Clinical trial NCT02169219
Conditions: Granulomatosis With Polyangiitis Microscopic Polyangiitis
Sponsor: Massachusetts General Hospital
Start date: 2014-06-01; Completion date: 2017-11-01
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this pilot study is to test whether an 8-week course of glucocorticoids, combined with rituximab, is effective in treating ANCA-associated vasculitis.

Detailed description:
The primary aim of this pilot study is to examine whether an 8 week course of glucocorticoids, in combination with rituximab, is effective in inducing and maintaining disease remission for up to 6 months in a subset of patients with ANCA-associated vasculitis (AAV) who have a more favorable prognosis.

This pilot study will enroll 20 patients with active AAV. Close patient follow-up will insure that any patients who require courses of glucocorticoids longer than two months will receive longer therapy, if appropriate for their well-being.

Arms: arm 1: This is a single-arm trial. All patients receive both rituximab and glucocorticoids. The protocol calls for the discontinuation of prednisone within two months of the baseline visit.
Interventions: intervention 1: Glucocorticoids intervention 2: Rituximab
Intervention descriptions: intervention 1: Patients will begin prednisone therapy at a dose selected by the investigator or the treating physician with oral prednisone 60mg or 1mg/kg (if weight less than 60kg) or intravenous methylprednisolone, up to 1g/day for three days.

Prednisone will be tapered over 8 weeks as follows:

* 60mg for 2 weeks
* 40mg for 2 weeks
* 30mg for 1 week
* 20mg for 1 week
* 10mg for 1 week
* 5mg for 1 week intervention 2: Rituximab will be administered in four weekly doses at 375mg/m2

Protocol documents:
Prot_SAP_000.pdf: 
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1
Short-Course Glucocorticoids and Rituximab  
in ANCA-Associated Vasculitis 
 
 
I. Background and Significance 
 
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are anti-
neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) affecting small 
and medium sized vessels.  Treatment of systemic AAV with cyclophosphamide and 
glucocorticoids (GCs) has significantly reduced the previously high mortality rate 
associated with these diseases.  Recently, rituximab, a monoclonal anti-CD20 antibody, 
was shown to be non-inferior to cyclophosphamide and azathioprine for the treatment for 
AAV.1  Based on this trial, rituximab, in combination with GCs, has been approved by 
the FDA for treatment of GPA and MPA.2   
 
Despite therapeutic advances in AAV, patients continue to be exposed to considerable 
treatment morbidity from long-term GC use.  GCs raise the risk of infection substantially, 
and this risk increases with higher doses and longer duration of treatment.  Moreover, the 
risk persists even after the discontinuation of GCs.3 GC-induced osteoporosis leads to 
significant morbidity with a 75% increase in the risk of fracture in the first 3 months of 
GC therapy and an overall fracture rate of 30-50% in patients treated with long-term 
GCs.4  Gastrointestinal bleeding (GIB) is another common cause of morbidity with a four 
fold increase in the rate of hospitalization for GIB in patients treated with GCs.5  Other 
adverse events include GC-induced diabetes, cataracts, hypertension and weight gain 
among others.6  Therefore, limiting the duration of GC treatment in this era of biologic 
therapies for AAV would be an important additional step forward in the treatment of 
these conditions. 
 
The optimal duration of GC treatment has not been studied in AAV.  Previous trials in 
AAV have used various dosing regimens, lasting 6-24 months.7-10  Because the aim of the 
trials was the investigation of a non-GC therapy, the comparison of GC regimens cannot 
be made directly.  A recent analysis of the data from the registry of the Glomerular 
Disease Collaborative Network demonstrated that in patients with AAV, GC courses of 
longer than 6 months were associated with greater risk of infection without a reduction in 
the risk of relapse. 11  In contrast, a meta-analysis performed by Walsh et al demonstrated 
that longer duration of GC therapy was associated with fewer AAV relapses.12  However, 
all of the trials included in the analysis used cyclophosphamide rather than rituximab to 
induce remission.  One course of rituximab depletes circulating B lymphocytes within 
two weeks of the first infusion and is as effective as prolonged treatment with 
cyclophosphamide followed by azathioprine at 18 months.13 Because of rituximab’s 
ability to deplete circulating B cells entirely for a period of 6 to 18 months (or even 
longer), treatment regimens that employ this therapy have the potential for substantial GC 
sparing.   
 
