Clinical trial NCT02749292
Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Keywords: rituximab maintenance remission
Sponsor: Massachusetts General Hospital
Start date: 2016-06-01; Completion date: 2022-01-31
Enrollment: 115 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the best management strategy to maintain remission in patients with ANCA vasculitis who have been treated with rituximab induced B cell depletion for at least two years. This study will compare intermittent B Cell depletion upon B cell return or intermittent B cell depletion upon serologic relapse.

Detailed description:
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 1 dose (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. 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 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 seen in clinic to have their ANCA titer 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.

Arms: arm 1: Subjects will not receive their regularly-scheduled every-six-month dose of rituximab and will instead receive rituximab 1000 mg IV x 1 dose once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months. 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. arm 2: Subjects will not receive regularly scheduled every six-month doses of rituximab (1000mg IV) and will instead be seen in clinic for ANCA titer monitoring every 3 months. Re-dosing will occur upon a significant ANCA titer increase. For MPO, a significant rise 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 who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, spaced \~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.
Interventions: intervention 1: Rituximab
Intervention descriptions: intervention 1: re-dosing dependent on interventional arm parameter.

Protocol documents:
Prot_SAP_000.pdf: 
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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.  


MGH Human Subject Research Application Form 
 Filename: MAINTANCAVAS 
5/21/20 
Page 11
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.  
 


MGH Human Subject Research Application Form 
 Filename: MAINTANCAVAS 
5/21/20 
Page 12
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. 


MGH Human Subject Research Application Form 
 Filename: MAINTANCAVAS 
5/21/20 
Page 13
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. 
 
References 
 
1. Jennette JC, Falk RJ, Gasim AH. Pathogenesis of antineutrophil cytoplasmic autoantibody 
vasculitis. Curr Opin Nephrol Hypertens 20(3): 263-270, 2011 
2. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS. 
Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 116(6): 488-498, 1992 
3. Boumpas DT, Austin HA,3rd, Vaughan EM, Yarboro CH, Klippel JH, Balow JE. Risk for sustained 
amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse 
cyclophosphamide therapy. Ann Intern Med 119(5): 366-369, 1993 
4. Huynh-Do U, Gantenbein H, Binswanger U. Pneumocystis carinii pneumonia during 
immunosuppressive therapy for antineutrophil cytoplasmic autoantibody-positive vasculitis. 
Arch Intern Med 155(8): 872-874, 1995 
5. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar 
V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR, European Vasculitis Study Group. 
Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 363(3): 
211-220, 2010 


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5/21/20 
Page 14
6. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, 
Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, 
Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, 
Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U, RAVE-ITN Research Group. Rituximab 
versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 363(3): 221-232, 2010 
7. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, Ekstrand A, Gaskin G, 
Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, 
Westman K, Pusey C, European Vasculitis Study Group. A randomized trial of maintenance 
therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 
349(1): 36-44, 2003 
8. Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, Kyndt X, Lifermann F, Papo T, 
Lambert M, Le Noach J, Khellaf M, Merrien D, Puechal X, Vinzio S, Cohen P, Mouthon L, Cordier JF, 
Guillevin L, French Vasculitis Study Group. Azathioprine or methotrexate maintenance for ANCA-
associated vasculitis. N Engl J Med 359(26): 2790-2803, 2008 
9. Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, 
Fessler BJ, Ding L, Viviano L, Tchao NK, Phippard DJ, Asare AL, Lim N, Ikle D, Jepson B, Brunetta P, 
Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg 
SR, Mueller M, Sejismundo LP, Mieras K, Stone JH, RAVE-ITN Research Group. Efficacy of 
remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 369(5): 417-427, 
2013 


