Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease
characterized by small vessel inflammation caused by pathogenic autoantibodies directed
against proteinase 3 (PR3) or myeloperoxidase (MPO). Immunosuppressive therapy can result in
remission; however, many patients relapse, which results in additional injury.

Rituximab, a humanized murine monoclonal antibody directed against CD20 located on the
surface of B-lymphocytes (B cells), is effective in depleting B cells. The RAVE and RITUXVAS
trials have shown efficacy of rituximab with steroids for induction of remission in ANCA
vasculitis, similar to cyclophosphamide and steroids. Rituximab is now FDA-approved for
induction of remission therapy in ANCA vasculitis. The utility of anti-B-cell therapy for
early induction of remission in ANCA vasculitis is not surprising given that ANCA are
pathogenic in vitro and in vivo. It is clear that remission in many patients is not sustained
with a single induction course of rituximab, and relapses often occur after B cell
re-population suggesting that scheduled, serial dosing of rituximab could result in sustained
remissions.

Despite yielding promising outcomes, rituximab is also associated with a number of adverse
events including infectious complications and late onset of neutropenia5, 15. Furthermore,
the complications of continuous B cell depletion for extended durations are unknown. One of
the major goals in the field is to utilize prolonged B cell depletion only in the
subpopulation of patients where the risk of disease relapse outweighs the risk of
treatment-related adverse events.

A rise in ANCA titers and reconstitution of B cells are promising biomarkers of impending
disease relapse following treatment with rituximab4-6

A prospective and longitudinal clinical trial is needed to determine the ideal treatment
strategy for long-term maintenance of remission. We propose to compare intermittent rituximab
dosing based on B cell return and a serologic ANCA flare

The study design is an open-label, single center, randomized and two-arm controlled trial to
evaluate the optimal maintenance of remission strategy that provides the best relapse-free
survival in patients with ANCA vasculitis as determined by relapse-free remission at 18, 24
and 36 months from enrollment. The investigators are looking to enroll and randomize 200
subjects with ANCA vasculitis on rituximab-induced continuous B cell depletion for a minimum
of two years to one of two arms as follows:

1. Intermittent B cell depletion with rituximab re-dosing upon B cell return: Subjects will
not receive their regularly-scheduled every-six-month dose of rituximab and will instead
receive rituximab 1000 mg IV x 2 doses (spaced 2-3 weeks apart) once peripheral B cells
return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in
clinic every three months.

2. Hold continuous dosing with rituximab with re-dosing upon a significant ANCA titer
increase: For MPO, a significant increase will be defined as a 5-fold rise in ANCA titer
and a level greater than 4 times the cutoff value for the assay. For PR3, a significant
rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above
the cutoff for the assay. Subjects will not receive regularly scheduled every six-month
doses of rituximab and will instead be monitored every three months. Subjects who
sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses,
~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a
specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value
for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a
maximum of 2 doses, at which time a new baseline ANCA titer will be established and the
cycle will re-start.

Inclusion Criteria:

1. All patients must be able and willing to give written informed consent and comply with
the requirements of the study protocol.

2. Diagnosis: ANCA vasculitis as defined by a positive MPO- and/or PR3-ANCA test together
with clinical features characteristic of ANCA-positive diseases as detailed in the
2012 Chapel Hill Consensus Conference Definitions(18).

3. eGFR ≥ 30 cc/min/1.73m2

4. Age: 18-82 years old

5. Treated with rituximab-induced continuous B cell depletion and in remission (defined
by a modified BVAS-WG=0 AND a prednisone dose of ≤ 7.5 mg) for at least 24 months.

6. CD20 (B cells) undetectable at time of enrollment/randomization

7. Urine Hcg negative for women of child bearing potential and not planning to become
pregnant for at least 12 months from enrollment and at least 12 months after any study
related rituximab dose

8. Judged to be otherwise healthy by the Investigator, based on medical history and
physical examination (no known active disease process for which life expectancy is
less than 36 months)

Exclusion Criteria:

1. Secondary Disease: disease suspected to be induced by levamisole-adulterated cocaine

2. All transplanted patients

3. Treatment: additional immunosuppressive agents other than rituximab and/or total daily
prednisone dose ≥ 7.5 milligrams

4. Hypogammaglobulinemia: IgG level < 250 mg/dL

5. Terminal cancer or other primary illness with life expectancy of less than 36 months

6. Active anti-GBM disease and other known autoimmune disease for which the need for
additional immunosuppression is likely

7. Pregnancy or breastfeeding