Clinical trial NCT02197767
Conditions: Fibrillary Glomerulonephritis
Keywords: fibrillary glomerulonephritis rituximab Rituxan MabThera Zytux™
Sponsor: Mayo Clinic
Start date: 2014-11-01; Completion date: 2017-04-01
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot study is being done to see if the study medication, Rituximab, preserves kidney function after 12 months of taking the drug.

Detailed description:
This is a Phase II, open-label pilot study to determine if the use of Rituximab reduces proteinuria over a 12 month period and is there preservation of kidney function with the use of this study drug. Each patient will be treated with 2 intravenous infusions of rituximab 1000 mg, two weeks apart for a total of 2 doses. Each patient will be retreated with identical 2 intravenous infusions of rituximab, two weeks apart at 6 months after the first infusion, irrespective of cluster of differentiation (CD) 20+ cell counts. Thus, each participant will receive 4 infusions of rituximab.

Arms: arm 1: rituximab 1000 mg infusion two weeks apart for a total of two infusions. Retreated with identical rituximab 1000 mg infusion two weeks apart at six months after the first infusion for a grand total of four infusions.
Interventions: intervention 1: rituximab
Intervention descriptions: intervention 1: 1000 mg infusion

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Single Center Pilot Trial of 
Rituximab in the Treatment of 
Fibrillary Glomerulonephritis 
 
NCT# 02197767 
 
March 7, 2016 


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Study Title 
 
A Single Center Pilot Trial of Rituximab in the Treatment of Fibrillary 
Glomerulonephritis 
 
 Study Drug 
Rituximab (Rituxan®) 
 
Support Provided By 
Genentech 
Biogen Idec  
 
Sponsor Investigator 
Stephen B. Erickson, MD 
 
Sub-Investigators 
Fernando Fervenza, MD, PhD 
John Dillon, MD 
Marie Hogan MD, PhD 
Edward Casey, DO 
Vesna Garovic, MD 
Eddie Greene, MD 
Nelson Leung, MD 
 
Research Coordinators 
Julie Ray 
Lori Riess 
 
 
 
 
 
 
 
Protocol Version Date: 3.6  3/7/2016 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
1.0 
INTRODUCTION 
1.1 
Disease Background 
1.2 
Rituximab Background 
1.2.1    Safety Profile 
1.3 
Study Rationale 
 
2.0 
OBJECTIVES 
2.1 
Primary 
2.2 
Secondary 
 
3.0 
STUDY DESIGN 
 
3.1 
Description of the Study 
3.2 
Rationale for the Study Design 
3.3 
Outcome Measures 
3.3.1 
Primary Outcome Measures 
3.3.2 
Secondary Outcome Measures 
3.3.3 
Safety Outcome Measures 
 
4.0 
STUDY POPULATION 
4.1  
Inclusion Criteria 
4.2 
Exclusion Criteria 
4.3 
Immunization during B-Cell Depletion 
 
5.0 
TREATMENT PLAN 
 
6.0 
STUDY MEDICATION  
6.1 
Rituximab 
6.1.1 
Rituximab Dosage and Administration 
6.1.2 
Rituximab Storage 
6.1.3 
Rituximab Overdosage 
 
7.0 
DOSE MODIFICATION / TOXICITY MANAGEMENT 
7.1 
Rituximab 
 
8.0 
CRITERIA FOR SUBJECT DISCONTINUATION 
8.1 
Rituximab Specific Criteria 
8.2 
General Criteria 
 
9.0 
CRITERIA FOR STUDY DISCONTINUATION 
 
10.0 
CLINICAL AND LABORATORY EVALUATIONS 


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10.1 
Pre-Treatment Evaluations 
10.2 
Evaluations During Treatment 
10.3 
Post-Treatment Evaluations 
 
11.0 
REPORTING OF ADVERSE EVENTS 
11.1 
Adverse Event and Reporting Definitions 
11.2 
Reporting of Serious Adverse Events Associated With Rituximab  
11.3 
Safety Reporting Requirements for IND Holders 
11.4 
Safety Reporting Requirements for IND Exempt Studies 
 
12.0 
EVALUATION OF RESPONSE 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Determination of Sample Size 
13.2 
Planned Efficacy Evaluations 
13.2.1 
Primary Efficacy Variables 
13.2.2 
Secondary Efficacy Variables 
13.3 
Methods of Analysis 
 
14.0 
RETENTION OF RECORDS 
 
REFERENCES/BIBLIOGRAPHY 
 
APPENDICES 
 
          
Appendix A: Study Flowchart/Schema 
 
Appendix B: Current NCI Common Terminology Criteria for Adverse Events v3.0 
(CTCAE) 
 
Appendix C: FDA MedWatch 3500A Form 
 
Appendix D: New York Heart Association (NYHA) Guidelines 
 
Appendix E: Guidelines for Rituximab Preparation and Administration 
  
Appendix F:    Pharmacokinetics / HACA Laboratory Instructions 
 
 
 
 
 
 
 
 
 


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1.0 
INTRODUCTION 
 
This document is a protocol for a human research study.  This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic 
research policies and procedures. 
 
1.1 
Disease Background   
 
Fibrillary glomerulonephritis (FGN) is generally recognized as an uncommon and 
untreatable form of nephritis. The largest series of 66 cases comes from the Mayo Clinic.  
During an average of 52.3 months of follow-up for 61 patients with available data, 13% 
had complete or partial remission, 43% had persistent renal dysfunction, and 44% 
progressed to ESRD, despite treatment with a variety of immunosuppressive agents. 4 
Biopsy appearance on light microscopy is variable, but it is specific using electron 
microscopy. Randomly oriented fibrils of approximately 20 nm in length that do not stain 
with Congo Red define the process. It can be visually confused with fibronectin deposits, 
but fibronectin can be distinguished by a family history and differential tinctorial 
properties. 9-12  Some authorities lump immunotactoid nephropathy with FGN, but we will 
separate the two for research purposes.  
 
Treatment of FGN has been attempted with prednisone, cytotoxics, pheresis, NSAIDs and 
colchicine. Improvement has been inconsistent but generally poor. 3,5,7  Thus, effective 
treatment is urgently needed. No animal models exist.  
 