There is evidence to suggest that certain subsets of patients with AAV may be more at 
risk for flares and severe disease manifestations.  Previous studies have shown that 


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patients with proteinase-3 (PR3) ANCA or diagnosis of GPA are at increased risk for 
flares as compared to patients with myeloperoxidase (MPO) ANCA or diagnosis of 
MPA.8,10,14,15  Unpublished data from the RAVE trial has demonstrated similar findings.   
 
We hypothesize that an 8 week course of GCs may be sufficient to control disease 
activity in a subset of patients with AAV who have a more favorable prognosis over a six 
months.  Such an approach would limit the cumulative GC dose by at least 45%, thus 
limiting GC toxicity.   
 
This protocol will test the hypothesis that short-course GCs in combination with 
rituximab are effective and safe in the induction of disease remission in a subset of 
patients with AAV.  Close patient follow-up will insure that any patients who require 
courses of GCs longer than two months will receive longer therapy, if appropriate for 
their well-being. 
 
II. Specific Aims 
 
The primary aim of this pilot study is to examine whether an 8 week course of GCs in 
combination with rituximab is effective at inducing and maintaining disease remission 
through the 6-month timepoint in patients a subset of patients with AAV who have a 
more favorable prognosis.   
 
 
III. Subject Selection 
 
A. Inclusion and exclusion criteria 
 
Inclusion criteria: 
- 
Patients ages 18-85 years old 
- 
Diagnosis of GPA or MPA according to the definitions of the Chapel Hill 
Consensus Conference 
- 
New diagnosis or disease flare with a Birmingham Vasculitis Activity 
Score/Wegener’s granulomatosis (BVAS/WG) of > 3. 
 
Exclusion criteria: 
- 
Renal disease in patients with PR3-ANCA as defined by any of the following: 
- 
Urinary red blood cell casts 
- 
Biopsy-proven glomerulonephritis  
- 
Increase in serum creatinine of >30% over baseline  
- 
Severe renal disease in patients with MPO-ANCA as defined by both of the 
following: 
- 
Urinary red blood cell casts or biopsy-proven glomerulonephritis  
- 
Estimated glomerular filtration rate < 30 ml/min/1.73m2 
- 
Diffuse alveolar hemorrhage requiring ventilatory support 
- 
GC treatment for longer than 14 days prior to enrollment unless patient has 
been on a stable maintenance dose of prednisone at the time of the flare 


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- 
Daily oral cyclophosphamide within 1 month prior to enrollment 
- 
Completed a remission induction course of cyclophosphamide or rituximab 
within 4 months of enrollment 
- 
Current or past HBV infection (e.g., HBsAg positive, regardless of antibody 
status, HBsAg negative but anti-HBcAb positive). 
- 
HIV infection 
- 
History of anti-GBM disease 
- 
Other uncontrolled disease, including drug and alcohol abuse, that may 
interfere with the study 
- 
Pregnancy or breastfeeding 
- 
History of severe allergic reactions to human or chimeric monoclonal 
antibodies 
 
B. Source of subjects and recruitment methods 
 
Subjects will be recruited via one of the following: 
 
- 
New diagnosis or flare of previously diagnosed disease in patients followed in 
the Massachusetts General Hospital (MGH) Rheumatology or Nephrology 
Units. 
- 
New diagnosis or flare of previously diagnosed disease in patients 
hospitalized at MGH. 
- 
Referrals from subspecialty colleagues who are aware of our interest in AAV. 
 
 
IV. Subject Enrollment 
 
A. Methods of enrollment and procedures for obtaining informed consent. 
 
- 
Drs. Stone, Miloslavsky, Unizony or Niles will discuss various treatment modalities 
with patients meeting the inclusion criteria.  In addition to the study treatment 
protocol, the following treatment options will be discussed: Rituximab and 
conventional duration of GC therapy (6-12 months); cyclophosphamide and 
conventional duration of GCs, followed by azathioprine or methotrexate.  Patients 
will be given adequate time to ask questions related to various treatment options and 
to discuss the study procedures in detail. 
 
- 
Informed consent will be discussed with all potential study subjects by Drs. Stone, 
Miloslavsky, Unizony or Niles.  In addition to the physicians, a nurse or coordinator 
will be available to answer patient’s questions.   
- 
Patients will be given up to seven days to consider treatment options.   
 
