Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing Based on B-cell Reconstitution vs a Serologic ANCA Flare
Phase: PHASE4
Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Sponsor: Massachusetts General Hospital

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PARTNERS HUMAN RESEARCH COMMITTEE 
DETAILED PROTOCOL 
 
MGH Vasculitis and Glomerulonephritis Program 
 
 
Maintenance of ANCA vasculitis remission by intermittent rituximab dosing based on B cell 
reconstitution vs a serologic ANCA flare. (MAINTANCAVAS) 
 
I. Background and Significance 
 
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is a systemic autoimmune disease 
characterized by small vessel inflammation caused by pathogenic autoantibodies directed against 
proteinase 3 (PR3) or myeloperoxidase (MPO)(1).  The disease is highly morbid, with greater than 
80% of patients suffering serious complications from irreversible organ damage or treatment-
related adverse events.(2)    
 
The devastating complications of ANCA vasculitis warrant prompt and aggressive 
immunosuppression.  Treatment is divided into two phases: induction immunosuppression to 
achieve remission, and maintenance immunosuppression to prevent relapse. Cyclophosphamide 
has traditionally been used as the backbone of induction regimens for ANCA Vasculitis.  While 
effective, cyclophosphamide is associated with serious adverse events including infection, gonadal 
toxicity leading to infertility, bone marrow suppression, and malignancy(2-4).  These complications 
have spurred the search for novel treatments with more favorable toxicity profiles.  Recently, the 
anti-CD 20 monoclonal antibody rituximab has emerged as an acceptable alternative to 
cyclophosphamide for induction therapy of AV(5,6). 
 
Azathioprine has traditionally been the preferred agent for maintenance therapy(7).  However, this 
strategy remains inadequate, with approximately 33% of patients relapsing at 2.5 years and a 
significant burden of treatment-related adverse events(8).  Similarly, rituximab induction without 
subsequent maintenance therapy leads to unacceptable relapse rates(9).  To circumvent these 
shortcomings, strategies employing continuous B cell depletion with maintenance rituximab dosing 
have been attempted.  In the largest study to date, we demonstrated that rituximab administered to 
maintain continuous B-cell depletion produces outstanding results with a 2 year major relapse rate 
of 5% and a survival that mirrors the general population(10).  Furthermore, a recent randomized 
trial confirmed that maintenance therapy with rituximab administered every 6 months is superior 
to daily azathioprine(11). 
 
Despite yielding promising outcomes, rituximab is also associated with a number of adverse events 
including infectious complications and late onset of neutropenia(9,12).  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 rituximab(9,13,14).  We therefore propose a randomized trial in 
which these two biomarkers are used to guide additional treatment in patients who have completed 
at least 2 years of successful rituximab maintenance therapy.  

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 The ANCA Assay 
Our group was the first to demonstrate the association of ANCA with the neutrophil serine protease, 
proteinase 3 (PR3)(15).  Since this time, our group has conducted numerous studies regarding the 
use of the ANCA assay in the diagnosis and management of ANCA vasculitis.  In one investigation, 
100% of patients in clinical remission who sustained a fourfold rise in ANCA titer without receiving 
immunosuppression relapsed at mean time of 5.8 months(13).  
 
Rituximab for Maintenance Therapy in ANCA Vasculitis     
Our group was one of the first to use rituximab as maintenance therapy for ANCA vasculitis in April 
of 2006.  We subsequently reported that continuous B cell depletion using rituximab was highly 
successful for early maintenance of remission in 39 patients with ANCA vasculitis(16).  This 
maintenance strategy was the first to use a regimen of scheduled rituximab administration in order 
to prevent B cell re-population.   
 
We recently reviewed the long-term results of 172 ANCA vasculitis patients cared for by our group 
who underwent rituximab-induced continuous B cell depletion for maintenance of remission and 
found that remission was maintained in the majority of patients with a very low rate of major 
relapse.  Most importantly, we found that this remission maintenance strategy appears to result in 
long-term survival matching that of the general U.S. population(10) (see Figure).   
 
