Conditions: Granulomatosis With Polyangiitis
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
This Phase IIa international multicenter, open-label, uncontrolled study will evaluate the safety and pharmacokinetics of rituximab (MabThera/Rituxan) in pediatric participants with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Participants will receive rituximab 375 milligrams per square meter (mg/m\^2) intravenously (IV) on Days 1, 8, 15 and 22.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Rituximab
Intervention descriptions: intervention 1: Participants will receive rituximab 375 mg/m\^2 IV infusion on Days 1, 8, 15 and 22. Rituximab infusions will be given at a rate of 25 milligrams per hour (mg/h). This may be escalated at a rate of 25 mg/h increments every 30 minutes to a maximum of 200 mg/h.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Phase IIA, International, Multicenter, Open-Label, Uncontrolled 
Study to Evaluate the Safety and Pharmacokinetics of 4 × 375 
mg/m2 Intravenous Rituximab in Pediatric Patients With Severe 
Granulomatosis With Polyangiitis (Wegener’s) or Microscopic 
Polyangiitis 
NCT Number: 
NCT01750697 
Document Date: 
Protocol, Version 5, dated 26-Apr-2016 
 
 


 
Title
26-Apr-2016 22:00:33
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland.  
However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, 
Inc. in the United States.  The information contained in this document, especially any unpublished data, 
is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board.  It is understood that this information will not 
be disclosed to others without written authorization from Roche except to the extent necessary to obtain 
informed consent from persons to whom the drug may be administered. 
 
Rituximab—F. Hoffmann-La Roche, Ltd 
Protocol WA25615, Version 5 
 
PROTOCOL 
TITLE: 
A PHASE IIA, INTERNATIONAL, MULTICENTER, OPEN-
LABEL, UNCONTROLLED STUDY TO EVALUATE THE 
SAFETY AND PHARMACOKINETICS OF 4 × 375 MG/M2 
INTRAVENOUS RITUXIMAB IN PEDIATRIC PATIENTS 
WITH SEVERE GRANULOMATOSIS WITH 
POLYANGIITIS (WEGENER’S) OR MICROSCOPIC 
POLYANGIITIS 
PROTOCOL NUMBER: 
WA25615 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2012-002062-13 
IND NUMBER: 
112501 
TEST PRODUCT: 
Rituximab (RO0452294) 
MEDICAL MONITOR: 
, MD 
SPONSOR: 
F. Hoffmann-La Roche, Ltd 
DATE FINAL: 
Version 1:  02 July 2012 
DATE AMENDED: 
Version 2:  13 October 2012 
Version 3:  31 May 2013 
Version 4:  27 March 2015 
Version 5:  See electronic date stamp below 


PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol WA25615 has been amended primarily to modify the exclusion criteria related 
to general health, prior medications and laboratory findings.  These changes have been 
made in order to extend the possibility of entry into this clinical study to a wider range of 
suitable GPA and MPA patients, who would otherwise have limited treatment options in 
this potentially life threatening and organ threatening disease. 
The changes to exclusion criteria (Section 4.1.2, see below) require that the treating 
physician assess benefit/risk, prior to participant study entry.  The changes do not have 
an impact on the scientific value of the trial and will allow a small proportion of patients 
who were not previously eligible the opportunity to participate in this study.  
Since changes have been made to the exclusion criteria, this is considered to be a 
substantial amendment to the protocol.   
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.  The rationale for each of the amendment changes is 
provided below: 
SECTION 4.1.2:  Exclusion Criteria 
Exclusions Related to General Health 
Current active infection is an exclusion criterion, however, a statement has been added 
to clarify that entry into this study may be reconsidered once any known active infection 
has fully resolved. 
Exclusions Related to Medications 
The criteria have been amended to permit prior treatment with rituximab and/or other B 
cell depleting therapies, provided last dose was more than 6 months before the baseline 
visit.   
Pediatric patients with active GPA or MPA disease require therapy which would likely be 
either cyclophosphamide or rituximab. Physicians would like to avoid the adverse effects 
of cyclophosphamide in this age group and the safety of six-monthly dosing of rituximab 
has been evaluated in MAINRITSAN (ClinicalTrials.gov number, NCT00748644; 
EudraCT number, 2008-002846-51) showing comparable safety and tolerability to the 
control (azathioprine). The Sponsor is aware of at least 10 pediatric patients who were 
previously screened for this study but were excluded because they had previously 
received off-label rituximab as treatment for their disease.  The proposed change has 
been made in order to extend the possibility of entry into this clinical study to a wider 
range of suitable GPA and MPA patients, who would otherwise have limited treatment 
options in this potentially life threatening and organ threatening disease.  
Rituximab—F. Hoffmann-La Roche, Ltd 
2/Protocol WA25615, Version 5 


Additional courses of rituximab can be administered after Month 6 in this trial. 
Retreatment with rituximab and entry into this study is at the discretion of the investigator 
and may be considered based on disease activity, previous tolerability and response to 
treatment, and the investigator’s assessment of any potential risks of repeat rituximab 
treatment. 
Exclusions Related to Laboratory Findings 
The laboratory exclusion level of serum IgG has been amended from the central 
laboratory LLN, which varies according to age, to an absolute exclusionary value of 
below 5.65 mg/mL.  This proposed IgG threshold was used as exclusion criteria in 
rheumatoid arthritis (RA) global clinical trials for rituximab, where adult patients were 
observed up to 11 years. 
Low IgG has also been observed in patients with GPA and MPA.  Severity of the 
underlying disease and prior immunosuppressive treatment may affect IgG levels at 
study entry.  The labelling documents for rituximab describe how changes in IgG, 
following rituximab or cyclophosphamide treatment, have been observed and were 
similar for both treatments in the RAVE randomised controlled study in GPA/MPA.  
Importantly decreases in immunoglobulins in RAVE were not reported to have been 
associated with serious infections and there was no increased rate in overall infections 
or serious infections in patients with low IgG (see rituximab Investigator Brochure section 
5.3.3.2).  Low IgG level is a laboratory abnormality that may have no clinical 
consequence and often does not require specific medical management.  It is of note that 
there was no protocol-defined low IgG laboratory exclusion level in RAVE.  
In this study, the current IgG exclusion criterion is based on the laboratory LLN and is 
variable depending on age.  Pediatric patients with active disease require therapy and 
there are limited treatment options available.  Physicians would like to avoid 
cyclophosphamide use in this pediatric patient population due to the well-described 
adverse effects.   
Rituximab—F. Hoffmann-La Roche, Ltd 
3/Protocol WA25615, Version 5 