 
V. Study Procedures 
 
A. Study visits and data collection 


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4
 
1. Screening visit 
a. Diagnosis of new onset AAV or flare with BVAS/WG > 3 will be 
confirmed by a complete history and physical examination performed by 
one of the investigators. 
b. Treatment options will be discussed with the patient and informed consent 
for study participants will be obtained by one of the investigators. 
c. The following laboratory values will be obtained – complete blood count 
(CBC), complete metabolic panel (CMP), erythrocyte sedimentation rate 
(ESR), C-reactive protein (CRP), ANCA, chronic hepatitis B infection 
panel, HIV antibody, B-cell flow cytometry, immunoglobulin levels (IgG, 
IgM and IgA), urinalysis and urine pregnancy test if applicable.  
d. Imaging as deemed necessary by the investigator 
e. Patients will begin GC therapy at a dose selected by the investigator or the 
treating physician with oral prednisone 60mg or 1mg/kg (if weight less 
than 60kg) or intravenous methylprednisolone, up to 1g/day for three days. 
f. Patients will be started on omeprazole 20mg daily, trimethoprim-
sulfamethoxazole one single strength tablet daily, calcium citrate 500mg 
twice daily and vitamin D 400 units twice daily. 
g. Prior clinical assessment (labs) within one year can be used to determine 
screen eligibility. 
 
2. Study visit 1 (no later than 14 days after the screening visit) 
a. Treatment options will be discussed with the patient and informed consent 
for study participants will be obtained by one of the investigators. 
i. All screening laboratory values must be completed  
b. First dose of rituximab 375mg/m2 administered (premedication with 
hydrocortisone 100mg IV, diphenhydramine 25-50mg IV or PO, 
acetaminophen 650mg PO) 
c. Prednisone 60mg daily continued 
d. Focused history and physical exam performed by one of the investigators 
e. BVAS/WG and Vasculitis Damage Index (VDI) assessed by one of the 
investigators 
f. Adverse events assessed by one of the investigators 
 
3. Study visit 2 – one week after first study visit 
a. Second dose of rituximab 375mg/m2 administered (premedication with 
hydrocortisone 100mg IV, diphenhydramine 25-50mg IV or PO, 
acetaminophen 650mg PO) 
b. Prednisone 60mg daily continued 
 
4. Study visit 3 – two weeks after first study visit 
a. Third dose of rituximab 375mg/m2 administered (premedication with 
hydrocortisone 100mg IV, diphenhydramine 25-50mg IV or PO, 
acetaminophen 650mg PO) 
b. Prednisone decreased to 40mg daily 


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c. Laboratory tests – CBC, CMP, ESR, CRP, urinalysis 
 
5. Study visit 4 – three weeks after first study visit 
a. Final dose of rituximab 375mg/m2 administered (premedication with 
hydrocortisone 100mg IV, diphenhydramine 25-50mg IV or PO, 
acetaminophen 650mg PO) 
b. Prednisone 40mg daily continued 
 
6. Study visit 5 – four weeks after first study visit 
a. Patient assessed for disease response defined as: 
i. no new disease manifestations 
ii. no worsening of existing disease 
iii. stable or improved BVAS/WG score 
b. Focused history and physical exam performed by one of the investigators 
c. Adverse events assessed by one of the investigators 
d. Prednisone decreased to 30mg daily if disease response is achieved 
e. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, urinalysis, B-cell flow 
cytometry 
 
7. Phone call – five weeks after first study visit 
a. Phone assessment for any new or ongoing symptoms performed by one of 
the physicians, research nurse or study coordinator 
b. Prednisone decreased to 20mg if no new symptoms 
c. Schedule urgent visit if new or worsening symptoms 
 
8. Phone call – six weeks after first study visit 
a. Phone assessment for any new or ongoing symptoms performed by one of 
the physicians, research nurse or study coordinatorPrednisone decreased to 
10mg if no new symptoms 
b. Laboratory tests – BMP, ESR, CRP, urinalysis 
c. Schedule urgent visit if new/worsening symptoms or worsening 
laboratories 
 
9. Phone call – seven weeks after first study visit 
a. Phone assessment for any new or ongoing symptoms performed by one of 
the physicians, research nurse or study coordinatorPrednisone decreased to 
5mg if no new symptoms 
b. Schedule urgent visit if new or worsening symptoms 
 