In the majority of cases, the disease is considered idiopathic, although it has also been 
seen in association with B cell lymphomas, hepatitis C, cryoglobulinemia and lupus. B 
cells mediate immune responses, and depletion of the CD 19 – 20 subtypes has proven 
effective in treating other glomerulopathies of various etiologies, especially membranous 
nephropathy, ANCA associated vasculitis and lupus nephritis. 
This together with anecdotal case reports and small series1,2,6,8  and observation that 
glomerular deposits in fibrillary GN are IgG4 dominant13 (similar to membranous 
nephropathy) suggest that FGN is immune mediated and is the rationale for using an 
agent such as Rituximab that is capable of depleting CD 20+ B cells and preventing the 
production of nephrotoxic immune globulins that initiate or mediate the disease.  
 
1.2 
Rituximab Background 
 
Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody 
directed against the CD20 antigen found on the surface of normal and malignant pre-B 
and mature B cells.  The antibody is an IgG1 κ immunoglobulin containing murine light-
and heavy-chain variable region sequences and human constant region sequences.  
Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 


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213 amino acids (based on cDNA analysis) and has an approximate molecular mass of 
145 kD.  Rituximab has a binding affinity for the CD20 antigen of ~8.0 nM. 
 
1.2.1 Safety Profile 
 
No dose-limiting effects were observed in the Phase I/II studies.  Reported adverse events 
including fever, chills, headache, nausea, vomiting, rhinitis, asthenia, and hypotension, 
occurred primarily during rituximab infusions and typically responded to an interruption 
of the infusion and resumption at a slower rate.   
 
Fatal Infusion Reactions:  Severe and fatal cardiopulmonary events, including 
angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, 
myocardial infarction, and cardiogenic shock, have been reported.  These severe reactions 
typically occurred during the first infusion with time to onset of 30-120 minutes.   
 
Cardiac Events:  Patients with preexisting cardiac conditions, including arrhythmia and 
angina, have had recurrences of these cardiac events during rituximab infusions. 
 
Tumor Lysis Syndrome:  Tumor lysis syndrome, some with fatal outcome,  has been 
reported and is characterized in patients with a high number of circulating malignant cells 
(≥25,000 ul) by rapid reduction in tumor volume, renal insufficiency, hyperkalemia, 
hypocalcemia, hyperuricemia, and hyperphosphatemia. 
 
Renal Events:  Rituximab has been associated with severe renal toxicity including acute 
renal failure requiring dialysis, and in some cases has led to death.  Renal toxicity has 
occurred in patients with high numbers of circulating malignant cells (≥25,000/mm2 ) or 
high tumor burden who experience tumor lysis syndrome and in patients administered 
concomitant cisplatin. 
  
Mucocutaneous Reactions:  Severe bullous skin reactions, including fatal cases of toxic 
epidermal necrolysis and paraneoplastic pemphigus, have been reported in patients 
treated with rituximab.  The onset of reaction has varied from 1 to 13 weeks following 
rituximab exposure. 
 
Hematologic Events:  In clinical trials, Grade 3 and 4 cytopenias were reported in 48% 
of patients treated with rituximab; these include: lymphopenia (40%), neutropenia (6%), 
leukopenia (4%), anemia (3%), and thrombocytopenia (2%).  The median duration of 
lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 
to 116 days).  A single occurrence of transient aplastic anemia (pure red cell aplasia) and 
two occurrences of hemolytic anemia following Rituximab therapy were reported.  
 
In addition, there have been a limited number of postmarketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia.  
 
Infectious Events:  Rituxan induced B-cell depletion in 70% to 80% of patients with 
NHL and was associated with decreased serum immunoglobulins in a minority of 


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patients; the lymphopenia lasted a median of 14 days (range, 1-588 days).  Infectious 
events occurred in 31% of patients: 19% of patients had bacterial infections, 10% had 
viral infections, 1% had fungal infections, and 6% were unknown infections.  Serious 
infectious events (Grade 3 or 4), including sepsis, occurred in 2% of patients. 
 
Hepatitis B Reactivation:  Hepatitis B virus (HBV) reactivation in some cases resulting 
in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs 
classified as CD20-directed cytolytic antibodies, including Rituxan.  Cases have been 
reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in 
patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive.  
Reactivation also has occurred in patients who appear to have resolved hepatitis B 
infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-
HBs] positive).   
  
Other Serious Viral Infections:  The following additional serious viral infections, either 
new, reactivated or exacerbated, have been identified in clinical studies or postmarketing 
reports. The majority of patients received Rituxan in combination with chemotherapy or 
as part of a hematopoietic stem cell transplant. These viral infections included JC virus 
(progressive multifocal leukoencephalopathy [PML]), cytomegalovirus, herpes simplex 
virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some 
cases, the viral infections occurred up to one year following discontinuation of Rituxan 
and have resulted in death. 
 
Progressive multifocal leukoencephalopathy (PML) 
PML is a rare disease caused by the reactivation of latent JC virus in the brain.  
Immunosuppression allows reactivation of the JC virus which causes demyelination and 
destruction of oligodendrocytes resulting in death or severe disability.  Rare cases of 
PML, some resulting in death, have been reported in patients with hematologic 
malignancies who have received rituximab.  The majority of these patients had received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant.  Cases of PML resulting in death have also been reported following the use of 
rituximab for the treatment of autoimmune diseases. The reported cases had multiple risk 
factors for PML, including the underlying disease and long-term immunosuppressive 
therapy or chemotherapy.  Most cases of PML were diagnosed within 12 months of their 
last infusion of rituximab.  
 
Physicians should consider PML in any patient presenting with new onset neurologic 
manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should 
be considered as clinically indicated.  In patients who develop PML, rituximab should be 
discontinued and reductions or discontinuation of any concomitant chemotherapy or 
immunosuppressive therapy should be considered. 
 
Posterior Reversible Encephalopathy Syndrome (PRES)/ Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) 
Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported.  Signs and symptoms include 


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visual disturbance, headache, seizures and altered mental status, with or without 
associated hypertension.   
 
