Trial Outcomes & Findings for Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing (NCT NCT02749292)

Last Updated: 2023-07-27

Results Overview

Relapses recording period was from 6/1/2016 to 12/31/2021. The outcome was reported as the number of participants with disease relapse who had either positive ANCA titers specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64.

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

115 participants

Primary outcome timeframe

Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

Results posted on

2023-07-27

Participant Flow

Participant milestones

Participant milestones
Measure	B Cell Reconstitution Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Overall Study STARTED	58	57
Overall Study COMPLETED	36	31
Overall Study NOT COMPLETED	22	26

Reasons for withdrawal

Reasons for withdrawal
Measure	B Cell Reconstitution Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Overall Study Physician Decision	1	0
Overall Study Withdrawal by Subject	5	7
Overall Study Minor relapse, BVAS-WG = 2	1	7
Overall Study Major relapse without ILD, BVAS-WG ≥ 3	2	4
Overall Study Major relapse with ILD, BVAS-WG ≥ 3	2	3
Overall Study Adverse Event	4	1
Overall Study Serious Adverse Event, Related, infection, COVID-19, with death	2	0
Overall Study Serious Adverse Event, Related, infection, COVID-19, without death	4	1
Overall Study Requiring glucocorticoids	0	3
Overall Study Cancer	1	0

Baseline Characteristics

Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).	Total n=115 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	36 Participants n=99 Participants	34 Participants n=107 Participants	70 Participants n=206 Participants
Age, Categorical >=65 years	22 Participants n=99 Participants	23 Participants n=107 Participants	45 Participants n=206 Participants
Age, Continuous	61 years STANDARD_DEVIATION 10 • n=99 Participants	62 years STANDARD_DEVIATION 12 • n=107 Participants	61 years STANDARD_DEVIATION 11 • n=206 Participants
Sex: Female, Male Female	30 Participants n=99 Participants	26 Participants n=107 Participants	56 Participants n=206 Participants
Sex: Female, Male Male	28 Participants n=99 Participants	31 Participants n=107 Participants	59 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	58 Participants n=99 Participants	56 Participants n=107 Participants	114 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	2 Participants n=99 Participants	1 Participants n=107 Participants	3 Participants n=206 Participants
Race (NIH/OMB) White	55 Participants n=99 Participants	53 Participants n=107 Participants	108 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=99 Participants	2 Participants n=107 Participants	3 Participants n=206 Participants
Region of Enrollment United States	58 participants n=99 Participants	57 participants n=107 Participants	115 participants n=206 Participants
ANCA serotype Anti-PR3	31 Participants n=99 Participants	31 Participants n=107 Participants	62 Participants n=206 Participants
ANCA serotype Anti-MPO	27 Participants n=99 Participants	26 Participants n=107 Participants	53 Participants n=206 Participants
Continuous Rituximab prior to entry Less than 3 years at entry	29 Participants n=99 Participants	28 Participants n=107 Participants	57 Participants n=206 Participants
Continuous Rituximab prior to entry More than 3 years at entry	29 Participants n=99 Participants	29 Participants n=107 Participants	58 Participants n=206 Participants
Induction Regimen- Rituximab and Cyclophosphamide Cyclophosphamide	10 Participants n=99 Participants	12 Participants n=107 Participants	22 Participants n=206 Participants
Induction Regimen- Rituximab and Cyclophosphamide Rituximab	16 Participants n=99 Participants	13 Participants n=107 Participants	29 Participants n=206 Participants
Induction Regimen- Rituximab and Cyclophosphamide Cyclophosphamide and Rituximab	32 Participants n=99 Participants	32 Participants n=107 Participants	64 Participants n=206 Participants
Induction Regimen- Plasma Exchange	12 Participants n=99 Participants	9 Participants n=107 Participants	21 Participants n=206 Participants
Clinical manifestations at diagnosis Scleritis	18 Participants n=99 Participants	13 Participants n=107 Participants	31 Participants n=206 Participants
Clinical manifestations at diagnosis Otitis	17 Participants n=99 Participants	17 Participants n=107 Participants	34 Participants n=206 Participants
Clinical manifestations at diagnosis Sinusitis	30 Participants n=99 Participants	26 Participants n=107 Participants	56 Participants n=206 Participants
Clinical manifestations at diagnosis Tracheal Stenosis	2 Participants n=99 Participants	2 Participants n=107 Participants	4 Participants n=206 Participants
Clinical manifestations at diagnosis Pulmonary Hemorrhage	6 Participants n=99 Participants	13 Participants n=107 Participants	19 Participants n=206 Participants
Clinical manifestations at diagnosis ILD	2 Participants n=99 Participants	1 Participants n=107 Participants	3 Participants n=206 Participants
Clinical manifestations at diagnosis Renal involvement (including RPGN, required Hemodialysis and HD dependent)	31 Participants n=99 Participants	30 Participants n=107 Participants	61 Participants n=206 Participants
Clinical manifestations at diagnosis Rapidly Progressive Glomerulonephritis (RPGN)	20 Participants n=99 Participants	15 Participants n=107 Participants	35 Participants n=206 Participants
Clinical manifestations at diagnosis Required Hemodialysis	1 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants
Clinical manifestations at diagnosis HD dependent	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
BVAS/WG at entry	0 units on a scale STANDARD_DEVIATION 0 • n=99 Participants	0 units on a scale STANDARD_DEVIATION 0 • n=107 Participants	0 units on a scale STANDARD_DEVIATION 0 • n=206 Participants
VDI at entry	1 units on a scale STANDARD_DEVIATION 1 • n=99 Participants	1 units on a scale STANDARD_DEVIATION 1 • n=107 Participants	1 units on a scale STANDARD_DEVIATION 1 • n=206 Participants
Creatinine at entry	1.04 mg/dL n=99 Participants	1.09 mg/dL n=107 Participants	1.08 mg/dL n=206 Participants
Ig levels at entry IgG	699 mg/dL n=99 Participants	750 mg/dL n=107 Participants	710 mg/dL n=206 Participants
Ig levels at entry IgM	23 mg/dL n=99 Participants	31 mg/dL n=107 Participants	29 mg/dL n=206 Participants
eGFR at entry	60 cc/min/1.73m^2 n=99 Participants	60 cc/min/1.73m^2 n=107 Participants	60 cc/min/1.73m^2 n=206 Participants
Disease status Previous relapse	16 Participants n=99 Participants	17 Participants n=107 Participants	33 Participants n=206 Participants
Disease status Newly diagnosed	42 Participants n=99 Participants	40 Participants n=107 Participants	82 Participants n=206 Participants