Relapse after Discontinuation of Rituximab 
Data from randomized clinical trials and observational studies suggest relapse is common if 
rituximab is discontinued indefinitely.  Among patients in the RAVE trial who achieved complete 
remission following treatment with rituximab, 32% had a relapse within 18 months(9).  
Furthermore, Alberici et al reported that 41% of patients who received maintenance rituximab 
every 6 months for 24 months relapsed at a median of 34.4 months following discontinuation of 
therapy(17).  Predictors of relapse included return of B cells and change from ANCA negativity to 
positivity(17).      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A prospective and longitudinal clinical trial is needed to determine the ideal treatment strategy for 
long-term maintenance of remission.  Here we propose to compare 2 strategies once patients have 

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been in sustained remission on scheduled rituximab dosing with a goal of undetectable B cells for 
greater than or equal to 2 years.  Target enrollment is 200 subjects over 48 months from the time 
the first patient is enrolled to be followed for a common close out date of 36 months after the last 
subject is enrolled.  
 
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.  Subjects with ANCA vasculitis in sustained remission on regularly scheduled 
rituximab infusions with a goal of undetectable B cells for a minimum of two years who meet 
specific entry criteria will  be randomized with stratification based on ANCA subtype and rituximab 
vintage (i.e., duration of continuous rituximab prior to enrollment) to one of two arms : 
 
1. Intermittent B cell depletion with rituximab re-dosing upon B cell return: Subjects will 
no longer receive regularly-scheduled every six-month doses of rituximab and will instead 
be seen in clinic with B cell monitoring every 3 months (beginning 6 months after their last 
rituximab dose).   B cell levels will be determined by the number of CD20 positive cells 
detected by peripheral blood flow cytometry.  Subjects will not receive rituximab if the B cell 
level remains < 10 cells/mm3. Once peripheral B cells levels rise to > 10 cells/mm3, they will 
receive rituximab 1000 mg IV x 1 dose.  If patients receive rituximab they will become B cell 
depleted, but will stay on their original study schedule. Following B cell depletion, subjects 
will be seen in clinic every three months, and B cell monitoring every 3 months will continue 
as scheduled.  Patients will continue to be dosed with rituximab each time the B cell count 
rises to 10 cells/mm3.  In the unique scenario that the B cells are detectable, but less than the 
threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell 
testing.  
 
2. Hold continuous dosing with rituximab with re-dosing upon significant ANCA titer 
increase:  Subjects will no longer receive regularly scheduled every six-month doses of 
rituximab, and will instead be seen in clinic with the ANCA titer monitoring every three 
months (beginning 6 months after their last rituximab dose).  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 value for the assay.  Patients who sustain a  significant 
increase in ANCA titer will receive rituximab 1000mg IV x 2 doses  (~2-3 weeks apart).  If 
the ANCA titer then falls to less than twofold above  baseline or falls below the specified 
threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) after 
rituximab, patients will be seen in clinic every three months, with monitoring of ANCA titers.  
However, if the ANCA titer remains twofold above baseline and above the specified 
threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) after 
rituximab, patients 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.  Once the 
new baseline ANCA titer is established, the patients will continue to be seen in clinic every 3 
months, with monitoring of ANCA titers.  Patients will continue to be dosed with rituximab 
each time they meet criteria for a significant ANCA titer rise.  In this arm, rituximab 
administration is not contingent upon B cell levels. Rituximab will only be dosed based on 
the ANCA titer as described above. Baseline ANCA titer will be recalculated to an average of 
the two highest of the last four values if all four are less than the original baseline. Patients in 

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the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal 
levels (>90 cells/uL). 
 