Bowel Obstruction and Perforation:  Abdominal pain, bowel obstruction and 
perforation, in some cases leading to death, were observed in patients receiving Rituxan 
in combination with chemotherapy for DLBCL. In post-marketing reports, which include 
both patients with low-grade or follicular NHL and DLBCL, the mean time to onset of 
symptoms was 6 days (range 1−77) in patients with documented gastro-intestinal 
perforation. Complaints of abdominal pain, especially early in the course of treatment, 
should prompt a thorough diagnostic evaluation and appropriate treatment. 
 
Immunogenicity:  Patients may develop a human anti-chimeric antibody (HACA) 
response with rituximab treatment.  The clinical significance of this is unclear. 
 
Pregnancy:  B-cell lymphocytopenia generally lasting less than 6 months can occur in 
infants exposed to rituximab in utero. 
 
Immunization:  Response rates may be reduced with non- live vaccines. 
 
Additional Safety Signals:  The following serious adverse events have been reported to 
occur in patients following completion of rituximab infusions: arthritis, disorders of 
blood vessels (vasculitis, serum sickness and lupus-like syndrome), eye disorders (uveitis 
and optic neuritis), lung disorders including pleuritis and scarring of the lung 
(bronchiolitis obliterans), that may result in fatal outcomes, and fatal cardiac failure. 
 
See the rituximab Investigator Brochure for additional details regarding safety experience 
with rituximab. 
 
1.3 
Study Rationale 
 
 
Although fibrillary nephritis may be a single pathological pathway for kidney injury of 
multiple etiologies, the immunofluorescent studies are clear that the fibrillary process is 
mediated by immune mechanisms. Biopsies typically stain for C3 and IgG (especially the 
IgG4 and IgG1 subclasses). A minority of the patients also have monoclonal proteins in 
circulation and in the biopsy. B cells mediate immune responses, and destruction of the 
CD 19 – 20 subtypes has proven effective in treating other glomerulopathies of various 
etiologies, especially membranous glomerulopathy and lupus nephritis. This together with 
anecdotal case reports and small series suggests rituximab has a rational role in the 
treatment of fibrillary GN. 
 
Thus it appears that FGN is immune mediated. This is the rationale for using an agent 
such as Rituximab that is capable of depleting CD 20+ B cells and preventing the 
production of nephrotoxic immune globulins that initiate or mediate the disease.  
 
 
 


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2.0 
OBJECTIVES 
 
2.1 
Primary 
 
Preservation of kidney function at 12 months as defined by stable or improved 24 hour 
creatinine clearance.   
 
2.2 
Secondary 
 
a.  Reduction in proteinuria at 12 months 
• Complete remission: < 300 mg proteinuria/24 hours 
• Partial remission: < 3500 mg proteinuria/24 hours 
b.  Improved quality of life at 12 months by validated questionnaire 
 
 
3.0 
STUDY DESIGN 
 
 
 
Diagnosis 
| 
↓ 
Screening for RTX 
| 
↓ 
Consent 
| 
↓ 
Time 0 
RTX infusions 
x2, 2 wks apart 
| 
↓ 
Time 3 mo 
Interim Eval 
| 
↓ 
Time 6 mo 
Interim Eval 
RTX infusions 
 x2, 2 wks apart 
| 
↓ 
Time 9 mo 
Interim Eval 
| 
↓ 
Time 12 mo 
Final Eval 
 


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3.1 
Description of the Study: Eleven (11) patients will be enrolled in the study and 
followed for 12 months. In all patients, proteinuria and other clinical laboratory 
parameters will be evaluated at study entry and at Day 28, Day 90, Day 180, Day 270, and 
Day 365 according to the test schedule listed below.  These tests are: full blood cell count 
with white cell differential, serum creatinine, BUN, sodium, potassium, calcium, glucose, 
uric acid, bicarbonate, AST, alkaline phosphatase, total bilirubin, total serum protein, 
albumin, lipid screen, urinalysis, and 24 hour urine collection for creatinine clearance, 
sodium, and total protein.  After successful enrollment, patients will be treated with an 
infusion dose of rituximab at Day 1 and at Day 15.  CD 20+ cell count will be drawn pre 
and post infusion at Time 0, Day 28, Day 180, and Day 365.   Patients will be retreated 
with a second dose of rituximab at 6 months independently of CD 20+ cell count.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Test Schedule and Monitoring for Rituximab Treatment 
 
 
 
  
1. PBFC: Peripheral blood flow cytometry. Quantitate B and T cell subsets. This test is performed on 
anticoagulated blood to identify the presence of various types of B and T lymphocytes, specifically CD 19-
20+, which should be eradicated by Rituximab treatment. 
2.  At screening (Time 0), if patients had any Time 0 study specific labs drawn clinically at Mayo  
within 30 days, those values may be appropriate to use upon the investigator’s review. 
3.  At screening (Time 0), if patients have had a negative Hepatitis b, Hepatitis c, or HIV value documented 
within two years of enrollment, those values may be appropriate to use upon the investigator’s review. 
4.  Blood from a 5 mL red top tube will be drawn and aliquoted into five 1 mL cryovials to be frozen and 
stored.  50 mL of urine will be drawn from the 24 hour collection and then will be aliquoted into five 10 mL 
conical tubes to be frozen and stored. 
 