If a potential subject for this study, has levels just below LLN (consistent with their 
disease status and or use of prior therapies) at screening, but within the new data-driven 
inclusion threshold, a benefit/risk assessment can be made by the treating physician as 
to whether entry into this study and treatment with rituximab is an option. 
SECTIONS 3.1.4 and 4.5.6.4: Extended Follow-Up Visits: 
As low IgG laboratory levels can be the result of many factors, including underlying 
disease and/or treatment with rituximab or other immunosuppressive agents (e.g., 
cyclophosphamide) typically used in GPA/MPA, the language has been clarified to 
include extended follow-up of peripherally depleted B cell patients and not to include 
separate extended safety follow-up of patients with a low IgG level only (without 
peripheral B cell depletion).  
Safety (adverse events), central laboratory and other immunological parameters, 
including immunoglobulins, will continue to be assessed in extended safety follow-up for 
peripherally B cell depleted patients.  Completion of extended safety follow-up will occur 
when peripheral B cell levels return to pre-rituximab baseline levels or to within the 
normal range for the population, whichever is lower. 
Text on B cell-depleting therapies (commercial or investigational) has been clarified. 
SECTION 3.2 and Synopsis:  END OF STUDY 
The study will end after all patients in extended safety follow-up have completed B cell 
follow-up as described above (this is in addition to the protocol-defined 18 months of 
follow-up that they will have already completed, up to the common close out date). 
SECTION 4.5.6.1.2:  Rescreening 
A statement has been added to clarify that in the case of a protocol amendment, 
potential patients may be reassessed for eligibility according to any updated inclusion 
and exclusion criteria. 
SECTION 5.2.3.7:  Hypogammaglobulinemia 
Edits have been made to improve clarity and consistency.  Language has been added to 
indicate that repeat dosing can be considered based on the assessed benefit/risk. 
OTHER ADMINISTRATIVE CHANGES: 
Remission Induction Phase (Synopsis)   
Text updated for consistency with protocol body Sections 4.3.2.2.1 and 4.5.6.2 
SECTION 1.2:  BACKGROUND ON RITUXIMAB 
Updates have been made to disease areas under clinical study and the global markets 
that the GPA/MPA indication has currently been approved in: 
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• 
A clinical study in pemphigus vulgaris has commenced 
• 
Rituximab has been approved in the European Union for the induction of remission 
in adult patients with GPA and MPA. 
 
SECTION 3.1.1:  Overview and Synopsis 
Number of sites and countries has been updated to reflect current recruitment strategy: 
two new countries (Canada and Serbia) have been added. 
FIGURE 1:  Study Design 
Language was clarified for extended safety-follow-up 
SECTION 3.1.8 Early Study Drug Withdrawal and SECTION 4.5.7 Early Withdrawal 
Visit 
A sentence has been added to clarify that from the point of early study or treatment 
withdrawal, a patient may no longer receive rituximab as part of this protocol. 
SECTION 3.4.2, SECTION 6.8 and SYNOPSIS:  Exploratory Efficacy Outcome 
Measures 
Two duplicate outcome measures have been deleted as they were inadvertently 
repeated in the previous protocol version. 
Rituximab—F. Hoffmann-La Roche, Ltd 
5/Protocol WA25615, Version 5 


PROTOCOL AMENDMENT, VERSION 5: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2:  BACKGROUND ON RITUXIMAB 
Clinical studies have been completed or are being undertaken by Roche in various 
disease areas, including rheumatoid arthritis (RA) and several other autoimmune 
disorders, including multiple sclerosis, pemphigus vulgaris, systemic lupus 
erythematosus (SLE), and AAV.  Rituximab is currently approved in more than 100 
countries for the treatment of relapsed or refractory non-Hodgkin’s lymphoma, chronic 
lymphocytic leukemia, and in combination with MTX for the treatment of RA patients who 
inadequately responded to one or more anti-tumor necrosis factor (anti-TNF) therapies. 
Preliminary open-label, single-institution experience suggested that rituximab helped 
control AAV and could potentially help re-establish tolerance to ANCA-target antigens 
(Specks et al. 2001; Keogh et al. 2005).  This preliminary information generated interest 
in performing a multicenter trial to assess the ability of rituximab to induce remission in 
patients with severe AAV.  The pivotal double-blind, double-dummy, placebo-controlled 
randomized trial called RAVE (Stone et al. 2010) provided evidence of a positive 
benefit−risk for rituximab in GPA (WG) and MPA that resulted in the FDA’s approval of 
rituximab for the treatment of these conditions in 2011.  This indication has since been 
approved in a number of other markets worldwide, including the European Union, 
Canada, Switzerland, South Korea, and Israel.  Review is underway in the European 
Union.
SECTION 3.1.1:  Overview
This is a Phase IIa, international, multicenter, open-label, single-arm study.  The primary 
objectives are to evaluate the safety and tolerability and the PK parameters of rituximab 
in pediatric patients with severe GPA or MPA.  At least 25 patients between 2 and 
18 years of age will be enrolled across approximately 20 23 sites in France, Germany, 
Italy, Turkey, Canada, Serbia, the United Kingdom (UK), and the United States (US).  
SECTION 3.1.4:  Extended Follow-Up 
At the common closeout date, patients whose peripheral B cells remain depleted and/or 
have immunoglobulin levels below the LLN for the population, will continue to attend 
study visits every 3 months until their peripheral B-cell counts have returned to 
pre-rituximab baseline levels or to within the normal range for the population, whichever 
is lower.  and until their immunoglobulin levels have returned to within normal limits for 
the population Safety (adverse events), central laboratory and other immunological  
parameters, including immunoglobulin, will continue to be assessed in extended safety 
follow-up (see Appendix 1).  
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If a patient receives any B cell-depleting therapy (commercial or investigational) or any 
other agent that affects the return of B cells or decreases immunoglobulin levels, 
including, but not limited to, rituximab, CYC, and AZA, on or after the common closeout 
date, he or she will not be followed any further (although routine clinical follow up after 
the end of the study will continue, according to local practice). 
Section 3.1.8:  Early Study Drug Withdrawal
The investigator may also withdraw a participant from study treatment if he or she judges 
that continuing on rituximab is no longer in the participant’s best interest.  These 
participants will remain in the study for follow-up, but will be asked to complete a 
withdrawal visit (see Appendix 1).  From the point of withdrawal, a patient may no 
longer receive rituximab as part of this protocol.  They will continue to be followed until 
the common closeout date.  At the common closeout date, patients whose peripheral B 
cells remain depleted and/or who have immunoglobulin levels below the LLN for the 
population, will continue to attend study visits every 3 months until their peripheral B-cell 
counts have returned to pre-rituximab baseline level or to within the normal range for 
the population, whichever is lower, and until their immunoglobulin levels have returned to 
within normal limits for the population (see Section 3.1.4). 
SECTION 3.2:  END OF STUDY 
At the time of the common closeout date for each patient, the scheduled study visit 
occurring before or at the common closeout date will represent the end of main study 
visit.  However, all participants with peripheral B-cell counts below the LLN or pre-
rituximab baseline value or with low immunoglobulin levels following rituximab exposure 
will enter extended follow up, as described in Section 3.1.4.  If the trial is stopped early, 
all participants will be withdrawn from the study at the time of the termination of the 
study. 
SECTION 3.4.2:  Exploratory Efficacy Outcome Measures
 
