-up. The overall response is not predefined to a specific time interval, but is defined as mean Fatigue score at least 4.5 for at least 8 consecutive weeks for moderate response, and mean Fatigue score at least 5.0 for at least 8 consecutive weeks for major response. Single response periods and the sum of response periods during 24 months follow-up will be recorded.
次要结局
- Short Form-36 (SF-36)(Changes in SF-36 scores during 24 months follow-up)
- Physical activity (Sensewear armband)(Analyzed at baseline and at interval 17-21 months)
- Self-recorded "Function level"(Course during 24 months follow-up)
- Fatigue Severity Scale(24 months)
- Clinical response duration(During 24 months follow-up)
- Sustained clinical response at 24 months(Assessment at 24 months)