Tests  
 
Time 0  
Day 
1 
Day 
15 
Day 
28 
Day 
90  
(3 
mo) 
Day 
180 
(6 
mo) 
Day 
181 
Day 
195 
Day 
270 
(9 
mo) 
Day 
365 
(12 
mo) 
History/Exam 
X 
 
 
X 
X 
X 
 
 
X 
X 
CBC with diff2 
X 
 
 
X 
X 
X 
 
 
X 
X 
BUN, creat, sodium, 
potassium, uric acid, tot 
prot, alb, bicarbonate, 
glucose, calcium, AST,  alk 
phos, total bili 2 
X 
 
 
X 
X 
X 
 
 
X 
X 
CD 20+ cells  (PBFC)1 
X 
 
 
X 
 
X 
 
 
 
X 
Lipid panel 2 
X 
 
 
 
X 
X 
 
 
X 
X 
Urine Pregnancy 
 
X 
X 
 
 
 
X 
X 
 
 
UA2 
X 
 
 
 
X 
X 
 
 
X 
X 
24h urine for protein 
X 
 
 
X 
X 
X 
 
 
X 
X 
24h creatinine for CrCl 
X 
 
 
X 
X 
X 
 
 
X 
X 
24h urinary Na+ 
X 
 
 
 
X 
X 
 
 
X 
X 
Pre-infusion medication 
(i.e.Tylenol, Benadryl 
 
X 
X 
 
 
 
X 
X 
 
 
Pre-infusion medication 
(i.e. methylprednisolone)  
 
X 
 
 
 
 
X 
 
 
 
Rituximab Infusion 
 
X 
X 
 
 
 
X 
X 
 
 
Quality of life-KDQOL 
X 
 
 
 
 
X 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optional Research Labs for 
antibodies (blood/urine)4 
X 
 
 
 
X 
X 
 
 
X 
X 
HIV, HBsAg, anti-HBc3 
x 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.2 
Rationale for the Study Design 
This is a pilot study. There is not enough treatment data to justify a head-to-head trial or 
even a placebo controlled trial yet. The number of patients required for more extensive 
studies will require a multi-centered trial, but that is premature until there is better 
evidence for effectiveness of rituximab treatment.  
 
3.3 
OUTCOME MEASURES 
 
3.3.1 Primary Outcome Measures 
Preservation of kidney function at 12 months as defined by stable or 
improved 24 hour creatinine clearance 
 
3.3.2 Secondary Outcome Measures 
a.  Reduction in proteinuria at 12 months   
• Complete remission: < 300 mg proteinuria/24 hours 
• Partial remission: < 3500 mg proteinuria/24 hours 
b. Quality of life at 12 months as determined by validated questionnaire 
 
3.3.3 Safety Outcome Measures 
Favorable experience with the use of rituximab in populations of patients with other 
forms of glomerulonephritis argues against the need for a data safety monitoring board in 
this small trial. We will monitor important laboratory parameters and other clinical 
manifestations as described above.  
 
 
4.0   STUDY POPULATION 
 
4.1  
Inclusion Criteria 
Patients must meet the following inclusion criteria to be eligible for study entry: 
• Fibrillary Glomerulonephritis with diagnostic biopsy performed within the last 2 
years 
• Proteinuria > 1 gm 
• Age > 18 years but < 80 years 
• Patients need to have adequately controlled blood pressure (BP<140/90 mmHg in 
>75% of the readings) for at least 3 months prior to enrollment with the use of 
ACEi and/or ARB, if tolerated. 
• Women must be post- menopausal, surgically sterile or practicing a medically 
approved method of contraception 
• Able and willing to give written informed consent and comply with the 
requirements of the study protocol 
• Adequate renal function as indicated by estimated GFR > 25 mL/min using 
CKD/EPI formula or a quantified creatinine clearance >25 mL/min, and/or serum 
creatinine <3.0 mg/dL in the presence of ACEi/ARB therapy 
• Adequate liver function, as indicated by total bilirubin, AST, and alkaline 
phosphatase levels (< 2 times the upper normal limit) 


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• Adequate bone marrow function, as indicated by hemoglobin >7.0 gm/dL, white 
count >3.0 x 10(9), platelet count >100 x 10(9) 
• Negative chest x-ray within one year 
• Negative serum pregnancy test (for women of child bearing age) 
• Men and women of reproductive potential must agree to use an acceptable method 
of birth control during treatment and for twelve month (1 year) after completion of 
treatment 
 
General Medical Concerns: 
• Normal organ function. 
• Men and women of reproductive potential must agree to use an acceptable method of 
birth control during treatment and for twelve months after completion of treatment 
• Subject has provided written informed consent 
• Subjects may continue to take their usual medications, except routine use of non-
steroidal anti-inflammatory drugs 
 
Rituximab-Specific Concerns: 
• Documentation of CD20 + status.   
• ANC: > 1000/ mm3 
• Adequate bone marrow function as indicated by  
o Platelets: > 100 x 10(9) 
o Hemoglobin: >7 gm/dL 
o White count > 3.0 x 10(9) 
(A bone marrow biopsy is not necessary prior to study entry) 
• Adequate renal function as indicated by estimated GFR > 25 ml/min using CKD-EPI 
formula and/or serum creatinine < 3.0 mg/dL in the presence of ACE inhibitor/ARB 
therapy  
• Adequate liver function, as indicated by AST, alkaline phosphatase and total bilirubin 
< 2x upper limit or normal unless related to primary disease 
 
 
4.2  
Exclusion Criteria 
 
Patients will be excluded from the study based on the following concerns: 
 
General Medical Concerns: 
• Pregnancy (a negative serum pregnancy test should be performed for all women of 
childbearing potential within 7 days of treatment), or lactating. 
• Known history of diabetes mellitus or a Hemoglobin A1c result > 6.0% within 90 
days prior to enrollment. 
• Inability to comply with study and/or follow-up procedures.   
 
Rituximab-Specific Concerns: 
 
• History of HIV (as documented as a positive lab value within one year of enrollment) 
• Presence of active infection 


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• New York Heart Association Classification III or IV heart disease  (See Appendix D) 
• Concomitant malignancies or previous malignancies within the last five years, with 
the exception of adequately treated basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix 
• History of psychiatric disorder 
• At the Investigator’s discretion, receipt of a live vaccine within 4 weeks prior to 
randomization 
• Positive hepatitis B or C serology is considered a potential exclusion criterion.  
Hepatitis B screening should include hepatitis B surface antigen (HBsAg) and core 
antibody (anti-HBc) in all patients.  For patients who show evidence of prior hepatitis 
B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but 
anti-HBc positive), consult with physicians with expertise in managing hepatitis B 
regarding monitoring and consideration for HBV antiviral therapy before and/or 
during Rituxan treatment.  For inclusion into the study, the patient must have a 
negative HBsAg and anti-HBc lab value within 2 years of signing consent. 
 