PRIMARY outcome

Timeframe: Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Number of Patients With Disease Relapse(s) as Defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 MPO	4 Participants	7 Participants
Number of Patients With Disease Relapse(s) as Defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 PR3	1 Participants	7 Participants

SECONDARY outcome

Timeframe: Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

Number of patients with serious adverse events (SAEs), including all episodes of late onset neutropenia (LON). SAE are defined in the Serious adverse event section. Serious adverse events were reported over the entire study period (5.5 years)

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Number of Patients Affected by Serious Adverse Events	15 Participants	14 Participants

SECONDARY outcome

Timeframe: Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

Number of disease relapse added with the number of SAE in each group

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Composite of Disease Relapse (Defined a BVAS/WG ≥ 2) and Serious Adverse Events	27 Number of events	36 Number of events

SECONDARY outcome

Timeframe: Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

Hypogammaglobulinemia defined as an IgG \< 250mg/dL

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Number of Patients With Hypogammaglobulinemia	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 5.5 years

number of deaths throughout the study.

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Patient Survival	2 number of deaths	0 number of deaths

SECONDARY outcome

Timeframe: Assessed throughout the study period, every 6 months unless such time point was not reached or was missed by the patient. Median follow-up period is of 4.1 years (IQR, 2.5 - 5.0)

Population: We collected data using the SF-36 on the quality of life due to its importance in the long-term treatment of ANCA vasculitis. Questionnaires were given to patients every 6 months throughout the study period. Some participants do not have scores at certain time points due to either a missed visit or not being enrolled anymore in the study.

