Synergetic B-cell Immodulation in SLE
Condition: Lupus Erythematosus, Systemic
MeSH terms: Lupus Erythematosus, Systemic
Study type: Interventional
Phase: Phase 2

Summary: 
      The present study investigates the potential of a new therapeutic approach in lupus nephritis
      combining rituximab (anti-CD20) and belimumab (anti-BAFF). The main goal of the study is to
      assess the reduction (and seroconversion) of pathogenic autoantibodies, to evaluate clinical
      improvement and assess the safety and feasibility of long-term B-cell depletion.
    

Detailed description: 
      Introduction Systemic lupus erythematosus (SLE) affects predominantly young women with
      childbearing potential (20-40 years) and inflammation can occur in virtually every organ,
      including kidneys, lungs, heart or brain. The disease course in SLE patients is typically
      characterized by frequent flares, requiring immunosuppressive treatment. Current,
      evidence-based treatment modalities for SLE consist of immunosuppressive treatment with high
      dose corticosteroids, cyclophosphamide or mycophenolic mycophenolate acid, that
      non-specifically target the immune system to reduce inflammation. Side-effects of these
      treatment strategies are (opportunistic) infections in the short term and risk for malignancy
      and cardiovascular disease in the long-term. Treating SLE patients with biologicals is an
      attractive alternative because biologicals specifically target the immune system by blocking
      cytokines or deplete one specific cell population, thereby reducing the risk for infections
      or malignancies as compared to conventional immunosuppressants. Furthermore, the scarce
      treatment options underscore the need to exploit new therapeutic possibilities for SLE
      patients who frequently experience a flare of the disease. These considerations led to the
      present study involving a proof-of-concept study in refractory SLE patients to assess the
      immunological consequences of a combination treatment with rituximab (anti-CD20) and
      belimumab (anti-BAFF).

      Objective of the study:

      A proof-of-concept study in refractory SLE patients to assess the immunological consequences
      of a combination treatment with rituximab (anti-CD20) and belimumab (anti-BAFF) to achieve
      long-term B-cell depletion. The immunological and clinical monitoring of refractory SLE
      patients will be monitored and the safety and feasibility of this combination treatment
      evaluated.

      Study design:

      This is a single-center, non-randomized, phase 2A, proof-of-concept study to evaluate the
      effects of a combination treatment with rituximab and belimumab. This combination therapy is
      designed to induce long-term B-cell depletion to achieve significant reduction of
      autoantibody-mediated immune complexes. In addition to standard therapy, SLE patients will
      receive 2 infusions of rituximab 1000 mg on day 0 and 14 (week 2) and belimumab on day 28
      (week 4) , 42 (week 6) and 56 (week 8), then every 28 days. The primary endpoint is at 24
      weeks after which an extended follow-up will take place, for subjects continuing belimumab,
      until 104 weeks after treatment start.

      Rituximab and Belimumab will be administered intravenously according to the manufacturer's
      instructions. Clinical and immunological parameters will be assessed every 8-12 weeks. The
      study medication is not blinded for patients nor physicians. The study intends to include 15
      refractory SLE patients.

      Study population:

      Patients with systemic lupus erythematosus, older than 18 years with refractory disease as
      specified by the inclusion criteria (mentioned above)

      Intervention:

      Rituximab Patients will be intravenously treated with Rituximab 1000mg on day 0 and day 14.
      Before every infusion of Rituximab patients will receive intravenous hydrocortisone 100mg
      together with oral acetaminophen 1000 mg and intravenous Tavegil 2 mg.

      Belimumab Patients will be intravenously treated with Belimumab 10mg/kg on day 28, day 42 and
      day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks. No pre-medication
      is administered

      Primary study parameters/outcome of the study:

      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.

      Secondary study parameters/outcome of the study:

      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 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 (British Isles Lupus Assessment Group) 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
    

Intervention name(s): Rituximab with belimumab
Intervention type(s): Drug
Intervention description(s): Rituximab treatment on dag 0 and 14, 1000mg iv Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks through 72 weeks.
Other intervention name(s): Belimumab
Intervention MeSH terms: Rituximab; Belimumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Antibodies, Monoclonal; mabthera; benlysta; Antinuclear Antibodies