4.3 
Immunization during B-Cell Depletion 
 
Efficacy and/or safety of immunization during periods of B-cell depletion have not been 
adequately studied.  It is recommended that a patient’s vaccination record and possible 
requirements be reviewed. Per the investigator’s discretion, the patient may have any 
required vaccination/booster administered at least 4 weeks prior to the initiation of study 
treatment.  Review of the patient’s immunization status for the following vaccinations is 
recommended:  tetanus; diptheria; influenza; pneumoccocal polysaccharide; Varicella; 
measles, mumps and rubella (MMR); and hepatitis B.  Patients who are considered to be 
at high risk for hepatitis B virus (HBV) infection and for whom the investigator has 
determined that immunization is indicated should complete the entire HBV vaccine series 
at least 4 weeks prior to participation in the study.   
 
 
5.0 
TREATMENT PLAN 
  
This is a Phase II, open-label study.  Each patient will be treated with 2 intravenous 
infusions of rituximab 1000 mg, two weeks apart for a total of 2 doses.  Each patient will 
be retreated with identical 2 intravenous infusions of rituximab, two weeks apart at 6 
months after the first infusion, irrespective of CD 20+ cell counts.  Thus each patient will 
receive 4 infusions of rituximab. 
 
Given the risk of Pneumocystis pneumonia for rituximab-treated patients and the 
associated significant mortality,14 study patients will be started on double strength 
Bactrim three times a week (or its equivalent) for Pneumocystis pneumonia prophylaxis. 
This treatment will continue until the end of the study (12 months) and the B cells 
(CD19/20+) have been repleted (>15 cells/microliter on peripheral blood flow 
cytometry).  B cells (CD19/20+) are expected to be replete by Month 12.  In the rare 
event that B cells (CD19/20+) are not replete by Month 12, flow cytometry should be 
repeated at Month 18 (see table 2b) and prophylaxis continued to that point of repletion. 


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This research study protocol allows the subject to receive up to “4” infusions of 
rituximab.  Even if the treatment is shown to be of benefit, additional infusions of 
rituximab beyond that allowed in the protocol cannot be given to the subject while she/he 
is participating in this study. 
 
Patients who flare will receive no additional treatment, because there is no known 
alternative. However, this should not be a concern because fibrillary glomerulonephritis is 
not a disease subject to flares, unlike ANCA associated vasculitis.  
 
Patients who drop out of the study will be encouraged to return for their usual nephrology 
follow-up visits.  
 
After study completion, patients will receive ongoing care from their usual nephrologist 
indefinitely. 
 
6.0 
STUDY MEDICATION  
 
6.1 
Rituximab 
 
Rituximab is a highly purified, 1328-amino acid antibody with an approximate molecular 
mass of 145 kD.  The chimeric mouse/human anti-CD20 antibody is a glycosylated IgG1 
κ immunoglobulin containing murine light and heavy chain variable regions and human 
γ1 heavy chain and κ light chain constant regions. 
 
Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for 
intravenous (IV) administration. Rituximab is supplied at a concentration of 10 mg/mL in 
either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The product is formulated for 
intravenous administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate 
dihydrate, 0.7 mg/mL polysorbate 80, and sterile water for injection. The pH is adjusted 
to 6.5. 
 
“Rituximab will be provided free of charge by Genentech and Biogen IDEC. The 
Sponsor/Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance 
with 21 Code of Federal Regulations (C.F.R.), Part 312.57 and 312.62 and Genentech 
requirements.” 
 
6.1.1 Rituximab Dosage and Administration 
 
 The dosage of rituximab to be used is 1000 mg given as an IV infusion once every 2 
weeks for two doses.  Rituximab may be administered in an outpatient setting and will be 
repeated in 6 months.  
 
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  Do not infuse 
rituximab concomitantly with another IV solution or other IV medications. 


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Preparation for Administration: Use appropriate aseptic technique. Withdraw the 
necessary amount of rituximab and dilute to a final concentration of 1 to 4 mg/mL into an 
infusion bag containing either 0.9% Sodium Chloride USP or 5% Dextrose in Water 
USP. Gently invert the bag to mix the solution. Discard any unused portion left in the 
vial.  Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration.  
 
Administration: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
Infusion and hypersensitivity reactions may occur.  Premedication, consisting of 
methylprednisolone, acetaminophen and diphenhydramine, should be considered before 
each infusion of rituximab.  Premedication may attenuate infusion-related events. Since 
transient hypotension may occur during rituximab infusion, consideration should be given 
to withholding anti-hypertensive medications 12 hours prior to rituximab infusion. 
 
For women of child bearing potential (WOCBP) a serum pregnancy test will be required 
at the screening visit.  For each WOCBP a urine pregnancy test will be required prior to 
each infusion. 
 
See Appendix E for more information. 
 
Administration Guidelines for Adult Patient Population 
 
First Infusion of both courses (Day 1 and Day 181): The rituximab solution for infusion 
should be administered intravenously at an initial rate of 50 mg/hr. Rituximab should not 
be mixed or diluted with other drugs. If hypersensitivity or infusion-related events do not 
occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum 
of 400 mg/hr.   
 
Rituximab infusion should be interrupted for severe reactions.  In most cases, the infusion 
can be resumed at a 50% reduction in rate (e.g., from 100mg/hr to 50mg/hr) when 
symptoms have completely resolved.  Most patients who have experienced non-life-
threatening infusion-related reactions have been able to complete the full course of 
rituximab therapy 
Subsequent Infusions (Day 15 and Day 195): If the subject tolerated the first infusion 
well, subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, 
and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 
mg/hr as tolerated.  If the first infusion was not well tolerated, the guidelines for the first 
infusion should be followed for the subsequent infusions. 
Subjects will remain in the Clinical Research Unit for a one hour observation period 
following each infusion. 
 
 
6.1.2 Rituximab Storage 
 


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Rituximab vials are stable at 2° to 8°C (36° to 46°F).  Do not use beyond expiration date 
stamped on carton. Rituximab vials should be protected from direct sunlight. 
 