The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status and is commonly used in health economics as a variable in the quality-adjusted life year calculation to determine the cost-effectiveness of a health treatment. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 36 months	76 score on a scale Standard Deviation 19	84 score on a scale Standard Deviation 10
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 24 months	69 score on a scale Standard Deviation 15	70 score on a scale Standard Deviation 16
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 6 months	84 score on a scale Standard Deviation 19	82 score on a scale Standard Deviation 23
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 6 months	66 score on a scale Standard Deviation 40	65 score on a scale Standard Deviation 45
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 6 months	79 score on a scale Standard Deviation 34	75 score on a scale Standard Deviation 41
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 6 months	65 score on a scale Standard Deviation 15	67 score on a scale Standard Deviation 23
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 6 months	83 score on a scale Standard Deviation 12	81 score on a scale Standard Deviation 16
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 6 months	89 score on a scale Standard Deviation 19	88 score on a scale Standard Deviation 21
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 6 months	79 score on a scale Standard Deviation 23	82 score on a scale Standard Deviation 20
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 6 months	66 score on a scale Standard Deviation 15	63 score on a scale Standard Deviation 20
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 36 months	74 score on a scale Standard Deviation 27	88 score on a scale Standard Deviation 19
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 36 months	50 score on a scale Standard Deviation 47	79 score on a scale Standard Deviation 36
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 36 months	65 score on a scale Standard Deviation 46	82 score on a scale Standard Deviation 27
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 36 months	58 score on a scale Standard Deviation 17	73 score on a scale Standard Deviation 17
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 36 months	83 score on a scale Standard Deviation 25	95 score on a scale Standard Deviation 13
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 36 months	69 score on a scale Standard Deviation 23	87 score on a scale Standard Deviation 16
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 36 months	60 score on a scale Standard Deviation 20	70 score on a scale Standard Deviation 20
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 12 months	79 score on a scale Standard Deviation 24	82 score on a scale Standard Deviation 23
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 12 months	61 score on a scale Standard Deviation 43	63 score on a scale Standard Deviation 43
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 12 months	82 score on a scale Standard Deviation 34	68 score on a scale Standard Deviation 42
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/ fatigue at 12 months	65 score on a scale Standard Deviation 20	65 score on a scale Standard Deviation 22
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 12 months	86 score on a scale Standard Deviation 11	81 score on a scale Standard Deviation 14
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 12 months	92 score on a scale Standard Deviation 18	86 score on a scale Standard Deviation 22
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 12 months	81 score on a scale Standard Deviation 19	80 score on a scale Standard Deviation 21
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 12 months	66 score on a scale Standard Deviation 17	63 score on a scale Standard Deviation 21
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 18 months	83 score on a scale Standard Deviation 19	82 score on a scale Standard Deviation 25
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 18 months	70 score on a scale Standard Deviation 41	62 score on a scale Standard Deviation 44
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 18 months	88 score on a scale Standard Deviation 29	74 score on a scale Standard Deviation 42
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 18 months	69 score on a scale Standard Deviation 14	68 score on a scale Standard Deviation 17
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 18 months	85 score on a scale Standard Deviation 9	81 score on a scale Standard Deviation 13
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 18 months	96 score on a scale Standard Deviation 9	92 score on a scale Standard Deviation 16
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 18 months	84 score on a scale Standard Deviation 18	82 score on a scale Standard Deviation 19
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 18 months	68 score on a scale Standard Deviation 17	67 score on a scale Standard Deviation 18
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 24 months	83 score on a scale Standard Deviation 24	88 score on a scale Standard Deviation 15
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 24 months	71 score on a scale Standard Deviation 40	71 score on a scale Standard Deviation 42
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 24 months	84 score on a scale Standard Deviation 33	80 score on a scale Standard Deviation 38
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 24 months	68 score on a scale Standard Deviation 15	76 score on a scale Standard Deviation 13
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 24 months	82 score on a scale Standard Deviation 15	85 score on a scale Standard Deviation 12
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 24 months	91 score on a scale Standard Deviation 20	94 score on a scale Standard Deviation 14
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 24 months	81 score on a scale Standard Deviation 22	82 score on a scale Standard Deviation 15
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 30 months	85 score on a scale Standard Deviation 17	88 score on a scale Standard Deviation 17
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 30 months	74 score on a scale Standard Deviation 38	72 score on a scale Standard Deviation 40
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 30 months	87 score on a scale Standard Deviation 27	80 score on a scale Standard Deviation 39
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 30 months	64 score on a scale Standard Deviation 16	72 score on a scale Standard Deviation 19
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 30 months	81 score on a scale Standard Deviation 12	84 score on a scale Standard Deviation 14
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 30 months	90 score on a scale Standard Deviation 19	94 score on a scale Standard Deviation 12
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 30 months	86 score on a scale Standard Deviation 17	83 score on a scale Standard Deviation 18
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 30 months	60 score on a scale Standard Deviation 14	70 score on a scale Standard Deviation 16
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 42 months	76 score on a scale Standard Deviation 25	82 score on a scale Standard Deviation 24
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 42 months	58 score on a scale Standard Deviation 49	60 score on a scale Standard Deviation 40
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 42 months	67 score on a scale Standard Deviation 47	76 score on a scale Standard Deviation 37
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 42 months	60 score on a scale Standard Deviation 19	70 score on a scale Standard Deviation 24
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 42 months	77 score on a scale Standard Deviation 18	85 score on a scale Standard Deviation 12
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 42 months	85 score on a scale Standard Deviation 15	87 score on a scale Standard Deviation 24
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 42 months	83 score on a scale Standard Deviation 16	82 score on a scale Standard Deviation 21
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 42 months	59 score on a scale Standard Deviation 13	63 score on a scale Standard Deviation 22
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 48 months	65 score on a scale Standard Deviation 29	95 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 48 months	67 score on a scale Standard Deviation 52	100 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 48 months	67 score on a scale Standard Deviation 52	100 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 48 months	52 score on a scale Standard Deviation 21	75 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 48 months	73 score on a scale Standard Deviation 29	85 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 48 months	65 score on a scale Standard Deviation 41	100 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 48 months	70 score on a scale Standard Deviation 32	80 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 48 months	61 score on a scale Standard Deviation 22	75 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 54 months	88 score on a scale Standard Deviation 14	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 54 months	50 score on a scale Standard Deviation 58	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 54 months	67 score on a scale Standard Deviation 38	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 54 months	67 score on a scale Standard Deviation 19	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 54 months	84 score on a scale Standard Deviation 5	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 54 months	84 score on a scale Standard Deviation 19	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 54 months	81 score on a scale Standard Deviation 26	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 54 months	59 score on a scale Standard Deviation 6	—
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Physical functioning at 60 months	72 score on a scale Standard Deviation 25	92 score on a scale Standard Deviation 3
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/physical at 60 months	33 score on a scale Standard Deviation 58	100 score on a scale Standard Deviation 0
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Role functioning/emotional at 60 months	100 score on a scale Standard Deviation 0	89 score on a scale Standard Deviation 19
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Energy/fatigue at 60 months	48 score on a scale Standard Deviation 24	71 score on a scale Standard Deviation 14
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Emotional well-being at 60 months	82 score on a scale Standard Deviation 10	83 score on a scale Standard Deviation 6
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Social functioning at 60 months	63 score on a scale Standard Deviation 38	92 score on a scale Standard Deviation 14
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores Pain at 60 months	53 score on a scale Standard Deviation 13	83 score on a scale Standard Deviation 13
Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores General health at 60 months	58 score on a scale Standard Deviation 32	70 score on a scale Standard Deviation 23