 
 
 
 
 
SECTION 4.1.2:  Exclusion Criteria
• 
Known active infection of any kind (excluding fungal infections of nail beds), or any 
major episode of infection requiring hospitalization or treatment with IV anti-infective 
agents within 4 weeks of baseline or completion of oral anti-infective agents within 
2 weeks prior to baseline 
Entry into this study may be reconsidered once the infection has fully 
resolved 
• 
Previous Ttreatment with rituximab or other biologic B cell−targeted therapy (e.g., 
anti-CD19, anti-CD20, anti-CD22, or anti-B-lymphocyte stimulator [BLys]/BAFF) 
within 6 months prior to baseline visit 
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• 
Previous treatment with any other cell-depleting therapies, including, but not limited 
to, investigational agents (e.g., alemtuzumab [CAMPATH®], anti-CD4, anti-CD5, 
anti-CD3, anti CD19 and, anti-CD11a, anti CD22, anti B lymphocyte stimulator 
[BLys]/BAFF, and anti CD20) 
• 
Level of IgG and/or IgM below LLN of age-specific reference range  
• 
Level of IgG below 5.65mg/ml 
SECTION 4.5.6.1.2:  Rescreening 
It will not be considered rescreening if blood samples have to be redrawn because of 
sample handling problems, breakage, or sample integrity.  In the case of a protocol 
amendment, potential patients may be reassessed for eligibility according to any 
updated inclusion and exclusion criteria. 
SECTION 4.5.6.4:  Extended Follow-Up Visits 
At the common closeout date, patients whose peripheral B cells remain depleted and/or 
who have immunoglobulin levels below the LLN for the population, will continue to attend 
study visits every 3 months until their peripheral B-cell counts have returned to pre-
rituximab baseline levels or to within the normal range for the population, whichever is 
lower.  and until their immunoglobulin levels have returned to within normal limits for the 
population Safety (adverse events), central laboratory and immunologic  parameters, 
including immunoglobulins, will continue to be assessed in extended safety follow-up 
(see Appendix 1).  If a patient receives any B cell−depleting therapy (commercial or 
investigational) or any other agent that affects the return of B cells or decreases 
immunoglobulin levels, including, but not limited to, rituximab, CYC and AZA, on or after 
the common closeout date, he or she will not be followed any further (although routine 
clinical follow-up after the end of the study will continue, according to local practice). 
SECTION 4.5.7:  Early Withdrawal Visit 
If the investigator judges that continuing rituximab is no longer in the participant’s best 
interest, the participant will be asked to complete a withdrawal visit and will remain in the 
study for follow-up (see Section 3.1.8).  From the point of withdrawal, a patient may no 
longer receive rituximab as part of this protocol.  A schedule of assessments for the 
withdrawal visit is provided in Appendix 1.   
Rituximab—F. Hoffmann-La Roche, Ltd 
8/Protocol WA25615, Version 5 


SECTION 5.2.3.7:  Hypogammaglobulinemia 
Patients with IgG and IgM levels below the LLN of the age specific reference 
rangeexclusionary levels per Section 4.1.2, at screening will not be enrolled in the study.  
The investigator should closely monitor the patient’s immunoglobulin levels during the 
study.  If immunoglobulin levels decrease below the normal rangefollowing rituximab 
treatment, and require specific medical care or management, repeat dosing can be 
considered at the discretion of the investigator, based on the assessed benefit/risk dosing 
should be interrupted or discontinued, as clinically appropriate and at the discretion of 
the investigator.  IVIg (restricted to replacement dosing for hypogammaglobulinemia) 
may be given at the discretion of the investigator.    
SECTION 6.8:  EXPLORATORY EFFICACY ENDPOINTS 
 
 
 
 
 
 
FIGURE 1:  Study Design 
Language was clarified for extended safety-follow-up 
APPENDIX 1:  Schedule of Assessments 
Footnotes were revised in-line with changes made to the text. 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 17 
PROTOCOL SYNOPSIS .................................................................................... 18 
1. 
BACKGROUND .......................................................................................... 30 
1.1 
Background on Granulomatosis with Polyangiitis 
(Wegener’s) and Microscopic Polyangiitis ............................. 30 
1.2 
Background on Rituximab...................................................... 32 
1.2.1 
Efficacy and Safety of Rituximab in Adult Patients 
with GPA and MPA................................................................ 36 
1.2.2 
Overall Safety of Rituximab in Rheumatoid 
Arthritis .................................................................................. 38 
1.3 
Study Rationale and Benefit–Risk Assessment..................... 39 
2. 
OBJECTIVES.............................................................................................. 40 
2.1 
Safety Objectives................................................................... 40 
2.2 
Pharmacokinetic Objectives .................................................. 40 
2.3 
Exploratory Efficacy Objectives ............................................. 40 
2.4 
Other Exploratory Objectives................................................. 40 
3. 
STUDY DESIGN ......................................................................................... 40 
3.1 
Description of Study .............................................................. 40 
3.1.1 
Overview................................................................................ 40 
3.1.2 
Remission Induction Phase ................................................... 43 
3.1.3 
Follow-Up Phase ................................................................... 43 
3.1.4 
Extended Follow-Up .............................................................. 44 
3.1.5 
Unscheduled Visits ................................................................ 44 
3.1.6 
Disease Relapse/Flare .......................................................... 44 
3.1.7 
Early Study Termination ........................................................ 46 
3.1.8 
Early Study Drug Withdrawal................................................. 46 
3.2 
End of Study.......................................................................... 47 
3.3 
Rationale for Study Design.................................................... 47 
3.3.1 
Rationale for Test Product Dosage........................................ 47 
3.3.2 
Rationale for Patient Population ............................................ 49 