Patients can be treated at any time during the study period with a total prednisone dose of ≤ 7.5 mg.  
Patients with a disease flare (defined by BVAS/WG ≥ 2) will have reached the primary endpoint and 
will be treated for relapse at the discretion of the investigator 
 
 
 
II. Specific Aims 
 
1. Primary Aim: To determine whether a rituximab-dosing protocol based on:  1) 
reconstitution of peripheral B cells or 2)a serologic ANCA flare is more efficacious in 
preventing relapse in patients with ANCA vasculitis.   Eligible patients will have 
completed a minimum of 2 years of rituximab maintenance therapy without relapse.  The 
endpoint will be disease relapse defined as a BVAS/WG ≥ 2.  Analysis will also be stratified 
based on ANCA subtype (due to differences in relapse between patients with MPO and PR3 
ANCA) and rituximab vintage. 
 
2. Secondary Aim 1:  To determine whether a rituximab-dosing protocol based on: 1) 
reconstitution of peripheral B cells or 2) a serologic ANCA flare is associated with 
more serious adverse advents.  Serious adverse events of interest include those related to 
vasculitis activity and those that develop as a consequence of rituximab therapy.  The main 
rituximab-associated serious adverse events noted in our cohort are infection, late-onset of 
neutropenia, and infusion reactions(10) 
 
3. Secondary Aim 2: To determine whether a rituximab-dosing protol based on: 1) 
reconstitution or peripheral B cells or 2) a serologic ANCA flare is associated with a 
greater composite of disease relapse (BVAS/WG ≥ 2 )  and serious adverse events.  
 
4. Secondary Aim 3:  To determine whether a rituximab-dosing protocol based on: 1) 
reconstitution of peripheral B cells or 2)a serologic ANCA flare  is associated with 
greater rituximab utilization during the study period.  While effective, rituximab 
therapy is costly and increases health care expenditures.  Evaluation of the relative cost of 
the 2 dosing-strategies will assist in the application of these dosing-strategies to the broad 
population of patients with ANCA vasculitis. 
 
 
III. Subject Selection 
 
Patients with ANCA vasculitis who are seen at MGH will be recruited as subjects and inclusion and 
exclusion criteria are detailed below. 
 
A. Inclusion and exclusion criteria 
 
Inclusion criteria: 
1.  All patients must be able and willing to give written informed consent and comply with the 
requirements of the study protocol. 

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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  ≥  20 cc/min/1.73m2 
4. Age: 18-82 years old 
5. Treated with continuous rituximab at regularly scheduled intervals with a goal of 
undetectable B cells for at least 24 months. 
6. In sustained remission (defined by a modified BVAS-WG=0 AND a prednisone dose of 
≤7.5mg for at least 12 months). 
7. Undetectable (<10mm3) B cells as quantified by the number of CD20+ cells on peripheral 
blood flow cytometry on day 0. 
8. 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 
9. 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 < 300mg/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 
 
B. Sources of subjects and recruitment methods 
 
Subjects will be recruited from the current pool of patients in the MGH Renal and Rheumatology 
Units of the Vasculitis and Glomerulonephritis Center. 
 
IV. Subject Enrollment 
 
A. Methods of enrollment 
Patients will be prescreened for eligibility by research staff prior to their scheduled rituximab 
infusion. Potential subjects will be assessed for eligibility utilizing existing data regarding current 
length of treatment with rituximab, prednisone dose (if any) and most recent Birmingham 
Vasculitis Activity Score.  
 
At a regularly scheduled clinic visit, study site personnel will assess a patient’s eligibility for 
enrollment, including review of the inclusion and exclusion criteria.  Patients meeting all the 
inclusion criteria and have no exclusionary criteria and  receive treatment for their ANCA 
Associated Vasculitis  by physicians in the MGH Renal and Rheumatology Unit’s Vasculitis and 
Glomerulonephritis Center will be offered the opportunity to participate in this study as part of 
their ongoing treatment. 

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B. Procedures for obtaining informed consent 
 
When a potential subject is identified, the research nurse will initially explain the study to the 
patient after their clinical visit with Dr. Niles, Dr. Cortazar, or Dr. Wallace. If the patient expresses 
further interest in participating in the study, Dr. Niles, Dr. Cortazar, or Dr. Wallace and the research 
nurse will then review the study details with the patient. The patient will be provided the 
opportunity to take the consent form home to further review and will follow-up with the research 
nurse or investigator within 14 days.  If they decline participation, they will continue to receive 
their standard of care as deemed appropriate by their treating clinician. Massachusetts General 
Hospital is expecting to enroll up to 200 subjects over 36 months. 
 