10. Study visit 6 – eight weeks after first study visit 
a. Patient assessed for partial disease remission defined as: 
i. no new disease manifestations 
ii. no worsening of existing disease 
iii. BVAS/WG < 3 
b. Adverse events assessed by one of the investigators 


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6
c. Prednisone discontinued (or reduced to patient’s stable chronic dose of 
prednisone in order to avoid adrenal insufficiency) if patient meets partial 
disease remission criteria Omeprazole discontinued 
d. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, urinalysis, B-cell flow 
cytometry 
 
11. Phone call – nine weeks after first study visit 
a. Phone assessment for any new or ongoing symptoms performed by one of 
the physicians, research nurse or study coordinatorLaboratory tests – 
CBC, CMP, ESR, CRP 
b. Schedule urgent visit if new/worsening symptoms or worsening 
laboratories 
 
 
12. Study visit 7– twelve weeks after first study visit 
a. Focused history and physical exam performed by one of the investigators 
b. BVAS/WG assessed by one of the investigators 
c. Adverse events assessed by one of the investigators 
d. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, urinalysis 
 
13. Phone call – sixteen weeks after first study visit 
a. Phone assessment for any new or ongoing symptoms performed by one of 
the investigators 
b. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, and urinalysis 
c. Schedule urgent visit if new/worsening symptoms or worsening 
laboratories 
 
14. Study visit 8 – twenty weeks after first study visit 
a. Focused history and physical exam performed by one of the investigators 
b. BVAS/WG assessed by one of the investigators 
c. Adverse events assessed by one of the investigators 
d. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, urinalysis 
 
15. Study visit 9 – twenty-four weeks after first study visit 
a. Focused history and physical exam performed by one of the investigators 
b. BVAS/WG and VDI assessed by one of the investigators 
c. Primary outcome measured - defined as BVAS/WG = 0 and prednisone 
dose = 0 (or maintained at patient’s stable chronic dose of prednisone in 
order to avoid adrenal insufficiency) with no preceeding flares. 
d. Adverse events assessed by one of the investigators 
e. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, urinalysis, B-cell flow 
cytometry, immunoglobulin levels (IgG, IgM and IgA). 
 
Following the completion of six months on protocol, subjects will be treated according to 
the best medical judgment of their treating physician and will continued to be followed 
for six additional months. 


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7
 
16. Study visit 10 – 9 months after first study visit 
a. Focused history and physical exam performed by one of the investigators 
b. BVAS/WG assessed by one of the investigators 
c. Adverse events assessed by one of the investigators 
d. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, urinalysis, B-cell flow 
cytometry 
17. Study visit 11 – 12 months after first study visit 
a. Focused history and physical exam performed by one of the investigators 
b. BVAS/WG and VDI assessed by one of the investigators 
c. Adverse events assessed by one of the investigators 
d. Sustained remission assessed – defined as BVAS/WG = 0, prednisone 
dose = 0 (or maintained at patient’s stable chronic dose of prednisone in 
order to avoid adrenal insufficiency) and no disease flares during the study 
period. 
e. Laboratory tests – CBC, CMP, ESR, CRP, ANCA, HACA, urinalysis, B-
cell flow cytometry, immunoglobulin levels (IgG, IgM and IgA) 
Additional visits may be required at the discretion of the investigator. 
 
Missed visits  
 
– If a subject is unable to attend a scheduled visit they may reschedule within 10 
days of the time specified by the protocol. 
 
– If a subject cannot attend a scheduled visit within 10 days of the date specified by 
the protocol a phone call and laboratory testing may be substituted on up to two 
occasions over the one year study period.  The phone call will include a focused 
history and BVAS/WG scoring. 
 
Mechanistic study 
 
Subjects may be asked to give a blood sample for mechanistic studies, not to exceed 
40ccs at the beginning of the study, at the 6 month timepoint, at the completion of the 
study and during disease flares.   
 
Reimbursement 
 
- Subjects will be given a $40.00 echeck for each study visit. 
 
Treatment of flares 
 
Limited flares - having a new occurrence or worsening of one or more minor BVAS/WG 
items with a total BVAS/WG score < 3. 
 
