Systemic lupus erythematosus MedDRA version: 17.0 Level: LLT Classification code 10025139 Term: Lupus erythematosus systemic System Organ Class: 100000004859
Conditions
Interventions
Trade Name: rituximab
Product Name: Rituximab
Pharmaceutical Form: Infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Sponsors
Leiden University Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 4.1. Inclusion criteria Subjects enrolled in the study must meet the following inclusion criteria: 1) age 18 years, 2) ACR diagnosis of SLE (1997 revised criteria, see appendix 1) 3) Severe SLE flare at screening (see also section 5.2.3.2.), defined as a situation in which 1 or more of the following criteria are met: - Increase in SLEDAI (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, trombocytopenia 6 points) despite conventional immunosuppressive treatment and 1 or more of the following criteria: - failure of the initial induction treatment at six months, for which a switch to another induction therapy regime has already been carried out; - intolerance or contraindication for cyclophosphamide and mycophenolate mofetil (MMF); - exceeding a cumulative dose of 15 gram of cyclophosphamide; - a second relapse within two years after start of the initial induction therapy - a relative contraindication for high-dose oral or intravenous (iv) prednisone, such as avascular osteonecrosis, previous psychosis on corticosteroids, osteoporosis and/or severe obesity (BMI =35 kg/m2). 5) 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. 6) 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. 7) Immune-complex mediated complement usage, as defined by: - a low C3 serum level = 0.9 g/L; OR - a low C4 serum level = 95 mg/L; OR - a reduced activation of the classical pathway =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Subjects will be excluded from participation if they meet any of the following exclusion criteria: 1) Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG 2) Significant B-cell depletion (peripheral B-cell counts < 60x10E6) 3) Significant hypogammaglobulinemia (IgG < 8.0 g/L) 4) Immunization with a live vaccine 1 month before screening 5) Active infection at time of screening, as follows: - Hospitalization for treatment of infection within previous 2 months 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 2 months of day 0 of the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: In this proof-of-concept study the primary objective is to assess whether a combination treatment ofrituximab (anti-CD20) and belimumab (anti-BAFF) will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation, which portentially forms the basis of a new therapeutic approach in severe SLE. ;Secondary Objective: Secondary goals are to evaluate clinical improvement, reduction of circulating immune complexes, safety and feasibility.; Primary end point(s): In this proof-of-concept study the primary objective is to assess whether a combination treatment of rituximab and belimumab will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation. Therefore, the primary endpoints are: - a sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start - an inhibition of the formation of NETs at 24 weeks after treatment start ;Timepoint(s) of evaluation of this end point: at 24 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The main secondary objective is to evaluate the effects of long-term B-cell depletion which will involve assessments of the clinical response correlated with immunological parameters. To this end, the relevant study parameters will be evaluated after 4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term). The secondary endpoints measured at these times are: - the effects on the reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies - the inhibition of the formation of NETs - seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies - the normalization of complement usage, i.e. C3/C4 levels and C1Q-binding Other secondary objectives are to evaluate: - the safety and feasibility of the combination treatment according to the WHO toxicity criteria - the clinical response of refractory SLE patients upon long-term B-cell depletion by: * a reduction in SLEDAI scores, no new BILAG A involvement and the SLE responder index * in case of lupus nephritis: the number of partial and complete renal responders * the number of moderate or severe flares and renal flares ;Timepoint(s) of evaluation of this end point: 4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term). | — |
Countries
Netherlands
Contacts
Public ContactTeng
Leiden University Medical Center
Outcome results
None listed