C. Treatment assignment and randomization 
 
Each subject will be stratified prior to randomization to ensure MPO- and PR3-ANCA serotypes and 
duration of rituximab therapy are approximately equal within each arm.  Randomization will occur 
using random permuted blocks to assign each subject to one of two arms: 
1. Treatment upon B cell return,  OR 
2. Treatment upon a significant rise in ANCA titer as defined above. 
 
V. Study Procedures 
 
A. Study visits and parameters to be measured 
 
1. Potential subjects will be identified during a clinical visit. Medical records will be reviewed 
by study staff and if found eligible then the potential subjects will be offered the opportunity 
to participate in the study at that visit. Potential subjects will have 14 days to decide on 
participation.  
2. “Day 0” is defined as the date of the last rituximab infusion prior to randomization and must 
be 6 months +/- 14 days from Study visit 1. Existing data will be collected from this date 
once enrolled and randomized. 
3. Study Visit 1:  Enrollment and Randomization 
a. Patients who agree to participate and have signed and dated the consent form will be 
randomly assigned to one of two treatment arms: 
i. Arm 1: Subjects will not receive their regularly-scheduled dose of rituximab, 
but will be asked to return to clinic for a follow-up visit 6 months after their 
last rituximab infusion. Subjects will then receive blood work and scheduled 
clinic visits every three months thereafter.  Once B cell return occurs, as 
defined as ≥ 10 cells/mm3, subjects will be scheduled to receive rituximab 
1000 mg IV x 1 dose. If a dose of rituximab is administered, the patient study 
schedule will not be adjusted.  Patients will continue to be evaluated every 
three months per study protocol.  If the B cells are detectable but <10 cells/m3 
, subjects will not be redosed,  but will be asked to return in 6 weeks for repeat 
B cell monitoring.  
 
Arm 2: Subjects will not receive their regularly scheduled dose of rituximab, 
but will be asked to return to clinic for a follow-up visit 6 months after the last 
rituximab infusion.  Subjects will then receive blood work and scheduled clinic 

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visits every three months thereafter.   If the ANCA titer has increased above 
the threshold for treatment described above, then the patient will be re-dosed 
with rituximab 1000mg IV x 2 doses 2-3 weeks apart .   If the ANCA titer 
remains twofold above baseline and above a specified threshold (the cuttoff 
value of the assay for PR3 and 4 times the cutoff value for MPO) , patients will 
continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 
additional doses, at which time a new baseline ANCA titer will be established. 
Subjects will continue to be evaluated every three months per protocol 
schedule.  
 
b. A detailed history and physical examination will be performed along with the 
following disease assessment surveys and blood and urine measurements: 
i. Demographic characteristics  
ii. Date of initial physician’s diagnosis of ANCA vasculitis 
iii. Length of continuous B cell depletion treatment 
iv. Medical history 
v. Vasculitis Damage Index (VDI) Score 
vi. Modified Birmingham Vasculitis Activity-WG (BVAS-WG) Score 
vii. Any adverse events since last infusion of rituximab 
viii. Prior and concomitant medications 
ix. Height and weight 
x. Blood work including but not limited to: 
1. Complete Blood Count 
2. Comprehensive Metabolic Panel 
3. eGFR 
4. ANCA titer 
5. ESR 
6. CRP 
7. Hep B sAg, Hep C Ab, HIV ½ (if not performed in the previous 12 
months prior to screening and only at enrollemnt) 
8. Immunoglobulin levels 
9. Flow cytometric analysis of peripheral B and T cells 
10. Urinalysis 
11. Urine human chorionic gonadotropin (hCG) in women of child bearing 
potential 
xi. Quality of life surveys SF36 v2 and EQ 5D-5L 
xii. Baseline ECG 
xiii. Cough assessment/scale 
 
