Exploring Durable Remission With Rituximab in Antineutrophil Cytoplasmic Antibody(ANCA)-Associated Vasculitis
Exploring Durable Remission With Rituximab in Antineutrophil Cytoplasmic Antibody(ANCA)-Associated Vasculitis
Rationale: Most recent insights in the treatment for patients with ANCA-associated vasculitis
 (AAV) have demonstrated that 'tailored' maintenance treatment with rituximab (RTX) is
 effective to achieve durable remission of disease. As such, RTX re-treatment can be tailored
 on the basis of relevant immunological parameters that reflect minimal residual autoimmunity
 (MRA) in AAV patients. Now, the present study intends to evaluate whether combining rituximab
 with cyclophosphamide is superior to current standard of care with rituximab only to induce a
 favorable immunological state of MRA in AAV patients that can beneficially influence, i.e.
 reduce, the necessity of tailored re-treatment with rituximab
Objectives: The primary objective is to prove the superiority of combination treatment RTX
 with cyclophosphamide to achieve a state of MRA as defined as number of patients that reach
 ANCA seroconversion to negative within 24 weeks. The secondary objectives are alternative
 measurements for MRA such as time to ANCA return, duration of B-cell depletion and the
 composition of the memory B-cell and plasma cell populations.

 Study design: Open label, two-center, randomized controlled trial Study population: Adult AAV
 patients with a clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic
 polyangiitis (MPA) who have 'generalised disease' and a positive ANCA-test for
 anti-proteinase-3 (PR3) or anti-myeloperoxidase (MPO).

 Intervention: In addition to standard of care corticosteroid therapy, AAV patients will be
 randomized to receive either standard induction therapy with 2 infusions of RTX 1000 mg or
 induction therapy combining 2 infusions of RTX 1000 mg RTX with 6 infusions of low dose
 intravenous cyclophosphamide 500mg. Thereafter, as part of standard of care patients will
 receive tailored RTX re-treatment as maintenance therapy.

 Main study parameters: AAV patients will be evaluated for MRA by prospectively and
 consecutively studying ANCA levels, B-cell depletion by standard flowcytometry and subsets of
 the B-cell and plasma cell compartment with high-sensitivity flowcytometry at predefined
 timepoints. Additionally, the study will perform safety and toxicity monitoring according to
 World Health Organization (WHO) toxicity criteria and evaluate the clinical response, the
 number of RTX re-treatments and the number of moderate and severe flares during study
 follow-up.

 Study duration: 2 years
Inclusion Criteria:

 Subjects enrolled in the study must meet the following inclusion criteria:

 1. Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic
 Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26

 2. Aged at least 18 years, with newly-diagnosed or relapsed AAV with 'generalised
 disease', defined as involvement of at least one major organ (e.g. kidney, lung,
 heart, peripheral or central nervous system), requiring induction treatment with
 cyclophosphamide or rituximab

 3. Positive test for anti-PR3 or anti-MPO (current or historic)

 4. Willing and able to give written Informed Consent and to comply with the requirements
 of the study protocol