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3.4 
Outcome Measures ............................................................... 50 
3.4.1 
Primary Outcome Measures.................................................. 50 
3.4.1.1 
Safety Outcome Measures .................................................... 50 
3.4.1.2 
Pharmacokinetic Outcome Measures.................................... 50 
3.4.2 
Exploratory Efficacy Outcome Measures............................... 50 
3.4.3 
Other Exploratory Outcome Measures .................................. 52 
3.4.4 
Pharmacodynamic Outcome Measures................................. 52 
3.4.5 
Patient-Reported Outcome Measures ................................... 52 
3.4.6 
Assessment of Damage......................................................... 52 
4. 
MATERIALS AND METHODS .................................................................... 52 
4.1 
Patients.................................................................................. 52 
4.1.1 
Inclusion Criteria.................................................................... 52 
4.1.2 
Exclusion Criteria................................................................... 53 
4.2 
Method of Treatment Assignment and Blinding..................... 55 
4.3 
Study Treatment.................................................................... 56 
4.3.1 
Formulation, Packaging, and Handling.................................. 56 
4.3.1.1 
Rituximab (Investigational Medicinal Product)....................... 56 
4.3.1.2 
Background Therapy (Non-Investigational 
Medicine Product).................................................................. 56 
4.3.2 
Dosage, Administration, and Compliance.............................. 57 
4.3.2.1 
Rituximab (Investigational Medicinal Product)....................... 57 
4.3.2.2 
Methylprednisolone (Non-Investigational 
Medicinal Product)................................................................. 58 
4.3.2.3 
Prednisolone or Prednisone (Non-Investigational 
Medicinal Product)................................................................. 59 
4.3.3 
Investigational Medicinal Product Accountability ................... 59 
4.3.4 
Retreatment with Rituximab................................................... 59 
4.3.5 
Post-Trial Access to Rituximab.............................................. 60 
4.4 
Concomitant Therapy ............................................................ 60 
4.4.1 
Glucocorticoids ...................................................................... 61 
4.4.2 
Plasmapheresis (Plasma Exchange)..................................... 61 
4.4.2.1 
Treatment of GPA and MPA after Month 6............................ 61 
4.4.3 
Vaccinations .......................................................................... 62 
4.4.3.1 
Passive Antibody Titers to Specific Antigens......................... 62 


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4.4.3.2 
Immunization and Humoral Responses to 
Clinically Relevant Vaccines.................................................. 62 
4.4.4 
Prohibited Therapy ................................................................ 63 
4.5 
Study Assessments ............................................................... 63 
4.5.1 
Medical History and Demographic Data ................................ 63 
4.5.2 
Efficacy Assessments............................................................ 64 
4.5.2.1 
Birmingham Vasculitis Activity Score for 
Wegener’s Granulomatosis (BVAS/WG) ............................... 64 
4.5.2.2 
Pediatric Vasculitis Activity Score (PVAS)............................. 64 
4.5.2.3 
Assessment of Damage:  Pediatric Vasculitis 
Damage Index ....................................................................... 65 
4.5.2.4 
Physician’s Global Assessment of Disease 
Activity ................................................................................... 65 
4.5.2.5 
Patient-Reported Outcomes .................................................. 65 
4.5.3 
Safety Assessments .............................................................. 66 
4.5.3.1 
Vital Signs.............................................................................. 66 
4.5.3.2 
Electrocardiograms................................................................ 66 
4.5.3.3 
Chest X-Rays and Computed Tomography 
Scans..................................................................................... 67 
4.5.3.4 
Physical Examinations........................................................... 67 
4.5.3.5 
Laboratory Assessments ....................................................... 67 
4.5.3.6 
Immunologic Assessments.................................................... 68 
4.5.4 
Pharmacokinetic Assessments.............................................. 69 
4.5.5 
Pharmacodynamic Assessments........................................... 69 
4.5.6 
Timing of Study Assessments ............................................... 69 
4.5.6.1 
Screening and Pretreatment Assessments............................ 69 
4.5.6.2 
Baseline Assessments (Day 1) and Remission 
Induction Phase..................................................................... 70 
4.5.6.3 
Follow-Up Visits..................................................................... 71 
4.5.6.4 
Extended Follow-Up Visits..................................................... 71 
4.5.7 
Early Withdrawal Visit............................................................ 71 
4.5.8 
Unscheduled Visits ................................................................ 71 
4.5.9 
Progressive Disease Before Remission................................. 72 
4.6 
Patient, Study, and Site Discontinuation................................ 72 
4.6.1 
Patient Discontinuation.......................................................... 72 


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4.6.2 
Criteria for Premature Study Drug Termination or 
Study Withdrawal by Investigator or Sponsor........................ 72 
4.6.3 
Documentation at Withdrawal from Study.............................. 73 
4.6.4 
Study and Site Discontinuation.............................................. 73 
5. 
ASSESSMENT OF SAFETY....................................................................... 74 
5.1 
Safety Parameters and Definitions ........................................ 74 
5.2 
Clinical Adverse Events......................................................... 74 
5.2.1 
Serious Adverse Events (Immediately Reportable 
to Roche)............................................................................... 75 
5.2.2 
Relationship to Study Drug.................................................... 75 
5.2.3 
Management of Specific Adverse Events .............................. 76 
5.2.3.1 
Infusion-Related Reactions following Rituximab 
Administration........................................................................ 76 
5.2.3.2 
Cardiovascular Events........................................................... 77 
5.2.3.3 
Infections ............................................................................... 77 
5.2.3.4 
Hepatitis B Infections............................................................. 77 
5.2.3.5 
Progressive Multifocal Leukoencephalopathy........................ 78 
5.2.3.6 
Neutropenia........................................................................... 78 
5.2.3.7 
Hypogammaglobulinemia ...................................................... 78 
5.2.3.8 
Skin Reactions....................................................................... 79 
5.2.3.9 
Pregnancy ............................................................................. 79 
5.2.3.10 
Collection of Additional Data for Certain Adverse 
Events.................................................................................... 79 
5.2.4 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to Roche) ....................................... 79 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 80 
5.3.1 
Adverse Event Reporting Period ........................................... 80 
5.3.2 
Eliciting Adverse Event Information ....................................... 80 
5.3.3 
Assessment of Severity of Adverse Events ........................... 80 
5.3.4 
Assessment of Causality of Adverse Events ......................... 81 
5.3.5 
Procedures for Recording Adverse Events............................ 82 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 82 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 82 


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5.3.5.3 
Persistent or Recurrent Adverse Events................................ 83 
5.3.6 
Laboratory Test Abnormalities............................................... 83 
5.3.6.1 
Abnormal Liver Function Tests.............................................. 84 
5.3.6.2 
Deaths ................................................................................... 84 
5.3.6.3 
Preexisting Medical Conditions.............................................. 85 
5.3.6.4 
Lack of Efficacy or Worsening of Granulomatosis 
with Polyangiitis (Wegener’s) and Microscopic 
Polyangiitis ............................................................................ 85 
5.3.6.5 
Hospitalization or Prolonged Hospitalization.......................... 85 
5.3.6.6 
Overdoses ............................................................................. 86 
5.3.6.7 
Patient-Reported Outcome Data ........................................... 86 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 86 
5.4.1 
Emergency Medical Contacts................................................ 87 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 87 
5.4.3 
Reporting Requirements for Pregnancies.............................. 87 
5.4.3.1 
Pregnancies in Female Patients............................................ 87 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 88 
5.4.3.3 
Abortions ............................................................................... 88 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 88 
5.5 
Follow-Up of Patients after Adverse Events .......................... 89 
5.5.1 
Investigator Follow-Up........................................................... 89 
5.5.2 
Sponsor Follow-Up ................................................................ 89 
5.6 
Post-Study Adverse Events................................................... 89 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 90 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 90 
6.1 
Determination of Sample Size ............................................... 90 
6.2 
Analysis Populations ............................................................. 91 
6.3 
Summaries of Conduct of Study............................................ 91 
6.4 
Demographics and Baseline Characteristics ......................... 91 
6.5 
Patient Disposition and Treatments....................................... 91 