- 
First limited flare - prednisone increase up to 40 mg/day for one week followed 
by 4 week taper (30mg, 20mg, 10mg, 5 week per week).  Lower starting 


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8
prednisone dose and shorter taper can be instituted at the discretion of the 
investigator. 
 
- 
Second limited flare - treatment according to best medical judgment of the 
investigator. 
Severe flares – BVAS/WG ≥ 3 or experiencing one of the major BVAS/WG items. 
- 
Patients with severe flares will be treated according to best medical judgment of 
the investigator.   
 
Termination of protocol 
 
The following pre-defined events will lead to subject’s treatment according to best 
medical judgment: 
 
- Two limited flares - defined as having a new occurrence or worsening of one or 
more minor BVAS/WG items. 
- One severe flare - defined as BVAS/WG ≥ 3 or experiencing one of the major 
BVAS/WG items) 
- Failing to achieve disease response at 4 weeks following the first rituximab 
infusion - defined as no new disease manifestations, no worsening of existing 
disease and stable or improved BVAS/WG score 
- Failing to achieve partial remission at 8 weeks following the first rituximab 
infusion - defined as no new disease manifestations, no worsening of existing 
disease and BVAS/WG < 3.   
 
Subjects treated according to best medical judgment will continue to be followed 
according to a modified visit schedule of no less than once every three months for 12 
months from study entry. 
 
Data Collection 
 
Data, including BVAS/WG scores, blood and urine test results, relevant radiology and 
pathology findings will be kept on data collection sheets and on Partners workstations or 
encrypted mobile devices using unique patient identifiers.  Drs. Stone, Miloslavsky, 
Unizony, Niles as well as Karen Laliberte, Andrew Murphy, Katherine Cosgrove and 
study staff will have access to coding sheets linking patient names and their unique 
identifiers.  The data collection sheets will be kept in a locked file cabinet in the 
Rheumatology Unit.   
 
Drs. Stone and Miloslavsky will review data on the number of subjects having limited or 
severe flares, achieving disease response, achieving partial remission and achieving 
remission after the first ten patients have been followed for six months.  Dr. Stone will be 
responsible for determining whether the research should be altered or stopped. 
 
PI’s intention is to maintain the subject files electronically through utilizing a Redcap 
database as well as accessing additional information from LMR.   The current Redcap 


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9
project has developed CRFs for almost all of the visits, and they are labeled by visit 
number (Screening visit, Visits 1-11). Specific visits may have multiple CRFs depending 
on the protocol-specific study procedures. With the exception of the laboratory CRF, the 
remaining data will be entered into the Redcap system by the clinician seeing the 
subjects. The plan is to have no paper worksheets and the data will be entered from the 
LMR clinical note by the clinicians. 
 
B. Drugs to be used 
a. Rituximab - patients will receive rituximab according to the regimen that the 
FDA has approved to treat AAV (375mg/m2).  They will also receive 
hydrocortisone 100 mg, acetaminophen 650 mg, and diphenhydramine 25 mg 
at the time of each infusion.  These medications are administered according to 
Rheumatology Infusion Center or the Nephrology Infusion Center protocols to 
decrease the likelihood of infusion reactions.  Common side effects include 
infusion reactions, cytopenias, and infection. 
b. Glucocorticoids – prednisone will be tapered off over eight weeks from a 
starting dose of 60mg or 1mg/kg, whichever is lower.  At the discretion of the 
investigators, patients can receive methylprednisolone 1g daily via 
intravenous infusion for three days at the onset of treatment.  For patients on 
stable chronic doses of prednisone (4 months or greater) prior to entering the 
trial, prednisone will be reduced to the chronic stable dose in order to avoid 
adrenal insufficiency due to rapid prednisone withdrawal. 
c. Trimethoprim-sulfamethoxazole will be prescribed for prophylaxis against 
pneumocystis infection.  Dapsone or atovaquone can be substituted for 
trimethoprim-sulfamethoxazole in case of allergy or at the investigator’s 
discretion. 
d. Omeprazole will be prescribed to prevent gastrointestinal ulceration. 
e. Calcium and vitamin D will be prescribed to prevent bone loss. 
 