Rituximab solutions for infusion are stable at 2° to 8°C (36° to 46°F) for 24 hours and at 
room temperature for an additional 24 hours. However, since rituximab solutions do not 
contain a preservative, diluted solutions should be stored refrigerated (2° to 8°C ).  No 
incompatibilities between rituximab and polyvinylchloride or polyethylene bags have 
been observed. 
 
 
 
 
6.1.3 Rituximab Overdosage 
 
There has been no experience with overdosage of rituximab in human clinical trials. 
Single doses higher than 500 mg/m2 have not been tested in controlled studies. 
 
7.0 
 DOSE MODIFICATION/TOXICITY MANAGEMENT 
 
A number of measures will be taken to ensure the safety of patients participating in this 
study.  These measures will be addressed through exclusion criteria (see Section 4.2) and 
routine monitoring as follows.   
 
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and during their participation in this study.  Safety evaluations will consist of 
medical interviews, recording of adverse events, physical examinations, blood pressure, 
and laboratory measurements.  Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or 
discontinuation at each study visit for the duration of their participation in the study.   
 
Subjects will remain in the Clinical Research Unit for a one hour observation period 
following each infusion. 
  
7.1 
Rituximab 
 
The dose of rituximab will remain constant throughout the trial. Rituximab infusion 
should be interrupted for severe reactions, e.g., rapid tumor lysis.  Treatment of infusion-
related symptoms with diphenhydramine and acetaminophen is recommended.  
Additional treatment with bronchodilators or IV saline may be indicated.  Epinephrine, 
antihistamines, and corticosteroids should be available for immediate use in the event of a 
hypersensitivity reaction to rituximab (e.g., anaphylaxis).  In most cases, the infusion can 
be resumed at a 50% reduction in rate (e.g., from 100mg/hr to 50mg/hr) when symptoms 
and laboratory abnormalities have completely resolved. 
   
Infusions should be discontinued in the event of serious or life-threatening cardiac 
arrhythmias.  Subjects who develop clinically significant arrhythmias should undergo 
cardiac monitoring during and after subsequent infusions.   


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Carriers of hepatitis B and patients with a history of hepatitis B infection or positive 
serology should be excluded from clinical trials except in situations where the potential  
benefit is determined to justify the risk of possible hepatitis B reactivation, which can be 
fatal. Patients with positive serology should have viral DNA levels checked and a 
gastrointestinal consultation obtained.  If treated with rituximab, such patients should be 
closely monitored for clinical and laboratory signs of active HBV infection and for signs 
of hepatitis throughout their study participation. 
 
 
 
 
8.0 
CRITERIA FOR SUBJECT DISCONTINUATION 
 
8.1 
Rituximab-Specific Criteria 
Subjects who meet the following criteria should be discontinued from the study: 
• Active HBV infection or hepatitis 
• Severe or life-threatening anaphylaxis or hypersensitivity reaction 
 
8.2 
General Criteria 
• Inability of subject to comply with study requirements 
• Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
Subjects who are carriers of hepatitis B at the time of discontinuation from study 
treatment will continue to be followed for clinical and laboratory signs of active HBV 
infection and for signs of hepatitis. 
 
9.0 
CRITERIA FOR STUDY DISCONTINUATION         
Determination by the investigator that it is not in the best interest of the patients to 
continue with study. 
 
10.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
10.1 
Pre-Treatment Evaluations 
The following evaluations must be performed within four weeks prior to the date of each 
patient's initial treatment with rituximab: 
• Pregnancy test (serum or urine) for women of childbearing potential. 
 


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• Medical history and documentation of the rationale for treatment of the patient's 
disease with rituximab. 
 
• Physical examination, including vital signs, blood pressure, performance status and 
tumor assessment. 
 
• Hematology (within 2 weeks of treatment): complete blood count (CBC) with 
differential and platelet count. 
 
• Serum Chemistries: glucose, BUN, creatinine, uric acid, total bilirubin, alkaline 
phosphatase, LDH, total protein, albumin, SGOT(AST), and calcium. 
 
• Immunology: Screening of patients at high risk for HBV infection and other 
evaluations as appropriate for trial.  Please note:  Rituximab will compete with CD20 
antibodies used in flow cytometry; use of CD20 to monitor B cells may provide false 
negative results for up to 6 months following treatment. 
 
 
10.2 
Evaluations During Treatment 
 Each patient will have a clinical evaluation at study entry and then at Day 28, Day 90, 
Day 180, Day 270, and Day 365 following the first rituximab infusion to include relevant 
medical history regarding response and potential side effects, and relevant physical 
examination to determine response and potential side effects. At subsequent visits, 
proteinuria and other clinical laboratory parameters will be evaluated according to the test 
schedule in section 3.1.  These tests are: full blood cell count with white cell differential, 
serum creatinine, BUN, sodium, potassium, calcium, glucose, uric acid, bicarbonate, 
AST, alkaline phosphatase, total bilirubin, total serum protein, albumin, lipid screen, 
urinalysis, and 24 hour urine collection for creatinine clearance, sodium, and total protein.  
Each patient will be asked to complete a quality of life- KDQOL questionnaire at study 
entry, Day 180, and at Day 365. 
Please include hydration where appropriate, and the following institutional guidelines for 
blood pressure monitoring: 
• HR every 15 minutes x 4; every 30 minutes x 2; then hourly during the rest of the 
infusion 
• BP every 15 minutes x 4; every 30 minutes x 2; then hourly during the rest of the 
infusion 
• RR every 15 minutes x 4; every 30 minutes x 2; then hourly during the rest of the 
infusion 
 
10.3 
Post-Treatment Evaluations     
Please note that subjects of both sexes must practice adequate birth control for a 
minimum of twelve months post-treatment. 
 
 
11.0 
REPORTING OF ADVERSE EVENTS 


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Safety Reporting of Adverse Events 
Assessment of Safety 
 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to {study drug}, all events of 
death, and any study specific issue of concern. 
 