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6.6 
Safety Analyses..................................................................... 91 
6.7 
Pharmacokinetic Analyses..................................................... 91 
6.8 
Exploratory Efficacy Endpoints.............................................. 92 
6.9 
Exploratory Pharmacodynamic Analyses .............................. 93 
6.10 
Exploratory Patient-Reported Outcome Analyses ................. 93 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 93 
7.1 
Data Quality Assurance......................................................... 93 
7.2 
Electronic Case Report Forms............................................... 94 
7.3 
Source Data Documentation.................................................. 94 
7.4 
Use of Computerized Systems .............................................. 95 
7.5 
Retention of Records............................................................. 95 
8. 
ETHICAL CONSIDERATIONS.................................................................... 95 
8.1 
Compliance with Laws and Regulations ................................ 95 
8.2 
Informed Consent .................................................................. 95 
8.3 
Institutional Review Board or Ethics Committee.................... 96 
8.4 
Confidentiality........................................................................ 97 
8.5 
Financial Disclosure .............................................................. 97 
9. 
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION............................................................................. 98 
9.1 
Study Documentation ............................................................ 98 
9.2 
Site Inspections ..................................................................... 98 
9.3 
Administrative Structure......................................................... 98 
9.3.1 
IxRS....................................................................................... 98 
9.3.2 
Central Laboratory................................................................. 98 
9.4 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 98 
9.5 
Protocol Amendments ........................................................... 99 
10. INTERNAL MONITORING COMMITTEE.................................................... 99 
11. REFERENCES ......................................................................................... 100 
 


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LIST OF TABLES 
Table 1 
Pediatric Patients with GPA or MPA Treated with Rituximab 
(Literature Reports)..................................................................... 34 
Table 2 
PVAS Features of Limited and Severe AAV ............................... 45 
Table 3 
BVAS/WG Features of Limited and Severe AAV ........................ 53 
Table 4 
Adverse Event Severity Grading Scale ....................................... 81 
 
LIST OF FIGURES 
Figure 1 
Study Design............................................................................... 42 
Figure 2 
Scatter Plots of AUC0inf versus Body Surface Area (A) and 
AUC0inf versus Body Weight (B) in the RAVE Study ................... 48 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 105 
Appendix 2 
Study-Specific Visit Windows.................................................... 109 
Appendix 3 
110 
Appendix 4 
Tanner Stages .......................................................................... 111 
Appendix 5 
EULAR/PRINTO/PRES 2008 Ankara Childhood Wegener’s 
Granulomatosis Criteria (with Glossary) and Classification 
Definition................................................................................... 112 
Appendix 6 
Chapel Hill Consensus Conference .......................................... 113 
Appendix 7 
Procedures for the Intravenous Administration of Rituximab .... 114 


 
Rituximab—F. Hoffmann-La Roche, Ltd 
17/Protocol WA25615, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IIA, INTERNATIONAL, MULTICENTER, OPEN-
LABEL, UNCONTROLLED STUDY TO EVALUATE THE 
SAFETY AND PHARMACOKINETICS OF 4 × 375 MG/M2 
INTRAVENOUS RITUXIMAB IN PEDIATRIC PATIENTS 
WITH SEVERE GRANULOMATOSIS WITH 
POLYANGIITIS (WEGENER’S) OR MICROSCOPIC 
POLYANGIITIS 
PROTOCOL NUMBER: WA25615 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2012-002062-13 
IND NUMBER: 
112501 
TEST PRODUCT: 
Rituximab (RO0452294) 
MEDICAL MONITOR: 
, MD 
SPONSOR: 
F. Hoffmann-La Roche, Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to your local study monitor. 
 




 
Study Design 
Description of Study 
This is a Phase IIa, international, multicenter, open-label, single-arm study.  The primary 
objectives are to evaluate the safety and tolerability and the PK parameters of rituximab in 
pediatric patients with severe GPA or MPA.  At least 25 patients between 2 and 18 years of age 
will be enrolled across approximately 23 sites in France, Germany, Italy, Turkey, Canada, 
Serbia, the United Kingdom, and the United States.   
The study comprises an initial 6-month remission induction phase, followed by a minimum 
12-month follow-up phase.  The common closeout date will occur 18 months after the 
enrollment of the last patient.   
At screening, all patients will be assessed for eligibility according to the inclusion and exclusion 
criteria.  Screening assessments will be performed in accordance with the schedule of 
assessments.  The screening visit may occur up to 28 days prior to the baseline visit.  Following 
screening, eligible patients will enter the remission induction phase of the study. 
Remission Induction Phase 
Prior to the first rituximab infusion, patients must receive three doses of methylprednisolone at 
30 mg/kg/day (up to 1 g/day) by intravenous (IV) infusion that can occur any time, up to and 
including Day 1.  If clinically indicated, and at the discretion of the investigator, additional daily 
doses (up to three) of methylprednisolone (30 mg/kg, up to 1 g/day) can be given by IV infusion.  
No more than six doses of methylprednisolone in total can be given.  All methylprednisolone 
doses must be completed prior to the first rituximab infusion.  The first rituximab infusion must 
occur no later than 14 days after the last dose of methylprednisolone infusion.  Subject to the 
investigator’s discretion, corticosteroid premedication with an IV infusion of 100 mg of 
methylprednisolone may be administered at least 30 minutes prior to the infusion of rituximab 
(but not prior to clinical assessments) if the patient has experienced an IRR with a previous 
rituximab infusion. 
Rituximab will be administered to patients as four weekly IV infusions of 375 mg/m2 on Days 1, 
8, 15, and 22.  The dose will be calculated using a patient’s body surface area (BSA) at 
screening.  Infusions can be given in a day care or inpatient setting.  It is acceptable to 
hospitalize a patient as per local clinical practice.  All patients will receive concomitant oral 
prednisolone or prednisone (maximum, 1 mg/kg/day or up to 60 mg/day, whichever is less), 
which will be tapered to a minimum of 0.2 mg/kg/day (or 10 mg/day, whichever is lowest) no 
later than by Month 6.  Following completion of rituximab infusions on Day 22, patients will 
complete study visits at Months 1, 2, 4, and 6 and will undergo assessments in accordance with 
the schedule of assessments.  
Patients who receive at least part of one IV infusion of rituximab but do not complete 
four weekly infusions should continue to receive protocol-defined concomitant oral prednisolone 
or prednisone and/or should receive treatment at the discretion of the investigator 
(local standard of care) but will remain in the study.  Patients who show some initial 
improvement but then, prior to Month 6, experience disease flare before remission that cannot 
be controlled by glucocorticoids should receive treatment at the discretion of the investigator 
(according to local standard of care) and will remain in the study.  Patients who, by Month 6, 
exhibit progressive disease before remission will receive additional treatment as per local 
standard of care and will remain in the study. 
The schedule of assessments will be the same for all patients in the study. 
Follow-Up Phase 
Following the remission induction phase, patients will be followed for a minimum of 12 months 
at visits every 3 months, in accordance with the schedule of assessments.  The optimal 
treatment after rituximab induction for GPA or MPA has not been established in adults or in 
pediatric patients.   After Month 6, patients who are protocol remission failures or experience 
disease flare that cannot be controlled by glucocorticoids alone should receive treatment in 
accordance with local standard of care at the discretion of the investigator and will remain in the 
study. 
After Month 6, if patients require retreatment with rituximab, additional courses will be provided 
by the Sponsor until the common closeout date.  Retreatment with rituximab is at the discretion 
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of the investigator and may be considered based on disease activity, previous response to 
treatment, and the investigator’s assessment of the risks with rituximab. 
After Month 18, patients will be followed at study visits every 3 months until the common 
closeout date.  The procedures performed at the follow-up visits will be similar to those 
performed at the Month 18 visit.  After the common closeout date, patients whose B cells 
remain depleted for the population will enter extended follow up. 
Extended Follow Up 
At the common closeout date, patients whose peripheral B cells remain depleted, will continue 
to attend study visits every 3 months until their peripheral B-cell counts have returned to pre-
rituximab baseline levels or to within the normal range for the population, whichever is lower.  
Safety (adverse events), central laboratory and immunological parameters, including 
immunoglobulins, will continue to be assessed in extended safety follow-up. 
If a patient receives any B cell−depleting therapy (commercial or investigational) or any other 
agent that affects the return of B cells including, but not limited to, rituximab, cyclophosphamide 
(CYC), and azathioprine, on or after the common closeout date, he or she will not be followed 
any further (although routine clinical follow up after the end of the study will continue, according 
to local practice). 
Number of Patients 
The planned enrollment is at least 25 patients. 
Target Population 
Patients must meet the following criteria for study entry: 
• 
Written informed consent for study participation obtained from patient’s parents or legal 
guardian, with assent as appropriate by the patient, depending on the patient’s level of 
understanding 
• 
Age at screening between ≥ 2 and < 18 years  
• 
Diagnosis of GPA (EULAR/PRINTO/PRES 2008, Ankara criteria for childhood Wegner’s 
granulomatosis [WG]) or diagnosis of MPA (according to the Chapel Hill Consensus 
Conference) 
• 
Newly diagnosed patients or patients with relapsing disease according to the following 
definition: 
The recurrence or new onset of potentially organ- or life-threatening disease (i.e., one or 
more major Birmingham Vasculitis Activity Score/WG (BVAS/WG) items listed in the 
following table or disease severe enough to require treatment with CYC).  
• 
For patients of reproductive potential (males and females), use of a reliable means of 
contraception (e.g., abstinence, hormonal contraceptive patch, intrauterine device, physical 
barrier) throughout their study participation 
• 
For all eligible patients, mandatory prophylactic treatment for Pneumocystis jiroveci 
infection 
 