SECONDARY outcome

Timeframe: Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

The rituximab utilization was measured in how many times a subject received Rituximab throughout the study which was then averaged for all subjects in each treatment arm, including those who did not receive any infusion.

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Mean Number of Rituximab Infusions Per Subject	3.6 Infusions per subject Standard Deviation 2.4	0.5 Infusions per subject Standard Deviation 1.5

SECONDARY outcome

Timeframe: 3 years starting at inclusion

The Vasculitis Damage Index (VDI) is a validated formal assessment tool in ANCA-associated vasculitis clinical trials. The VDI distinguishes vasculitis-induced chronic damage from active inflammation or persistent disease. Each item represents a disease manifestation and is given a score (of 1) if present for at least 3 months. Neither the cause of damage (vasculitis vs treatment) nor an ongoing activity are taken into consideration. The VDI includes 64 items categorized into 11 groups (by organ system) and the scored items are summed to give a total score ranging from 0 to 64. A higher score means more accrued damage.

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Organ Damage as Assessed by the Vasculitis Damage Index (VDI). VDI at inclusion	1.27 score on a scale Standard Deviation 1.24	1.07 score on a scale Standard Deviation 1.11
Organ Damage as Assessed by the Vasculitis Damage Index (VDI). VDI at 3 years	1.42 score on a scale Standard Deviation 1.11	1.08 score on a scale Standard Deviation 1.16

SECONDARY outcome

Timeframe: Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64.