11.1  Adverse Event and Reporting Definitions 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol-
imposed intervention, regardless of attribution. 
 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
fibrillary glomerulonephritis that were not present prior to the AE reporting 
period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the subject 
at immediate risk of death. It does not include an AE that, had it occurred in a 
more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
• It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 


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Methods and Timing for Assessing AND Recording Safety variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment or initiation of any study procedures 
and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should 
only report SAEs that are attributed to prior study treatment. 
 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to rituximab (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline: 
There is a plausible temporal relationship between the onset of the AE and administration 
of rituximab, and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to rituximab; and/or the AE abates or resolves upon discontinuation of 
rituximab or dose reduction and, if applicable, reappears upon re-challenge. 
Evidence exists that the AE has an etiology other than rituximab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to rituximab administration (e.g., 
cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, 
under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred 
to elevated hepatic enzymes or hepatitis. 
 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include:  
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?”  


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Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.1.2), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report “Unexplained Death”. 
 
c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only if 
the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the procedure 
itself, should be reported as the SAE. For example, if a subject is hospitalized to undergo 
coronary bypass surgery, record the heart condition that necessitated the bypass as the 
SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
 
e. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 90 
days after the last dose of study drug, a report should be completed and expeditiously 
submitted to the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy 


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should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female subject exposed to rituximab 
should be reported as an SAE. 
 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior rituximab exposure. If 
the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female subject who participated in the 
study, this should be reported as an SAE.  
 
g. 
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor 
will agree to the reconciliation periodicity and format, but agree at minimum to exchange 
monthly line listings of cases received by the other party. If discrepancies are identified, 
the Sponsor and Genentech will cooperate in resolving the discrepancies. The responsible 
individuals for each party shall handle the matter on a case-by-case basis until satisfactory 
resolution. 
 
h.      AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the Product  
 
  
11.2 
Reporting of Serious Adverse Events Associated With Rituximab 
Investigators must report all SAEs to Genentech within the timelines described below. 
The completed MedWatch/case report should be faxed immediately upon completion to 
Genentech Drug Safety at: 
 
(650) 225-4682 
OR 
(650) 225-5288 
 
• Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available. 
• Serious AE reports that are related to the Rituximab and AEs of Special Interest 
(regardless of causality) will be transmitted to Genentech within fifteen (15) 
calendar days of the Awareness Date. 
• Serious AE reports that are unrelated to the Rituximab will be transmitted to 
Genentech within thirty (30) calendar days of the Awareness Date. 
• Additional Reporting Requirements to Genentech include the following: 
• Any reports of pregnancy following the start of administration with the Rituximab 
will be transmitted to Genentech within thirty (30) calendar days of the Awareness 
Date.  


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• All Non-serious Adverse Events originating from the Study will be forwarded in a 
quarterly report to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
When an adverse event has been identified, the study team will take appropriate action 
necessary to protect the study participants and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow up and reporting required. 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-
UPIRTSOs according to the Mayo IRB Policy and Procedures. 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, 
if assigned, brief adverse event description, and notation that additional or follow-
up information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the patient for whom and adverse event was reported. For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative 
noted above or the MSL assigned to the study. Relevant follow-up information should be 
submitted to Genentech Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
11.3    Safety Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 


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Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use 
of Rituximab. An unexpected adverse event is one that is not already described in the 
Rituximab Investigator Brochure. Such reports are to be telephoned or faxed to the FDA 
and Genentech within 7 calendar days of first learning of the event. 
 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably 
or possibly related to the use of Rituximab.  An unexpected adverse event is one that is 
not already described in the Rituximab investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed by the investigator 
with the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a MedWatch 3500 form, but 
alternative formats are acceptable (e.g., summary letter). 
Randomization Codes for blinded clinical trials. 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also 
be faxed to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 
IND Annual Reports 
Copies to Genentech: 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. Copies of such reports should be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 
 


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Study Close-Out 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be 
sent to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
rituxan-immunology-gsur@gene.com 
 
11.4   Safety Reporting Requirements for IND Exempt Studies 
For Investigator Sponsored IND Exempt Studies there are some reporting requirements 
for the FDA in accordance with the guidelines set forth in 21 CFR 314.80. 
 
Postmarketing 15 Day “Alert Report”: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly related to 
the use of rituximab.  An unexpected adverse event is one that is not already described in 
the Investigator Brochure.  Such reports are to be submitted to the FDA (2 copies) at the 
following address:  Central Document Room, 12229 Wilkins Avenue, Rockville, MD 
20852. 
 
All Postmarketing 15 Day “Alert Reports” submitted to the FDA by the Sponsor-
Investigator must also be faxed to: 
Genentech Drug Safety 
Fax:  (650) 225-4682 or (650) 225-1683 
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission, it is also provided on Rituxan CD-ROM). 
 
For questions related to safety reporting, contact: 
Genentech Drug Safety 
Tel:       1-888-835-2555 
                      Or 
Fax:  (650) 225-1682 or (650) 225-1683 
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission). 
 
12.0 
EVALUATION OF RESPONSE 
 
It is recommended that an evaluation of response be carried out no earlier than one month 
following completion of therapy.  Re-evaluation of response should be carried out at a 
minimum of yearly intervals.  
 
Please denote at which timepoint subject response will be evaluated and documented. 
 
For consistency across studies, GNE/Biogen IDEC requests that the investigators 
  refer to the NCI proposed guidelines, Cheson, JCO 17: 1244-53 (for NHL). 
 


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Response Criteria [Time to progression, overall survival, etc.]  
 
 
 
 
13.0      STATISTICAL CONSIDERATIONS 
 
 
13.1 
Determination of Sample Size: 
This is a pilot study in a population of patients with a rare disease for which only a few 
case reports are available.  As such, it is impossible to calculate a sample size.  We plan 
to recruit 11 (eleven) patients as described above.  We do not think we can recruit more 
patients than this in 2 years.  
13.2    Planned Efficacy Evaluations 
 
13.2.1 Primary Efficacy Variables 
            . 
     a.  Preservation of kidney function at 12 months as determined by          
stable or increased 24h creatinine clearance 
 
13.2.2  Secondary Efficacy Variables 
a.  Reduction in proteinuria 
•  Complete remission: < 300 mg proteinuria/24 hours 
• Partial remission: < 3500 mg proteinuria/24 hours 
 
b.  Quality of life at 12 months by validated questionnaire 
 
 
13.3   Methods of Analysis 
 
 
a. Pre- and post-treatment proteinuria and estimated glomerular filtration rate will 
be compared by t-test. Proteinuria will be log transformed. 
b. Quality of life will be measured pre- and post-treatment by a validated kidney 
disease questionnaire. 
 