Toxicity Grading Scale 
 
All adverse events will be recorded and classified according to the most recent version of 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), published June 10, 2003.  Adverse events will include those associated with 
glucocorticoid therapy, including hypertension, diabetes, osteoporosis, fractures, weight 
gain, adrenal insufficiency and others.  Adverse events should be recorded and graded 1 
to 5 according to the CTCAE grades provided below: 
- 
Grade 1 = Mild adverse event 
- 
Grade 2 = Moderate adverse event 
- 
Grade 3 = Severe and undesirable adverse event  
- 
Grade 4 = Life-threatening or disabling adverse event 
- 
Grade 5 = Death 
 
VI. Statistical Analysis 
 
The following variables will be collected during the study: 


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10
- 
Baseline variables 
o Age 
o Sex 
o Disease type (GPA or MPA) 
o ANCA type 
o New or relapsing disease 
o If relapsing disease - treatment prior to flare  
o BVAS/WG 
o VDI 
- 
BVAS/WG at visits 1 and 5-11 
- 
VDI at visits 9 and 11 
- 
Laboratory data at baseline and at visits 3, 5, 6, 7, 8, 9, 10 and 11 and after phone 
calls at 6,9 and 16 weeks of the study 
o CBC 
o CMP 
o ESR  
o CRP 
o ANCA 
o Urinalysis 
o Flow cytometry for B-cells (measured at visits 1, 5, 9, 10, 11) 
o HACA (measured at visits 1, 9, 11) 
o Quntitative immunoglobulins (measured at visits 1, 9 and 11) 
o Mechanistic studies (optional) (visit 1, 9, 11) 
- 
Prednisone dose at each visit 
- 
Adverse events 
 
Study endpoints 
 
Primary endpoint (assessed at 24 weeks) - Number of patients entering remission defined 
as BVAS/WG = 0 and prednisone dose = 0 (or maintained at patient’s stable chronic dose 
of prednisone in order to avoid adrenal insufficiency). 
 
Secondary endpoints (assessed at 24 weeks) 
- 
Number of early treatment failures defined as patients who have new or 
worsening disease manifestations assessed at 4 weeks after study entry 
- 
Number of severe flares defined as flare with BVAS/WG ≥ 3 or experiencing one 
of the major BVAS/WG items 
- 
Number of limited flares defined as having a new occurrence or worsening of one 
or more minor BVAS/WG items 
- 
Number of patients having a disease response 
- 
Number of patients entering partial remission 
- 
Number of patients entering sustained remission defined as BVAS/WG = 0, 
prednisone dose = 0 (or maintained at patient’s stable chronic dose of prednisone 
in order to avoid adrenal insufficiency)  and no disease flares during the study 
period. 
- 
Area under the curve BVAS/WG 


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11
- 
Total GC dose 
 
Statistical Methods 
 
Continuous data will be summarized using descriptive statistics (e.g., mean, standard 
deviation, median, minimum, and maximum).  Categorical data will be assessed using the 
Chi-square and the Fisher exact tests as appropriate.  Descriptive statistics and two-sided 
95% confidence intervals will be calculated to assist in the interpretation of efficacy 
outcomes. 
 
Power Analysis 
 
We plan to enroll a convenience sample of 20 patients for this pilot study.  This is based 
on the number of patients that we anticipate being able to enroll in one calendar year. 
 
 
VII. Risks and Discomforts 
 
Rituximab has been FDA approved for the treatment of AAV (April, 2011).   
 
A. 
Complications of peripheral intravenous line insertion 
 
The insertion of a peripheral intravenous line is associated with a mild degree of 
discomfort at the insertion site for a short period of time.  Small degrees of bleeding or 
bruising may occur at the site.  Skin irritation and rarely cellulitis can result at the site of 
intravenous catheter insertion.   
 
We have experienced infusion nurses who are expert in the insertion of peripheral 
intravenous catheters.   
 
B. 
Potential side-effects of rituximab 
 
Infusion reactions occur in a minority of patients treated with rituximab.  These reactions 
are normally treated effectively by stopping the infusion and when the symptoms resolve, 
restarting the infusion at one-half the rate of the previous dose..  In addition, such 
reactions are often prevented by the administration of hydrocortisone (100 mg), 
acetaminophen (650 mg), and diphenhydramine (25 mg) before the infusion.  Rituximab 
will be administered by an experienced infusion nurse who oversees up to two patient 
infusions at any given time. 
 