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Number of Major Relapses Defined as a BVAS/WG ≥ 3	4 number of events	7 number of events

SECONDARY outcome

Timeframe: Median follow-up period of 4.1 years (IQR, 2.5 - 5.0)

Number of infections mild and severe, whether they were treated or not with antibiotics

Outcome measures

Outcome measures
Measure	B Cell Reconstitution n=58 Participants Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 Participants 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Number of Infections Serious Adverse Events- Infections	12 number of events	6 number of events
Number of Infections Adverse Events- Infections	72 number of events	59 number of events

Adverse Events

B Cell Reconstitution

Serious events: 15 serious events

Other events: 46 other events

Deaths: 2 deaths

Serologic ANCA Flare

Serious events: 14 serious events

Other events: 44 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

John L Niles

Massachusetts General Hospital- Vasculitis and Glomerulonephritis Center

Phone: 617-726-4132

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	B Cell Reconstitution n=58 participants at risk Subjects will not receive their regularly-scheduled every-six-month dose of rituximab (1000mg IV) and will instead receive rituximab 1000 mg IV x 1 dose only 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 (1 dose of 1000mg IV) 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. Rituximab: re-dosing dependent on interventional arm parameter.	Serologic ANCA Flare n=57 participants at risk 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. In this arm, rituximab administration is not contingent upon B cell levels but on significant ANCA titer rise 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 the ANCA arm will move to once yearly CD20 testing after CD20 levels return to normal levels (\>90 cells/uL).
Infections and infestations Upper Respiratory Infection (Cold)	36.2% 21/58 • Number of events 28 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	29.8% 17/57 • Number of events 24 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Renal and urinary disorders Urinary Track Infection	8.6% 5/58 • Number of events 9 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	10.5% 6/57 • Number of events 7 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Musculoskeletal and connective tissue disorders Gout flare	3.4% 2/58 • Number of events 4 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 2 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Respiratory, thoracic and mediastinal disorders Cough	8.6% 5/58 • Number of events 6 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	14.0% 8/57 • Number of events 9 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Sinusitis	5.2% 3/58 • Number of events 5 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	12.3% 7/57 • Number of events 8 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations COVID-19 Positive	15.5% 9/58 • Number of events 9 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	7.0% 4/57 • Number of events 4 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Immune system disorders Allergic Reaction to Rituximab Infusion	5.2% 3/58 • Number of events 3 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Immune system disorders Allergic reaction unrelated to Rituximab	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Vaginitis	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	3.5% 2/57 • Number of events 2 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Cardiac disorders Asymptomatic Sinus tachycardia	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Musculoskeletal and connective tissue disorders Right thigh pain	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Respiratory, thoracic and mediastinal disorders Bronchitis	5.2% 3/58 • Number of events 3 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	7.0% 4/57 • Number of events 4 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Cardiac disorders Heart murmurs	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Renal and urinary disorders Hematuria	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations pleural infection	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Musculoskeletal and connective tissue disorders Myalgias and arthralgias. Severe pains and frank arthritis in knees.	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Respiratory, thoracic and mediastinal disorders Pleuritic chest pain	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Hepatobiliary disorders Mild fatty replacement of the liver	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Musculoskeletal and connective tissue disorders Metacarpophalangeal tenderness	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Nervous system disorders Headache/ Migraine	5.2% 3/58 • Number of events 3 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Influenza	5.2% 3/58 • Number of events 3 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	7.0% 4/57 • Number of events 5 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Cellulitis	5.2% 3/58 • Number of events 3 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Cardiac disorders Conduction disorder (LBBB)	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Musculoskeletal and connective tissue disorders Fall injury	3.4% 2/58 • Number of events 3 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	3.5% 2/57 • Number of events 2 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) colonoscopy finding:tubulovillous adenomatous colon poplyp	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Renal and urinary disorders Renal calculi	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Rash in distribution of trigeminal nerve - consistent with zoster	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
General disorders Hypotension, fatigue, cough, HA, fever, malaise, volume depletion from high dose valtrex reaction	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Urine cx positive for E.coli	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Conjunctivitis	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	3.5% 2/57 • Number of events 2 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Skin and subcutaneous tissue disorders Paronychia	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Hepatobiliary disorders Elevated Liver Function Tests	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	5.3% 3/57 • Number of events 3 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Musculoskeletal and connective tissue disorders Mandibular pain	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Immune system disorders Neutropenia	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Vascular disorders Epistaxis	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Immune system disorders Jaw swelling,	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Cardiac disorders Distal Ventricular Tachycardia	0.00% 0/58 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Gastrointestinal disorders Stomach discomfort	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Sore throat	1.7% 1/58 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	0.00% 0/57 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.
Infections and infestations Pneumonia	3.4% 2/58 • Number of events 2 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.	1.8% 1/57 • Number of events 1 • June 1 2016 to December 2021 (5 years and 6 months). The earliest Adverse event reported was on 2/6/2017 and the latest adverse event reported was on 12/25/2021 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.