Synergetic B-cell Immunomodulation in SLE - 2nd Study.

  • STATUS
    Recruiting
  • End date
    Sep 7, 2025
  • participants needed
    70
  • sponsor
    Leiden University Medical Center
Updated on 7 March 2021
rituximab
immunosuppressive agents
elisa
myositis
vasculitis
azathioprine
mycophenolate
belimumab
pericarditis
nephritis
baff
anti-dna antibodies

Summary

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.

Description

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:

a multi-center, randomized, controlled, open-label study

Study population:

SLE patients with a severe flare with major organ involvement or persistent high disease activity despite conventional treatment

Intervention

In addition to standard therapy, SLE patients will receive self-administered, subcutaneous injections of belimumab every week for the entire study period and 2 infusions of rituximab 1000 mg on day 28 (week 4) and day 42 (week 6).

Main study parameters:

The primary clinical efficacy parameter is the treatment failure rate during the 2 years study period. Secondary endpoints are clinical and non-biased immunological effects of the treatment summarized as follows: reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibody production at 28 weeks, total renal response rate at 28 weeks, regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation at 28 weeks; sustained, long-term B-cell depletion during 104 weeks; sustained reduction of relevant anti-nuclear autoantibodies, including seroconversion during 104 weeks; and sustained regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation during 104 weeks. Additionally, the study will perform safety and toxicity monitoring according to Common toxicity Criteria (CTC) developed by the National Cancer Institute (NCI) with the use of Common Terminology Criteria for Adverse Events (CTCAE) and evaluate the reduction of concomitant immunosuppression and the number of moderate and severe flares during study follow-up.

Study duration: 104 weeks.

Nature and extent of the burden and risks associated with participation and potential

benefits

The study will include SLE patients with a severe flare necessitating remission induction treatment with intensive immunosuppression. The use of belimumab followed by rituximab can ameliorate disease activity even more than conventional treatment in the short-term and contribute to the successful tapering of concomitant immunosuppressive treatment. The latter will possibly lead to the reduction of infectious complication as compared to conventional treatment. The risks are predominantly related to the side effect profile of rituximab and belimumab and infectious complications of long-term B-cell depletion.

Details
Condition SYSTEMIC LUPUS ERYTHEMATOSUS
Treatment Belimumab Injection
Clinical Study IdentifierNCT03747159
SponsorLeiden University Medical Center
Last Modified on7 March 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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%

Exclusion Criteria

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
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