4. Study Visits 2-16: Study visit 2 will occur at the 6 month time point from Day “0” (+/- 14 
days) and subsequent visits will take place every three months (+/- 14 days) thereafter until 
a common close out date of 36 months after the last subject is enrolled.   
a. Subjects will be seen every three months in clinic and the same measurements will be 
performed as listed in the Enrollment and Randomization Visit. 
i. The VDI Score will only be calculated every other visit after Study visit 2 as 
this score is designed to measure cumulative damage every six months. 
ii. Subject quality of life assessments SF 36v2 and EQ-5D-5L will be assessed 
every 6 months from time of Study visit 2.  

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iii. ECG will be performed every 12 mos  
iv. Adverse Events will be assessed at each visit  
v. Cough assessment/scale 
b. In cases where subjects need to come in for an infusion in between scheduled visits, 
the visit directly after the infusion may be done over the phone instead of coming in 
to the clinic.  This will be decided at the discretion of the PI based on any hardships 
the patients may have related to distance of travel.  The same measurements will be 
performed as an on-site visit (VDI score, BVAS, adverse events, and 
cough/assessment), except for the ECG and blood draw. The ECG will be added to the 
next office visit, and blood work will be deferred for that visit, and resumed at the 
next time point.  Subject Quality of Life Assessments SF36v2 and EQ-5D-5L may be 
mailed to subjects for completion, then returned at the next office visit.    
c. If subjects miss their scheduled visits and are unable to reschedule in window, a 
deviation will be filed and an investigator will call them to assess AEs and disease 
activity.  
d. Subject visits can be completed as telemedicine with remote lab draws during the 
COVID-19 pandemic. Lab draws may be delayed up to 4 weeks at the investigator’s 
discretion. A minor deviation will be filed if lab draws occur outside that window.  
 
B. Drugs to be used 
 
Rituximab (Rituxan, Genentech), which is FDA-approved for GPA and MPA, will be used in the study. 
 
C. Devices to be used 
 
Not applicable 
 
D. Procedures/surgical interventions 
 
Not applicable 
 
E. Data to be collected and when the data is to be collected 
 
At present, there is no standard of care for maintenance of remission in ANCA vasculitis beyond the 
two-year mark; thus, the role of continuous versus intermittent B cell depletion requires 
investigation.  Efficacy and toxicity are the foci of our outcome analysis for this study and will be 
assessed through analysis of primary and secondary endpoints. 
 
The following variables will be collected at EACH study visit: 
1. VDI (every 6 months) 
2. Modified BVAS/WG 
3. Laboratory data at baseline and at subsequent visits 
a. Complete Blood Count 
b. Comprehensive Metabolic Panel 
c. eGFR 
d. ANCA titer 
e. ESR 
f. CRP 

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g. Immunoglobulin levels (every 6 months) 
h. Urinalysis 
i. Urine Hcg for women of child bearing potential (only at screening and when 
reinfused with rituximab) 
j. Flow cytometric analysis of peripheral B and T lymphocyte markers 
4. Concomitant medications at each visit 
5. Adverse events assessment 
 
 
VI. Biostatistical Analysis 
 
A. Specific data variables being collected for the study (e.g. data collection sheets) 
 
Data variables collected are listed above and we will also verify contact information at each visit to 
ensure appropriate follow-up. 
 