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5/21/20 
Page 15
10. Pendergraft WF,3rd, Cortazar FB, Wenger J, Murphy AP, Rhee EP, Laliberte KA, Niles JL. Long-
term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with 
ANCA vasculitis. Clin J Am Soc Nephrol 9(4): 736-744, 2014 
11. Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, Maurier F, Decaux O, Ninet J, 
Gobert P, Quemeneur T, Blanchard-Delaunay C, Godmer P, Puechal X, Carron PL, Hatron PY, Limal 
N, Hamidou M, Ducret M, Daugas E, Papo T, Bonnotte B, Mahr A, Ravaud P, Mouthon L, French 
Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated 
vasculitis. N Engl J Med 371(19): 1771-1780, 2014 
12. Tesfa D, Ajeganova S, Hagglund H, Sander B, Fadeel B, Hafstrom I, Palmblad J. Late-onset 
neutropenia following rituximab therapy in rheumatic diseases: Association with B lymphocyte 
depletion and infections. Arthritis Rheum 63(8): 2209-2214, 2011 
13. Han WK, Choi HK, Roth RM, McCluskey RT, Niles JL. Serial ANCA titers: Useful tool for 
prevention of relapses in ANCA-associated vasculitis. Kidney Int 63(3): 1079-1085, 2003 
14. Cartin-Ceba R, Golbin JM, Keogh KA, Peikert T, Sanchez-Menendez M, Ytterberg SR, Fervenza FC, 
Specks U. Rituximab for remission induction and maintenance in refractory granulomatosis with 
polyangiitis (wegener's): Ten-year experience at a single center. Arthritis Rheum 64(11): 3770-
3778, 2012 
15. Niles JL, McCluskey RT, Ahmad MF, Arnaout MA. Wegener's granulomatosis autoantigen is a 
novel neutrophil serine proteinase. Blood 74(6): 1888-1893, 1989 
16. Rhee EP, Laliberte KA, Niles JL. Rituximab as maintenance therapy for anti-neutrophil 
cytoplasmic antibody-associated vasculitis. Clin J Am Soc Nephrol 5(8): 1394-1400, 2010 


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 Filename: MAINTANCAVAS 
5/21/20 
Page 16
17. Alberici F, Smith RM, Jones RB, Roberts DM, Willcocks LC, Chaudhry A, Smith KG, Jayne DR. 
Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for 
ANCA-associated vasculitis. Rheumatology (Oxford) 54(7): 1153-1160, 2015 
18. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin 
L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr 
AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone 
JH, Takahashi K, Watts RA. 2012 revised international chapel hill consensus conference 
nomenclature of vasculitides. Arthritis Rheum 65(1): 1-11, 2013 
  
 
 
 
 
 