 
14.0 
RETENTION OF RECORDS 
 
We will retain all documentation of adverse events, records of trial drug receipt and 
dispensation, and all IRB correspondence for at least 2 years after the investigation is 
completed according to 21 CFR 312.57.. 
 
 
REFERENCES/BIBLIOGRAPHY 
 
Publication Numbers below are 3 abstracts presented at the 2012 American Society of 
Nephrology: 
 


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1. Pub Number: [SA-PO382] 
Long-Term Follow Up of Rituximab Treatment for Fibrillary Glomerulonephritis 
Jonathan J. Hogan, MD, Michaela Restivo, MD, Pietro A. Canetta, MD, Jai 
Radhakrishnan, MD, FASN, Gerald B. Appel, MD, FASN, Andrew S. Bomback, MD 
 
 
2. Pub Number: [SA-PO1043] 
Favorable Response to Rituximab in Diffuse Sclerosing Variant of Fibrillary 
Glomerulonephritis 
Asad J. Chaudhary, MD, Geeta G. Gyamlani, MD, Barry M. Wall, MD 
 
 
3. Czarnecki PG, Lager DJ, Leung N et al. Long-term outcome of kidney 
transplantation in patients with fibrillary glomerulonephritis or monoclonal 
gammopathy with fibrillary deposits. KI 75: 420-7, 2009 
 
 
4. Collins, M, Navaneethan SD, Chung M et al. Rituximab treatment of fibrillary 
glomerulonephritis. Am J Kid Dis 52: 6, 1156-62, 2008 
 
 
5. Nasr SH, Valeri AM, Cornell LD et al. Fibrillary glomerulonephritis: a report of 66 
cases from a single institution. J Am Soc Nephrol 6: 775-84, 2011 
 
 
6. Pub Number: [SA-PO350] 
Immunosuppressive Therapy in Fibrillary Glomerulonephritis 
 
 
7. Vincent Javaugue, Alexandre Karras, MD, Francois Glowacki. Long Term Disease 
Outcomes in Fibrillary Glomerulonephritis: A Case Series of 27 Patients. Am J Kid 
Dis 2013: 62:679. 
 
 
8. Bhat P, Weiss S, Appel GB, Radhakrishnan J. Rituximab Treatment of 
Dysproteinemias Affecting the Kidney: A Review of 3 Cases. Am J Kid Dis 2007; 50: 
641. 
 
 
9. Alpers CE, Rennke HG, Hopper J Jr, Biara CG. Fibrillary Glomerulonephritis: An 
Entity with Unusual Immunofluorescent Features Kid Int 1987; 31:781. 
 
 
10. Iskandar SS, Faulk RJ, Jennette JC. Clinical and Pathological Features of Fibrillary 
Glomerulonephritis. Kid Int 1992; 42:1401. 
 


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11. Rosenstock JL, Markowitz GS, Valeri AM, et al. Fibrillary and Immunotactoid 
Glomerulonephritis: Distinct Entities with Different Clinical and Pathological 
Features. Kid Int 2001; 63:1450. 
 
 
12. Fogo A, Qureshi N, Horn RG. Morphological and Clinical Feature of Fibrillary 
Glomerulonephritis versus Immunotactoid. Am J Kid Dis 1993; 22:367. 
 
 
13. Bridoux F, Hugue V, Coldefy O, Goujon JM, Bauwens M, Sechet A, Preud'Homme 
JL, Touchard G. Fibrillary glomerulonephritis and immunotactoid (microtubular) 
glomerulopathy are associated with distinct immunologic features. Kidney Int 2002; 
62: 1764. 
 
14.  Martin-Garrido I, Carmona E, Specks U, Limper A.  Pneumocystis Pneumonia in 
Patients Treated with Rituximab.  Chest 2013; 144 (1): 258-265. 
 
 
 
 
 
 
 
 
 
 
APPENDIX A:  STUDY FLOW CHART/SCHEMA 
[test schedule located under section 3.1] 
 
 
APPENDIX B:  CURRENT NCI COMMON TERMINOLOGY CRITERIA FOR       
ADVERSE EVENTS (CTCAE) 
[please refer to the following web link: ] 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
APPENDIX C: 
FDA MEDWATCH 3500A FORM 
[provided as separate document on Rituxan CD-ROM] 
 
 
APPENDIX D: 
NEW YORK HEART ASSOCIATION (NYHA) 
GUIDELINES 
[provided as separate document on Rituxan CD-ROM] 
 


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APPENDIX E:  
GUIDELINES FOR RITUXIMAB PREPARATION AND 
ADMINISTRATION 
[provided as separate document on Rituxan CD-ROM] 
 
APPENDIX F:           PHARMACOKINETICS / HACA LABORATORY  
INSTRUCTIONS 
[provided as separate document on Rituxan CD-ROM] 
 
 
 
 
 
 
  ] 
        
 
 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Investigator Sponsored Trials  
 
SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-4683 
 
Study Number 
(Genentech study number) 
 
Principal Investigator 
 
Site Name 
 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
(DD/MON/YYYY) 
____ / _____ /_____ 
Follow-up Report Date 
(DD/MON/YYYY) 
____ / _____ /_____ 
 
 
Subject Initials 
(Please enter a dash if the patient 
has no middle name) 
____ - ____ -____ 


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PLEASE PLACE MEDWATCH REPORT or IND SAFETY REPORT BEHIND THIS 
COVER SHEET 
 
 
Please contact Genentech Safety for any questions regarding SAE or IND Safety 
reporting at (888) 835-2555