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BVAS/WG Features of Limited and Severe AAV 
Severe (Major) BVAS/WG Items a
Limited (Minor) BVAS/WG Items b
Cutaneous gangrene 
Arthralgias/arthritis 
Scleritis 
Fever (> 38°C) 
Retinal exudates/hemorrhage 
Purpura 
Sensorineural hearing loss 
Skin ulcer 
Mesenteric ischemia 
Mouth ulcers 
Alveolar haemorrhage 
Conjunctivitis/episcleritis 
Red blood cell urinary casts 
Orbital mass/proptosis 
Rise in serum creatinine 30% over 
baseline value 
Uveitis 
Aseptic meningitis 
Bloody nasal discharge/nasal crusting 
Spinal cord lesions 
Sinus involvement 
Cerebrovascular accident caused by vasculitis 
Swollen salivary gland 
Cranial nerve palsy 
Subglottic inflammation 
Conductive deafness c
Sensory peripheral neuropathy 
Motor mononeuritis multiplex 
Pericarditis 
 
Pleurisy 
 
Pulmonary nodules or cavities 
 
Other pulmonary infiltrates secondary to 
vasculitis, endobronchial lesions, and 
hematuria 
AAV = ANCA-associated vasculitis; ANCA = anti-neutrophil cytoplasmic antibody 
BVAS = Birmingham Vasculitis Activity Score; WG = Wegner’s granulomatosis.  
a Any of these items must be attributable to the active underlying disease. 
b Minor items with a significant risk of morbidity may be classified as severe (i.e., BVAS/WG 3). 
c Additional testing may be required to make the diagnosis. 
 
Patients who meet any of the following criteria will be excluded from study entry: 
Exclusions Related to GPA or MPA 
• 
Diagnosis of Churg−Strauss syndrome, as defined by the Chapel Hill Consensus 
Conference 
• 
Limited disease that would not normally be treated with CYC 
• 
Severe disease requiring mechanical ventilation due to alveolar hemorrhage 
• 
Requirement for plasmapheresis or dialysis at screening 
 
Exclusions Related to General Health 
• 
Incomplete recovery from recent surgery or < 12 weeks since surgery prior to baseline or 
planned within 24 weeks of baseline 
• 
Lack of peripheral venous access 
• 
Pregnancy or breastfeeding 
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• 
Evidence of 1) other significant uncontrolled concomitant disease, including, but not limited 
to, cardiovascular disease, nervous system, pulmonary, renal disease 
(including anti-glomerular basement membrane disease); or 2) hepatic, endocrine, or 
gastrointestinal disorders that, in the investigator’s opinion, would preclude or interfere with 
patient participation 
• 
Primary or secondary immunodeficiency (history of or currently active), including known 
history of human immunodeficiency virus infection 
• 
Evidence of active tuberculosis (patients receiving chemoprophylaxis for latent tuberculosis 
infection are eligible for the study) 
• 
Known active infection of any kind (excluding fungal infections of nail beds), or any major 
episode of infection requiring hospitalization or treatment with IV anti-infective agents within 
4 weeks of baseline or completion of oral anti-infective agents within 2 weeks prior to 
baseline.   
Entry into this study may be reconsidered once the infection has fully resolved  
• 
History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 
24 weeks prior to baseline 
• 
History of serious recurrent or chronic infection 
• 
History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ 
(except basal cell and squamous cell carcinoma of the skin that have been excised and 
cured) 
• 
Currently active alcohol or drug abuse or history of alcohol or drug abuse 
 