ICF_001.pdf: 
Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 1 of 16
Subject Identification
Protocol Title: Maintenance of ANCA vasculitis remission by intermittent 
rituximab dosing based on B-cell reconstitution vs a serologic ANCA flare. 
(MAINTAINCAVAS)
Principal Investigator: John L. Niles, MD
Site Principal Investigator:      
Description of Subject Population: Adults who have been diagnosed with GPA 
(granulomatosis with polyangiitis) (GPA was formerly known as 
Wegener's Granulomatosis) or microscopic polyangiitis (MPA) and have 
been receiving Rituxan (rituximab) for treatment for a minimum of two 
years.
About this consent form
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form.
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.”
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep.
Why is this research study being done?
This research study is being done to figure out the best way to maintain remission in ANCA 
vasculitis with rituximab induced B cell depletion. The fixed rituximab dosing schedule appears 
to be safe and effective; however, patients with ANCA vasculitis likely cannot remain on 
continuous rituximab forever.  
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 2 of 16
Subject Identification
Rituximab along with glucocorticoids (steroids) are approved by the U.S. Food and Drug 
Administration (FDA) to treat ANCA Vasculitis. 
We are asking you to take part in this study because you have granulomatosis with polyangiitis 
(GPA) or microscopic polyangiitis (MPA) and have been on Rituximab for at least two years as 
part of your treatment.  
GPA and MPA are autoimmune diseases (the body reacting against its own tissues) that cause 
injury in different organs in your body.  Sinuses, lungs and kidneys are the most common sites of 
injury.  Injury can also occur in other sites, including:  nerves, skin, joints, muscles and eyes. 
The immune system defends against bacteria, viruses, tumors and other foreign substances in the 
body.  However, in GPA and MPA, the immune system attacks some of your own tissue.  The 
treatment for GPA and MPA is immunosuppression with medications to decrease the immune 
system response.  Without treatment, people with GPA and MPA are at risk of permanent 
damage to the tissues and organs affected by these diseases.  Rituximab has been used 
successfully to treat these diseases and keep them from coming back.   Rituximab every 6 
months is safe and effective; however, it is important to know if patients with ANCA vasculitis 
should remain on continuous rituximab forever or should we be watching and waiting for B cell 
return or a rise in the ANCA level.
About 200 subjects will take part in this research study at Massachusetts General Hospital 
(MGH).
There are no additional costs to subjects for participation in this study. 
How long will I take part in this research study?
If you decide to take part in the study, you will be followed for about 3 years after the last study 
participant is enrolled and may continue for a longer period of time if Dr. Niles (the principal 
investigator) decides to extend the study.  During this time, we will ask you to make about 12-14 
visits over 3 years; these will be part of your regular scheduled visit with Dr. Niles.  
What will happen in this research study?
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures.
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 3 of 16
Subject Identification
Study Visits will take place during your regularly scheduled clinic visits and will take 
approximately 30 minutes for each visit. 
If you are unable to attend a scheduled visit, an investigator may call you to check-in and 
complete study forms to assess disease activity and damage. 
Screening:
Before you begin the study, a member of the study team will review your length of time on 
rituximab and the history of your GPA or MPA to find out if you can be in the study.  This 
information will be from your medical record. The study staff will determine if you are eligible 
to participate in the study during one of your regularly scheduled office visits.
Enrollment/Randomization Visit (Study Visit 1)
This will either be at your planned rituximab infusion or up to 6 months after your last dose of 
rituximab.  
You will be randomly assigned to one treatment or the other.  Which treatment you receive will 
be determined by chance (like flipping a coin). You will know which group you are assigned to; 
however, neither you nor the study doctor will be able to choose which treatment you receive. 
You will not know which group you are in before you agree to participate.
Study Group 1:  Intermittent B-cell depletion
1. You will not receive rituximab infusions at regular intervals
2. You will have a study visit every 3 months
3. We will monitor routine urine and blood work including monitoring your B-cells and 
ANCA titer level
a.
If your B-cells have returned, you will be scheduled for 1 dose of rituximab.
b. After the infusion, you will continue to have study visits every three months
c.
Rituximab will not be given again until your B-cells have returned.
Study Group 2:  Re-Dosing with rituximab upon significant ANCA titer increase
1. You will not receive rituximab infusions at regular intervals
2. You will have a study visit every 3 months
3. We will monitor routine urine and blood work including monitoring your B-cells and 
ANCA titer level
a.
If your ANCA titer level has increased at or above a specified level, you will be 
scheduled for 2 doses of rituximab approximately 2 weeks apart
b. After the second infusion, you will continue to have study visits every three 
months.
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 4 of 16
Subject Identification
c.
If your ANCA titer level remains at or above the specified level, you will 
continue to receive rituximab once every 6 months for a maximum of 2 additional 
doses, at which time a new baseline ANCA titer level will be determined. 
At this visit, we will:

Ask you about your medical history

Collect information from your medical record

Do a physical exam, including height, weight and vital signs

Collect routine blood work

Ask you for a urine sample

Test your urine for pregnancy, if you are a female able to become pregnant.  
Pregnant women cannot take part in this research study.

Do an ECG (electrocardiogram)

Ask you to fill out some questionnaires about your general health and well-
being, quality of life, mental health, emotional health and mood. 
.  
ECG (electrocardiogram) 
This test checks the electrical activity of your heart.  We will place several small, sticky pads on 
your chest, arms, and legs.  Each pad has a wire attached.  The wires connect to a machine that 
makes a recording of your heart rhythm.  This painless test takes about 15 minutes.  
Study Visits 2-16: Study visit 2 will occur at the 6 month time point from your last 
rituximab infusion. This may be the same day as Study Visit 1. We will only collect one set 
of blood work and information on this visit date. All other visits will be every 3 months 
until 3 years after the last subject is enrolled. 
Each Visit
At each visit during this part of the study, we will assess your GPA or MPA as part of your 
regular care. We will: 
1. Collect routine urine and blood work (about 4 teaspoons of blood per visit, for a total of 
about 2 cups over the course of the study) including monitoring for your B-cells and 
ANCA titer level
2. Check a urine pregnancy test for women of child bearing potential. 
3. Perform a physical exam including vital signs
4. Assess for any adverse events since your last visit
At each 6 month interval we will ask you to complete the questionnaires about your health, well-
being, quality of life, mental health, emotional health and mood. 
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 5 of 16
Subject Identification
Once a year we will repeat the ECG. 
After You Complete the Study
After you complete the study, we will continue to treat you for your condition as determined 
appropriate by Dr. Niles and Dr. Cortazar. 
Stopping the Study Early
If you decide to stop taking part in the study for any reason, we will ask you to make a final 
study visit.  If you cannot make it to an office visit, one of the study staff will call you on the 
phone. 