B. Study endpoints 
 
Primary endpoints: 
 
 
1. Disease flare defined as a BVAS/WG  ≥ 2.  A subgroup analysis will be performed by 
ANCA subtype. 
 
Secondary endpoints: 
1. Proportion of patients with serious adverse events (SAEs), including all episodes of  Late 
Onset Neutropenia (LON, absolute neutrophil count < 1000 cells/mm3) 
2. The composite of disease flare (defined as BVAS/WG ≥ 2) and serious adverse events. 
3. Total rituximab utilization during the study period 
4. Accrued organ damage as assessed by the Vasculitis Damage Index (VDI) 
5. Patient quality of  life assessment using the SF-36v2 and EQ-5D-5L surveys every 6 
months 
6. Number of major (modified BVAS-WG ≥ 3) relapses 
7. Survival 
8. Hypogammaglobulinemia (IgG < 400 mg/dL) 
9. All infections 
 
C. Statistical methods 
 
Data will be analyzed by the intention-to-treat principle.  Randomization will be stratified on ANCA 
subtype (MPO vs PR3) and rituximab vintage ( < 3 years vs > 3 years).  Rituximab vintage is the 
duration of continuous rituximab therapy administered prior to enrollment in the study.  We have 
contracted with the company StudyTRAX to perform randomization on stratified variables via 
random permuted blocks.   
 
Continuous data will be summarized using descriptive statistics.  Continuous data will be assessed 
using the t-test or Wilcoxon rank-sum test as appropriate.    Categorical data will be assessed using 
the Chi-square and the Fisher exact tests as appropriate.  The probability of remaining free of 
relapse will be estimated using the Kaplan-Meier method.  The difference between the two 

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treatment strategies will be assessed using the log-rank test.  P values of 0.05 will be considered 
significant.  
 
D. Power analysis 
 
Using a two-sided logrank test with an alpha level of 0.05, a projected relapse risk of 15% in the 
superior group and 30% in the inferior group, and an estimated enrollment time of 36 months,  it 
was determined that 180 patients are required to detect a significant difference with a power of 
0.80.  We aim to enroll 200  patients in the study. 
 
 
 
VII. Risks and Discomforts 
 
Subjects may experience side effects while receiving rituximab, which is given as part of their 
regular medical care for their GPA or MPA.  As per the entry criteria,  subjects  have been on 
rituximab for 2 years prior to enrollment, the side effects have been discussed in detail and a signed 
consent for rituximab is obtained for every patient receiving rituximab at the first dose and 
annually thereafter. 
 
The effects of rituximab on a fetus are unknown and may be harmful.  Individuals of childbearing 
potential should use effective birth control during treatment and for 12 months after their last 
rituximab infusion.   Prior to any infusion of rituximab to a woman of childbearing potential, a urine 
pregnancy test is performed and recorded.  If a woman is found to be pregnant, she will then be 
removed from the study and followed based on best medical judgment as deemed appropriate by 
the clinician investigator.  
 
A. Complications of surgical and non-surgical procedures 
 
Not applicable 
 
B. Drug side effects and toxicities 
Common side effects of Rituxan 
• Infusion reactions may be fatal. Serious infusion reaction with hives, low blood pressure, 
breathing difficulties, irregular heartbeat and chest pain are very rare. Medications given as 
pre mediction: Benadryl 25mg PO, tylenol 650mg PO and Solucortef 100mg IV, are always 
given and can prevent these reactions.  We will temporarily stop the infusion immediately if 
a reaction occurs.  
• Within 24 hours of the 1st infusion 
o Chills, itching, hives, sneezing, throat irritation 
o “flu like” symptoms: headache, nausea, joint pain 
 
• Possible serious side effects or reactions that can occur at any time 
o Infections are a concern with all drugs that affect the immune system. If you 
develop a severe infection, we will check your labs including a complete blood 
count.  This is always something that needs attention and treatment 
o Reactivation (getting symptoms again) of Hepatitis B and other viral 
infections. Hepatitis B Core is always checked at the screening or first visit.  

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o Worsening of asthma symptoms  
o A rare brain infection, progressive multifocal leukoencephalopathy (PML), has 
been reported in people taking this medication. This infection is rare, 
associated with weakened immune systems, and can lead to death or severe 
disability. 
o Skin reactions, painful sores, ulcers, blisters and peeling skin (rare) 
 
There may be other risks of rituximab that are currently unknown. 
 
As with any drug, the major possible side effect of rituximab can be an allergic reaction.  Allergic 
reactions can be mild or more serious, and can even result in death.   
 