Exclusions Related to Medications 
• 
History of a severe allergic or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of rituximab or to murine proteins 
• 
Treatment with rituximab or a biologic B cell−targeted therapy (e.g., anti-CD19, anti-
CD20, anti-CD22, or anti-B-lymphocyte stimulator [BLys]/BAFF) within 6 months prior 
to baseline visit 
• 
Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator 
• 
Previous treatment with other cell-depleting therapies, including, but not limited to, 
investigational agents (e.g., alemtuzumab [CAMPATH®], anti-CD4, anti-CD5, anti-CD3, and 
anti-CD11a) 
• 
Receipt of oral or IV CYC within the previous 4 months prior to the baseline visit 
• 
Receipt of infliximab within the previous 3 months prior to the baseline visit 
• 
Receipt of adalimumab within the previous 2 months prior to the baseline visit 
• 
Receipt of etanercept within the previous 1 month prior to the baseline visit 
• 
Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the 
investigational drug (whichever is longer) 
• 
Receipt of any live or attenuated vaccine within 28 days prior to baseline  
It is recommended that a patient’s vaccination record and the need for immunization should 
be carefully reviewed and updated prior to receiving rituximab. 
• 
Intolerance or contraindications to IV glucocorticoids 
 
In case of receipt of any other immunosuppressant therapy (apart from corticosteroids), contact 
the Sponsor. 
Exclusions Related to Laboratory Findings 
• 
Positive serum human chorionic gonadotropin measured at screening or a 
positive pregnancy test prior to the first rituximab infusion for participants of childbearing 
potential 
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Investigational Medicinal Products 
Test Product 
For this trial, rituximab will be given as an IV infusion of 375 mg/m2 once a week for 
4 consecutive weeks, starting at the baseline visit.  The dose for rituximab will be calculated 
according to the participant’s BSA at the screening visit after the participant’s eligibility has been 
established, and it will remain the same for all four infusions.  Each participant’s actual body 
height and weight, measured during the 28-day period before baseline (i.e., during the 28 days 
before the start of administration of open-label rituximab) will be used to calculate a patient’s 
BSA according to the Dubois formula. 
Comparator 
Not applicable. 
 
Non-Investigational Medicinal Products 
Patients should be medicated pre-infusion with paracetamol/acetaminophen and cetirizine 
hydrochloride (or similar antihistamine), both according to labeled age-related doses, to be 
given 1 hour (± 15 minutes) before each infusion of rituximab.  Subject to investigator’s 
discretion, corticosteroid premedication with an IV infusion of 100 mg of methylprednisolone 
may be administered at least 30 minutes prior to infusion of rituximab (but not prior to clinical 
assessments) if the patient has experienced an IRR with a previous rituximab infusion. 
Methylprednisolone 
Prior to the first rituximab infusion, patients must receive three doses of methylprednisolone at 
30 mg/kg/day (up to 1 g/day) by IV infusion that can occur any time after screening, up to and 
including Day 1.  If clinically indicated, and at the discretion of the investigator, additional daily 
doses (up to three) of methylprednisolone (30 mg/kg, up to 1 g/day) can be given by IV infusion.  
No more than six doses of methylprednisolone in total can be given.  All methylprednisolone 
doses must be completed prior to the first rituximab infusion.  The first rituximab infusion must 
occur no later than 14 days after the last dose of methylprednisolone infusion. 
Prednisolone or Prednisone 
On Day 1 and following completion of IV glucocorticoids, all patients will receive concomitant 
oral prednisolone or prednisone (1 mg/kg/day or up to 60 mg/day or equivalent, whichever is 
lower), the dose of which will be tapered to a minimum of 0.2 mg/kg/day (or 10 mg/day, 
whichever is the lowest) no later than Month 6. 
The general guidance on the suggested oral steroid dose-tapering schedule is to taper from 
1 mg/kg/day (60 mg/day, maximum) at the start of treatment, to 0.8 mg/kg/day by Month 1, and 
then by 0.1−0.2 mg/kg/day each month to 0.2 mg/kg/day (or 10 mg/day, whichever is the 
lowest), which should be reached no later than Month 6. 
Oral prednisone (used in some non-UK sites) may be substituted for prednisolone at the same 
dose as long as there is no hepatic impairment. 
The steroid-tapering practice is specific to a particular patient and as such should be tailored 
individually for each patient at the time of study entry, at the discretion of the investigator. 
Comparator 
Not applicable. 
Statistical Methods 
Primary Analysis 
This is an exploratory, open-label, single-arm study, with the primary objective of evaluating 
safety and pharmacokinetics of rituximab in pediatric patients with GPA or MPA.  Therefore, 
there will be no formal statistical hypothesis testing.  An analysis will be conducted when the 
last patient enrolled reaches 6 months.  Full details of all planned tables, listings, graphs, and 
descriptive analyses will be provided in a Statistical Analysis Plan, which will be finalized prior to 
this analysis.  An outline of the proposed analyses is provided herein. 
The safety and tolerability of rituximab will be evaluated from AEs, laboratory tests, vital signs, 
ECGs, chest X-rays, and as defined by protocol.  Safety parameters will be summarized or 
listed for the safety population. 
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Non-linear mixed-effects modeling technique (NOMMEM®) will be used to analyze the PK data 
with the population PK model developed from adult patients with GPA and MPA in the RAVE 
study.  The primary PK parameters will be clearance and volume of distribution.  The secondary 
PK parameters (area under the rituximab plasma concentration−time curve from Time 0 to 
infinity [AUCinf], maximum plasma concentration [Cmax]) will be calculated for each patient.  
PK concentrations will be summarized by visit.  PK parameters will be tabulated and 
summarized (i.e., by mean, standard deviation, coefficient of variation, median, and minimum 
and maximum).  PK exposure and response relationships will be explored. 
Determination of Sample Size 
The planned sample size of 25 patients was determined on the basis of the epidemiology of 
pediatric anti−neutrophil cytoplasmic antibody-associated vasculitis (AAV) and information from 
existing patient cohorts.  This sample size takes into the account the number of pediatric 
patients that would be eligible for treatment with rituximab and that could be expected to be 
enrolled within a reasonable timeframe.  The primary objective of this study is to evaluate the 
safety and pharmacokinetics of rituximab in these patients.  The planned sample size would be 
sufficient to provide a reasonable estimate of variability for the mean PK parameters based on 
the observed intra-patient variability from the RAVE study.  It would also ensure 95% probability 
of observing at least one AE when the underlying incidence of that event is ≥ 11%. 
Given the exploratory nature of this study, there will be no formal statistical hypothesis testing.  
The study will focus on exploratory estimation of the efficacy and PD endpoints.  The planned 
sample size of 25 would allow estimation of the percentage of patients in remission at 6 months 
to within 20% of the point estimate (the distance from the point estimate to the upper or lower 
limit of a 95% confidence interval).
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Definition 
AAV 
ANCA-associated vasculitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCA 
anti-neutrophil cytoplasmic antibody 
AST 
aspartate aminotransferase 
AUC 
area under the concentration−time curve  
Area under the rituximab plasma concentration−time 
curve from Time 0 to infinity 
AUC0–inf  
AZA 
azathioprine  
BE 
Behavior 
BLys 
B-lymphocyte stimulator 
BP 
bodily pain/discomfort 
BSA 
body surface area 
BVAS 
Birmingham Vasculitis Activity Score 
BW 
body weight 
CARRA 
North American Childhood Arthritis & Rheumatology 
Research Alliance 
CD 
cluster of differentiation 
CH 
change in health 
 
