Combining rituximab with cyclophosphamide for treating ANCA-associated vasculitis

Evaluating Clinical and Immunological Effects of Rituximab With Cyclophosphamide Compared to Rituximab Alone in AAV Patients

This study is testing if combining two medications, rituximab and low-dose cyclophosphamide, can help people with ANCA-associated vasculitis need fewer treatments to stay in remission.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 100 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Leiden University Medical Center (Academic / other)
• Drugs / interventions: rituximab, cyclophosphamide
• Locations: 4 sites (Leiden, Zuid-Holland and 3 other locations)
• Trial ID: NCT03942887 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness of combining rituximab (RTX) with low-dose cyclophosphamide (CYC) compared to RTX alone in patients with ANCA-associated vasculitis (AAV). The primary goal is to determine if this combination reduces the number of RTX infusions needed to maintain remission over two years. The study is open-label, multicenter, and involves a 1:1 randomization of adult patients diagnosed with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Secondary objectives include assessing minimal residual auto-immunity and the relationship between auto-immunity and disease flares.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with newly-diagnosed or relapsed AAV involving major organs and a positive ANCA test.

Not a fit: Patients who are pregnant, breastfeeding, or have significant hypogammaglobulinemia will not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to fewer treatments needed to maintain remission in AAV patients, improving their quality of life.

How similar studies have performed: Other studies have shown promising results with rituximab in AAV treatment, but this specific combination approach is novel.

Eligibility criteria

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

Exclusion criteria:

Subjects will be excluded from participation if they meet any of the following exclusion criteria:

1. Pregnant or breast-feeding
2. Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
3. Significant hypogammaglobulinemia (IgG \< 4.0 g/L) or an IgA deficiency (IgA \< 0.1 g/L)
4. Active infection not compatible with start of remission-induction therapy in the opinion of the treating physician and/or investigator, e.g.:

   * 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
5. Have a history of a primary immunodeficiency
6. Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study
7. Have a neutrophil count of \< 1.5x10E9/L
8. Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin \> 3 times the upper limit of normal before start of dosing
9. Have any other clinically significant abnormal laboratory value in the opinion of the investigator
10. Required dialysis or plasma exchange within 12 weeks prior to screening
11. Received intravenous glucocorticoids, \>3000mg methylprednisolone equivalent, within 4 weeks prior to screening
12. Immunization with a live vaccine 1 month before screening
13. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation.
14. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies

Where this trial is running

Leiden, Zuid-Holland and 3 other locations

• Leiden University Medical Center — Leiden, Zuid-Holland, Netherlands (Recruiting)
• Noordwest Ziekenhuisgroep — Alkmaar, Netherlands (Not_yet_recruiting)
• Meander Medical Center — Amersfoort, Netherlands (Recruiting)
• HagaZiekenhuis — Den Haag, Netherlands (Not_yet_recruiting)

Study contacts

• Principal investigator: YKO Teng, MD, PhD — LUMC Leiden
• Study coordinator: YKO Teng, MD, PhD

Conditions ANCA Associated Vasculitis; ANCA; Crescentic glomerulonephritis; systemic autoimmune disease; Renal failure; Renal insufficiency; small vessel vasculitis; GPA