Other known risks of rituximab treatment are: 
 
Common but mild and transient side effects: 
 
- 
Within 24 hours of the 1st infusion - chills, itching, hives, sneezing, swelling, 
throat irritation or tightness 


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12
- 
Headache  
- 
Nausea 
- 
Upper respiratory tract infections 
- 
Joint pain 
 
Possible serious side effects or reactions: 
- 
Serious infusion reaction with hives, low blood pressure, breathing difficulties, 
irregular heartbeat and chest pain are very rare. Infusion reactions occur more 
commonly during the first infusion but can occur during any administration of 
rituximab.  Medications given with the infusion can prevent them and the infusion 
can be stopped immediately if a reaction occurs.  Resuming the infusion at half 
the rate after the symptoms has resolved is frequently effective at preventing 
further infusion reactions. 
- 
Infections are a concern with all drugs that affect the immune system.  Rituximab 
has been associated with reactivation of hepatitis B virus and progressive 
multifocal leukoencephalopathy infection, in addition to other common viral and 
bacterial pathogens.  Rituximab may decrease immunoglobulin levels.  In the 
event of a severe infection immunoglobulins will be checked in order to 
determine whether the administration of intravenous immunoglobulin is indicated. 
- 
Skin reactions, painful sores, ulcers, blisters and peeling skin (rare). 
- 
Decreased white blood cell counts. 
 
We anticipate that the risk of many of the infections which patients treated with the 
combination of rituximab and GCs are prone to will be attenuated by the shorter GC 
courses prescribed in this protocol. 
 
There may be other risks of rituximab that are currently unknown. 
 
 
VIII. Potential Benefits 
 
Benefits to participating individuals 
 
Individual patients may benefit from effective control of their disease with decreased 
toxicity from GC therapy. 
 
Benefits to society 
 
Results of this study may elucidate the optimal dose of GCs in the treatment of severe 
autoimmune disease such as AAV.  Decreasing administration of GCs may decrease their 
side effects and thus decrease the cost burden on society associated with treatment of 
severe autoimmune disease. 
 
 
IX. Monitoring and Quality Assurance 
 


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13
Drs. Stone and Miloslavsky will monitor study data to ensure the safety of patients.  A 
formal compilation of safety and efficacy data will be performed after ten patients have 
been enrolled in the study and followed for six months. 
 
Specific elements related to the safety of study subjects that will be examined include: 
 
- 
Deaths 
- 
Flares 
- 
Failure to achieve disease response, partial remission or remission. 
- 
Hospitalizations from any cause 
- 
Infections 
- 
Infusion reactions 
- 
Status of peripheral B cell pool with regard to reconstitution 
- 
Other unexpected and serious adverse events 
 
Specific elements of efficacy that will be examined include: 
 
- 
Decrease in disease activity as assess by the BVAS/WG score 
- 
Ability to discontinue GCs 
 
The study will be terminated if 60% of subjects fail the primary endpoint.  This includes 
patients who have one severe flare, two limited flares or discontinue the study medication 
due to an adverse event. 
 
Adverse event reporting guidelines: 
 
Taking into account the nature, size, and complexity of the research protocol, the 
expected risks of the research, and the type of subject population being studied, an 
independent medical monitor has been identified to assess the ongoing safety of this 
study. Dr. Paul Monache, BU medical center rheumatologist, who specializes in 
vasculitis, will serve in this role. The Independent Medical Monitor will regularly review 
adverse events; reports from these reviews by the Medical Monitor should be submitted 
to the IRB, upon receipt. The medical monitor will review adverse events on a quarterly 
basis.  The medical monitor will issue a written report for each quarterly review, which 
will include: subject study ID number for adverse events that were reviewed, and the 
monitor’s overall determination as to whether there are any safety concerns, and if so, 
recommendations.  This quarterly report from the medical monitor will be submitted to 
the IRB as an Other Event, upon receipt.   
 
 
Adverse events and unanticipated problems involving risks to subjects or others will be 
reported to the PHRC in accordance with PHRC adverse event and unanticipated 
problems reporting guidelines. 
 
 
X. References 


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14
 
1. Stone JH, Merkel PA, Spiera R et al. Rituximab versus Cyclophosphamide for 
ANCA-Associated Vasculitis. N Engl J Med 2010;363:221-32. 
2. Rituximab label. 
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