A Randomized Trial to Investigate the Reset of Humoral Autoimmunity by Combining Belimumab with Rituximab in Severe Systemic Lupus Erythematosus
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 70
- 试验地点
- 4
- 主要终点
- Treatment failure rate
研究概览
简要总结
In follow-up of the previous SynBioSe Study the present study is a randomized controlled trial designed to further investigate the long-term clinical and imunological efficacy of combination B-cell targeting by starting treatment with belimumab (anti-BAFF) followed by rituximab(anti-CD20) in lupus nephritis patients.
详细描述
Rationale:
The SynBioSe-1 study is the first study to comprehensively describe the clinical and immunological effects of combining rituximab (RTX) and belimumab (BLM) in patients with systemic lupus erythematosus (SLE). From the pioneering SynBioSe-1 study, we have learned that combining RTX+BLM was safe and well-tolerated with important clinical responses. Immunologically, we unexpectedly observed that long-term B-cell depletion was not achieved due to migration of mature B-cells triggered by depletion of BAFF serum levels. The latter observation was in contrast to the study's null-hypothesis that combination therapy would lead to long-term B-cell depletion. The contrary was demonstrated, namely the relative early recirculation of mature B-cells. As such, the immunological and clinical lessons from the SynBioSe-1 study in conjunction with accumulating data from several large studies on combination B-cell targeted treatment have led to the postulation that starting treatment with RTX+BLM would result in an improved B-cell targeting strategy, notably on tissue-resident autoreactive B-cells, associated with improved long-term clinical disease amelioration. Therefore, the present SynBioSe-2 study is designed to further investigate the long-term clinical and imunological efficacy of combination B-cell targeting by starting treatment with belimumab followed by rituximab.
Objectives:
The primary objective is to assess whether combination treatment BLM+RTX will lead to reduced treatment failure and the improvement of pivotal, SLE-specific autoimmune phenomena compared to SLE patients treated with standard of care.
Study design:
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Have a clinical diagnosis of SLE according to the SLICC criteria 2012
- •Severe, active SLE disease defined as a situation in which 1 or more of the following criteria are met:
- •SLEDAI-2K (SLE Disease Activity Index) with 12 or more points
- •New or worse SLE-related activity of major organs, i.e.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, thrombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL)
- •high disease activity that requires or warrants induction treatment by switching to or increasing dosage of oral mycophenolate
- •New, persisting or progressive disease activity despite the use of conventional maintenance immunosuppressive treatment (e.g. mycophenolate or azathioprine)
- •Positive for relevant SLE-specific autoantibodies defined as a situation in which 1 or more of the following criteria are met:
- •ANA seropositivity, as defined by a positive ANA-titer ≥ 1:80, before and at screening :
- •Positive test results from 2 independent time points within the study screening period; OR
- •One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer, ANA by ELISA) must include the date of the test.
- •Anti-DNA seropositivity, as defined by a positive anti-dsDNA serum antibody ≥ 30 IU/mL, before and at screening:
- •Positive test results from 2 independent time points within the study screening period.
- •One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA) must include the date of the test.
- •Female subjects are eligible to enter the study if she is:
- •Not pregnant or nursing
- •Of non-child-bearing potential (i.e. after hysterectomy, postmenopausal, bilateral ovariectomy or documented bilateral tubal ligation or other permanent female sterilization procedure)
- •in agreement to not become pregnant (if female subjects of childbearing potential) and therefore must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.
排除标准
- •Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
- •Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
- •Immunization with a live vaccine 1 month before screening
- •Active infection at time of screening, as follows:
- •Hospitalization for treatment of infection within previous 60 days of day 0 of the study
- •Use of parenteral (intravenous of intramuscular) antibiotics (including anti-bacterials, anti-virals, anti-fungals or anti-parasitic agents) within previous 60 days of day 0 of the study
- •Serological evidence of viral hepatitis defined as: patients positive for HbsAg test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication
- •Have a historically positive HIV test or test positive at screening for HIV
- •Have a history of a primary immunodeficiency
- •Have a neutrophil count of < 1.5x10E9/L
- •Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study
- •Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
- •Have any other clinically significant abnormal laboratory value in the opinion of the investigator
- •Have current drugs or alcohol abuse or dependence within 365 days prior to Day 0 of the study
- •Have an active malignant neoplasm or one in the history of the last 5 years, except basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years
- •Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who, in the investigator's opinion, poses a significant suicide risk
- •Have any other clinically significant abnormal laboratory value, any intercurrent significant medical or psychiatric illness that in the opinion of the investigator would make the candidate unsuitable for the study
研究组 & 干预措施
BLM+RTX treatment arm
Intervention 1 Belimumab injection: subcutaneous weekly injections with 200mg belimumab (BML) for the duration of the entire study period of two years.
Intervention 2 Rituximab infusion: Two intravenously infusions of 1000mg rituximab (RTX) at week 4 and week 6 after the start of belimumab.
Intervention 3: Standard of care: induction therapy with three intravenously infusions methylprednisolone of 1000mg (or 500mg if weight is below 60kg), oral prednisolone 60mg with a quick tapering scheme to reach 5mg in 10 weeks and mycofenolate mofetil start dosis 500mg twice daily with maximum dosis of 2000mg twice daily depending on tolerance and area under curve (AUC) aimed at 60mg*hour/L.
干预措施: Belimumab Injection (Drug)
结局指标
主要结局
Treatment failure rate
时间窗: 2 years
The treatment failure rate will be measured at 104 weeks in both treatment arms with the hypothesis that lower treatment failure rates will be obtained in the RTX+BLM arm.
次要结局
- Change of immune complex-mediated excessive neutrophil extracellular traps (NET) formation(28 weeks)
- Evaluation of the clinical response by SLICC(2 years)
- Evaluation of the clinical response by the amount of moderate and severe flares.(2 years)
- Change of memory B-cell numbers(28 weeks)
- Evaluation of the clinical response by QoL questionnaires(2 years)
- Evaluation of the renal response(2 years)
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability](2 years)
- Change of disease relevant auto-antibodies present at baseline, in particular anti-dsDNA(28 weeks)
- Sustained change of autoantibody production(2 years)
- Seroconversion of disease relevant auto-antibodies(2 years)
- Sustained change of memory B-cell numbers(2 years)
- Sustained change of immune complex-mediated excessive neutrophil extracellular traps (NET) formation(2 years)
- Evaluation of the clinical response by SLEDAI(2 years)
- Evaluation of the clinical response by the ability to reduce concomitant immunosuppression without flares(2 years)
研究者
Y.K.Onno Teng
Dr. Y.K.O. Teng, Nephrologist
Leiden University Medical Center