Subjects cannot receive a live vaccine such as zostavax while receiving rituximab.   
 
 
C. Risk of relapse 
 
The discontinuation of maintenance rituximab will likely lead to an increase in disease relapse.  
Relapses have the potential to cause irreversible organ damage, resulting in significant morbidity.  
Particularly concerning is the potential for recurrence of rapidly progressive glomerulonephritis 
leading to ESRD and dialysis dependence.   The risk of relapse must be weighed against the harms of 
ongoing treatment with immunosuppression.  While no randomized clinical trials have been 
performed, standard of care is to continue maintenance therapy for 1-2 years.  To mitigate the risk 
of significant morbidity from disease relapse, we have restricted entry to patients treated with 
maintenance therapy for a minimum of 2 years and excluded patients with an eGFR < 20 
ml/min/1.73 m2. 
 
D. Device complications/malfunctions 
 
Not applicable 
 
E. Psychosocial (non-medical) risks 
 
There are no known psychosocial risks associated with this study, however there may be unknown 
risks that will be addressed if they become known.  
 
F. Radiations Risks 
 
Not applicable 
 
VIII. Potential Benefits 
 
A. Potential benefits to participating individuals 
  
There may not be any direct benefits to subjects who participate in this trial. Information learned 
by conducting this trial may benefit future patients by helping determine a long term plan with 
regards to rituximab administration for patients with GPA or MPA.  
 

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B. Potential benefits to society 
 
This study, once completed, will be a landmark trial in the field of remission maintenance therapy 
for ANCA vasculitis.  Currently, specialists do not know the ideal treatment strategy for this subset 
of patients and this study is likely to provide the answer.  In addition, if it is found that either Arm 1 
or Arm 2 are as effective as ongoing continuous therapy, there will be cost-effective benefit to 
society in that less rituximab will be required to maintain remission. 
 
IX. Monitoring Quality and Assurance 
 
A. Independent monitoring of source data 
 
The PI on this study will be responsible for the data management, integrity of this data and 
adherence to the IRB-approved protocol. The PI will review the accuracy and completeness of 
entries, source documents, and informed consent on a regular basis. 
 
Privacy of subjects will be protected and confidentiality of data collected maintained. All 
individually identifiable information will be stored in a secure, locked, location in the PI’s office. 
Password-protected computer databases will be used with limited access to the study data. Files for 
data analysis will contain codes instead of identifiers. All identifiers will be removed once study is 
completed.  
 
 
B. Safety monitoring 
 
The patient’s treating physician will be responsible for the treatment of any adverse events, in 
accordance with the approved product labeling and the physician’s discretion. 
 
Subjects will be withdrawn from the study at any point for the following reasons: 
1. Serum IgG < 250 mg/dL at any point during the study. 
2. Modified BVAS-WG ≥ 2 
3. Require daily  prednisone >7.5mg 
4. WBC <3,000 
5. Serious Infections that require hospitalization. 
 
 
The investigators will also review the data every 6 months to ensure there are no safety concerns or 
clear inferiority in one arm that would warrant early termination of the trial. 
 
C.Outcomes monitoring 
 
The following outcomes will be collected throughout the study period as appropriate: 
 
1.  Disease flare defined as a BVAS/WG ≥2 (primary aim). A subgroup analysis will be 
performed by ANCA subtype. 
2. Proportion of patients with serious adverse events (SAEs), including all episodes of LON.  
3. Number of infections (mild and severe). 
4. Total rituximab utilization during the study period. 

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5. Patient quality of  life assessment using the SF-36v2 and EQ-5D-5L surveys every 6 
months 
6. Number of major (modified BVAS-WG ≥ 3) relapses 
7. Survival 
8. Hypogammaglobulinemia (IgG < 400 mg/dL) 
 
 
D. Adverse event reporting guidelines   
 
All adverse events will be reported per PHRC guidelines which includes unanticipated problems 
involving risks to subjects/others, including adverse events, within 5 working days/7 calendar days 
of the date that the investigator first became aware of the problem. 
 
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