You will be asked about any changes to your GPA or MPA treatment since the last visit 
or phone call.

You will be asked questions about any side effects because of a medical condition and 
medication use.

You will be asked why you are no longer participating in the study.

The study doctor will determine the best care for you

Do a physical exam

Ask you about any side effects or health problems since your last visit

Draw a blood sample

Ask you for a urine sample

Ask you to fill out some questionnaires
Any of your information gathered up until that point in time may still be used for study purposes. 
We may also ask that we follow you observationally with a phone call. 
Also, the study doctor may take you out of the study without your permission.  This may happen 
because:

The study doctor thinks it is best for you to stop taking the study drug

You can’t make the required study visits

We stop doing the study for other reasons
If this happens, the study doctor will explain why you need to stop taking part in the study.  We 
will ask you to come in for a final study visit as described above.
Review of Medical Records from Hospital Admissions or Emergency Department 
Visits
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 6 of 16
Subject Identification
Partners  has an electronic system that lets your study doctors know if you are admitted to a 
Partners Hospital, or if you visit a Partners Hospital Emergency Department.  We want to make 
sure the study doctors know about any possible problems or side effects you experience while 
you are taking part in the study.
Storing Samples and Health Information at [BWH/MGH] for Future Use
We would like to store some of your health information for future research related to ANCA 
Vasculitis.  We will label your health information with a code instead of your name.  The key to 
the code connects your name to your samples and health information.  The study doctor will 
keep the key to the code in a password protected computer/locked file.
Do you agree to let us store your health information for future research related to ANCA 
vasculitis?
 Yes
 No
Initials___________
Study Information Included in Your Electronic Medical Record
A notation that you are taking part in this research study may be made in your electronic medical 
record.  Information from the research that relates to your general medical care may be included 
in the record (for example: list of allergies, results of standard blood tests done at the hospital 
labs).
Please ask your study doctor if you have any questions about what information will be included 
in your electronic medical record.
What are the risks and possible discomforts from being in this research 
study?
Risks of Taking Rituximab
Taking rituximab may cause you to have one or more of the side effects listed below.
You may experience side effects while receiving rituximab, which is given to you by your 
doctors as part of your regular medical care for your GPA or MPA.  Your doctor will explain the 
possible side effects of Rituximab and other regular medical treatment and drugs.
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 7 of 16
Subject Identification
Common side effects of Rituximab:

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
o
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 with the infusion can prevent these 
reactions.  We can stop the infusion immediately if a reaction occurs.
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.  We check hepatitis status at baseline visit to prevent 
reactivation.
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.  Common symptoms 
of an allergic reaction are rash, itching, skin problems, swelling of the face and throat, or trouble 
breathing.  If you think you are having an allergic reaction, call the study doctor right away.  If 
you are having trouble breathing, call 911 immediately. 
You CANNOT receive a live vaccine such as zostavax while you are taking rituximab.  Talk 
with the study doctor before you receive any vaccine.
Risks to an Embryo or Fetus, or to a Breastfeeding Infant
The effects of rituximab on a fetus (developing baby still in the womb), or on a breastfeeding 
infant, are unknown and may be harmful.  Individual of childbearing potential should use 
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 8 of 16
Subject Identification
effective birth control during treatment and for 12 months after rituximab therapy.  If at any time 
during the study you suspect that you have become pregnant, please notify the study doctor 
immediately.  Prior to any infusion of Rituximab to a woman of childbearing age, a urine 
pregnancy test is done and recorded, this must be negative.
Acceptable birth control methods for use in this study are:

hormonal methods, such as birth control pills, patches, injections, vaginal 
ring, or implants

barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm)

intrauterine device (IUD)

abstinence (no sex)
If you miss a period, or think you might be pregnant during the study, you must tell the study 
doctor immediately.  If you become pregnant, you must stop taking the study drug and stop 
taking part in the study.  The study doctor may ask for your permission to collect information 
about the outcome of your pregnancy and the condition of your newborn. 
No pregnancy test is needed if:

You are a menopausal woman and have not had a period for the past 12 months or more

There is a documented method of surgical sterilization 
o
hysterectomy (removal of the uterus with or without the removal of the ovaries)
o
tubal ligation
o
transvaginal occlusion (plugging the opening of the tubes with a coil
If you are sexually active and able to father a child, you must agree to use one of the birth control 
methods listed below.  You must use birth control 12 months after your last dose of rituximab. 
Acceptable birth control methods that you can use in this study are:

condoms with spermicide (a foam, cream, or gel that kills sperm)

abstinence (no sex)
Acceptable birth control methods that your partner(s) should use are:

hormonal methods, such as birth control pills, patches, injections, vaginal 
ring, or implants

barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm)

intrauterine device (IUD)
If your female partner becomes pregnant, we would like to follow the outcome of the pregnancy. 
You should notify us immediately if your partner becomes pregnant. She may be asked to sign a 
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 9 of 16
Subject Identification
release of medical information form that gives her doctors permission to provide information to 
us. You will not have to stop taking part in the study if your partner becomes pregnant. 
Risks of Taking Rituximab with Other Medications
Do not take cisplatin while you are receiving the rituximab infusions. Taking this medication and 
rituximab together may cause serious side effects.  In addition, on the day of your rituximab 
infusion, do not take your blood pressure medications in the morning.  In some patients, blood 
pressure decreases temporarily during a rituximab infusion.  Waiting to take your blood pressure 
medications will help avoid a dangerously low blood pressure.  
For your safety during this study, call your study doctor BEFORE you take any:

New medications prescribed by your own doctor.

Other medications sold over-the-counter without a prescription

Dietary or herbal supplements
Risk of Relapse of Disease
Discontinuing routinely scheduled rituximab will possibly lead to an increase in disease relapse. 
Relapses have the potential to cause irreversible organ damage especially in subjects with 
disease affecting their kidneys. However, the risk of relapse must be weighed against the harms 
of ongoing treatment with immunosuppression. To decrease the risk of worsening organ damage, 
we have restricted entry to those subjects who have acceptable prespecified kidney function. 
Subjects will be assessed at regular intervals and as needed to assess for worsening disease 
activity. If the investigator feels that your disease is coming back (relapsing) then he will treat 
you with the appropriate medical care and  may be removed from the study if necessary.
Risks of Blood Draws
You may have a bruise (a black and blue mark) or pain where we take the blood samples.  There 
is also a small risk of infection, lightheadedness, and/or fainting
What are the possible benefits from being in this research study?
You may not directly benefit from taking part in this research study.  Currently, specialists do not 
know the ideal long term treatment plan for patients in remission with ANCA Vasculitis. We 
hope that this study provides some answers to that question. 
Others with ANCA Vasculitis may benefit in the future from what we learn in this study. 
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 10 of 16
Subject Identification
What other treatments or procedures are available for my condition?
You do not have to take part in this research study to be treated for ANCA Vasculitis.  Your 
doctor will continue to treat you as deemed appropriate which may or may not include 
continuing on regularly scheduled rituximab infusions. 
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part? 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive.
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study.
What should I do if I want to stop taking part in the study?
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed.
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed.
Will I be paid to take part in this research study?
You will not be paid to participate in this study.
We may use your information to develop a new product or medical test to be sold.   The hospital 
and researchers may benefit if this happens.  There are no plans to pay you if your samples are 
used for this purpose.  
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 11 of 16
Subject Identification
What will I have to pay for if I take part in this research study?
Study funds will pay for study-related procedures, study visits that are done ONLY for 
research. The study visit schedule is part of your usual care even if you were not participating in 
the study. Lab tests and infusions are also part of your usual care and will be billed to insurance. 
Study funds will pay for certain study-related items and services.  We may bill your health 
insurer for, among other things, routine items and services you would have received even if you 
did not take part in the research.  You will be responsible for payment of any deductibles and co-
payments required by your insurer for this routine care or other billed care.  If you have any 
questions about costs to you that may result from taking part in the research, please speak with 
the study doctors and study staff.  If necessary, we will arrange for you to speak with someone in 
Patient Financial Services about these costs.
What happens if I am injured as a result of taking part in this research 
study?
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer.
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form.
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form.
If I have questions or concerns about this research study, whom can I 
call?
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 12 of 16
Subject Identification
Dr. John L. Niles is the person in charge of this research study, he or is designee will try to 
answer all your questions.  If you have questions or concerns at any time, or if you need to report 
any infection or injury related to the research, you may speak with a member of the research 
staff:
John L Niles, M.D.
Nephrologist
617-726-4132
Reza Zonozi M.D.
Nephrologist
617-726-4132
Anushya Jeyabalan M.D.
Nephrologist
617-726-4132
Karen A. Laliberte RN 
Nurse Manager
617-724-6594
Pravarut Nithagon
Coordinator
617-726-4132 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 617-424-4100.
You can talk to them about:

Your rights as a research subject

Your concerns about the research

A complaint about the research
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help.
If I take part in this research study, how will you protect my privacy?
During this research, identifiable information about your health will be collected.  In the rest of 
this section, we refer to this information simply as “health information.”  In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so.
In this study, we may collect health information about you from:

Past, present, and future medical records

Research procedures, including research office visits, tests, interviews, and 
questionnaires
Who may see, use, and share your identifiable health information and why they may 
need to do so:

Partners research staff involved in this study
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 13 of 16
Subject Identification

The sponsor(s) of this study, and the people or groups it hires to help perform this 
research

Other researchers and medical centers that are part of this study and their ethics boards

A group that oversees the data (study information) and safety of this research

Non-research staff within Partners who need this information to do their jobs (such as for  
treatment, payment (billing), or health care operations)

The Partners ethics board that oversees the research and the Partners research quality 
improvement programs.

People from organizations that provide independent accreditation and oversight of 
hospitals and research

People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers

Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research) 

Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law)

Other:       
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance.  We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private.
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information.
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission.
Your Privacy Rights
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 14 of 16
Subject Identification
You have the right not to sign this form that allows us to use and share your health information 
for research; however, if you don’t sign it, you can’t take part in this research study.   
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study.
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others.
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished.
Informed Consent and Authorization
Statement of Person Giving Informed Consent and Authorization

I have read this consent form.

This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study.

I have had the opportunity to ask questions.

I understand the information given to me.
Signature of Subject:
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above.
Subject
Date
Time (optional)
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 15 of 16
Subject Identification
Statement of Study Doctor or Person Obtaining Consent

I have explained the research to the study subject.

I have answered all questions about this research study to the best of my ability.
Study Doctor or Person Obtaining Consent
Date
Time (optional)
Consent of Non-English Speaking Subjects Using the “Short Form” in the 
Subject’s Spoken Language
Statement of Hospital Medical Interpreter
As someone who understands both English and the language spoken by the subject, I interpreted, 
in the subject's language, the researcher's presentation of the English consent form.  The subject 
was given the opportunity to ask questions.
Hospital Medical Interpreter
Date
Time (optional)
OR
Statement of Other Individual (Non-Interpreter)
As someone who understands both English and the language spoken by the subject, I represent 
that the English version of the consent form was presented orally to the subject in the subject’s 
own language, and that the subject was given the opportunity to ask questions.
Name
Date
Time (optional)
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021


Partners HealthCare System
Research Consent Form
General Template - Drug Clinical Trial
Version Date:  October 2014
Page 16 of 16
Subject Identification
Witness to Consent of Subjects Who Cannot Read or Write or are Physically 
Unable to Talk or Write
Statement of Witness
I represent that the consent form was presented orally to the subject in the subject’s own 
language, that the subject was given the opportunity to ask questions, and that the subject has 
indicated his/her consent and authorization for participation by (check one box as applicable):
 Making his/her mark above
 Other means ________________________________________________________________
(fill in above)
Witness
Date
Time (optional)
Consent Form Version:       
ICF_Maintancavas March 2021
Consent Form Title: MAINTANCAVAS_ICF_MAR_2021 Clean
IRB Protocol No: 2015P002541
Sponsor Protocol No: Maintancavas Detailed Protocol V11 January 3, 2020
Consent Form Valid Date: 8/20/2021
IRB Amendment No: AME38
Sponsor Amendment No: N/A
Consent Form Expiration Date: 3/23/2022
IRB Amendment Approval Date: 8/20/2021