  
 
 
CI 
confidence interval 
CL 
Clearance 
Cmax
maximum plasma concentration 
CT 
computed tomography 
CTC 
Common Toxicity Criteria 
CYC 
cyclophosphamide 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EC 
Ethics Committee 
EDC 
electronic data capture 
EU 
European Union 
EUVAS 
European Vasculitis Study Group 
FA 
family activities   
FACS 
fluorescence activated cell sorter 
FC 
family cohesion 
FDA 
Food and Drug Administration 
GBE 
general behavior  
GBM 
glomerular basement membrane 
GFR 
glomerular filtration rate 
GGH 
global health 
GH 
general health perceptions 
GPA 
granulomatosis with polyangiitis 
HACA 
Human antichimeric antibody 
 
 
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Abbreviation 
Definition 
HbA1c
glycosylated hemoglobin 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV Ab 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ITP 
immune thrombocytopenic purpura 
IVIg 
intravenous immunoglobulin 
IV 
Intravenous 
IxRS 
interactive voice/web-based response system  
JIA 
juvenile idiopathic arthritis 
LLN 
lower limit of normal 
MH 
mental health 
MMF 
mycophenolate mofetil 
MPA 
microscopic polyangiitis 
MPO 
myeloperoxidase  
MTX 
Methotrexate 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NIH 
National Institutes of Health 
PD 
pharmacodynamics 
PE 
parent impact − emotional  
PF 
physical functioning 
PhS 
physical summary score 
PK 
Pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
by mouth 
PReS 
Pediatric Rheumatology European Society 
PRES 
posterior reversible encephalopathy syndrome 
PRINTO 
Pediatric Rheumatology International Trials 
Organization 
PRO 
patient-reported outcome 
PR3 
proteinase 3 
PsS 
psychosocial summary score 
PT 
parent impact − time 
PVAS 
Pediatric Vasculitis Activity Score 
PVDI 
Pediatric Vasculitis Damage Index 
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Abbreviation 
Definition 
RA 
rheumatoid arthritis 
REB 
role/social limitations − emotional/behavioral 
RP 
role social limitations − physical 
RPLS 
reversible posterior leukoencephalopathy syndrome 
RTX 
Rituximab 
SAE 
serious adverse event 
SD 
standard deviation 
SE 
self-esteem 
SLE 
systemic lupus erythematosus  
TNF 
tumor necrosis factor 
TTP 
thrombotic thrombocytopenic purpura 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
VDI 
Vasculitis Damage Index  
WG 
Wegener’s granulomatosis 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON GRANULOMATOSIS WITH POLYANGIITIS 
(WEGENER’S) AND MICROSCOPIC POLYANGIITIS  
Granulomatosis with polyangiitis (GPA; also known as Wegener’s granulomatosis [WG]) 
and microscopic polyangiitis (MPA) are the two major forms of small-vessel systemic 
vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies 
(ANCAs) (Hoffman and Specks 1998).  Together, these conditions are termed 
“ANCA-associated vasculitis” (AAV) because of their strong association with highly 
specific autoantibodies.  AAV encompasses autoimmune disorders in which tolerance 
has been lost to one of two self-antigens, proteinase 3 (PR3) or myeloperoxidase 
(MPO), leading to the production of PR3- or MPO-ANCAs.  Animal models, in vitro 
experiments, and many clinical observations in humans suggest that endothelial injury 
and tissue damage depend on the pro-inflammatory effects of ANCAs resulting from the 
interaction of these specific antibodies with their target antigens on the surface of 
activated neutrophils and monocytes. 
If untreated, GPA and MPA progress from limited disease processes (e.g., inflammation 
centered on the upper respiratory tract or lung) to a generalized phase characterized by 
multiple complications of small-vessel vasculitis (e.g., leukocytoclastic vasculitis of the 
skin, mononeuritis multiplex, alveolar hemorrhage, rapidly progressive 
glomerulonephritis, and mesenteric vasculitis) (Walton 1958; Fienberg 1981; 
Hoffman et al. 1992; Guillevin and Lhote 1998; Reinhold-Keller et al. 2000).  The 
prognosis for untreated GPA is poor, with a low likelihood of survival (Walton 1958). 
In addition, patients can suffer neurological complications. Posterior reversible 
encephalopathy syndrome (PRES), also known as reversible posterior 
leukoencephalopathy syndrome (RPLS), has been described in patients with severe 
hypertension or renal failure, patients with connective tissue diseases (including GPA 
and MPA) and patients receiving immunosuppressive treatments such as 
cyclophosphamide, high-dose corticosteroids and rituximab (Primavera et al. 2001, 
Foocharoen et al. 2006, Ishikura K et al. 2012, Staykov and Schwab, 2012). Signs and 
symptoms include visual disturbance, headache, seizures and altered mental status, 
with or without associated hypertension and should be investigated as soon as possible. 
For further information, please refer to the paragraph 6.1.8 Nervous system of the 
Investigator Brochure.  
Conventional therapies for GPA and MPA are associated with a high degree of 
treatment failures and disease relapses.  Preventing fatal outcomes in severe disease 
requires immunosuppressive therapy consisting of glucocorticoids and cytotoxic agents, 
usually cyclophosphamide (CYC).  Although most patients achieve remission 
(Hoffman et al. 1992; Nachman et al. 1996; Reinhold-Keller et al. 2000; Jayne 2001), a 
majority of the patients also experience disease flares when therapy is tapered or 
discontinued.  Moreover, the treatment options currently used for adult GPA and MPA 
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are associated with substantial toxicities that frequently result in severe and permanent 
patient morbidity and mortality (Jayne et al. 2003).  Although mortality due to GPA and 
MPA has been significantly reduced through the use of CYC and other therapies, there 
continue to be major unmet needs, such as improved remission rates, prevention of 
flares, and reduction of toxicities associated with current therapy.  Therefore, novel and 
targeted mechanism-based treatment approaches are needed.  
Pediatric patients with GPA and MPA share many signs and symptoms of the disease 
with adults.  Similar to adults, the majority of pediatric patients have respiratory tract 
symptoms and/or renal involvement.  Similar to adult disease, wider organ involvement 
may occur because of complications of small-vessel vasculitis, but the relative 
frequencies of certain clinical manifestations may differ.  For example, in one study, 
nasal deformity and fixed subglottic stenosis were 2-fold and 4-fold more common at 
onset in childhood GPA than in adult-onset GPA (Rottem et al. 1993). 
Outcomes in pediatric GPA and MPA are also similar to those associated with adult 
disease.  Childhood disease carries considerable disease-related morbidity and 
mortality, mainly from progressive renal failure or aggressive respiratory involvement.  In 
a review by Eleftheriou and Brogan (2009), flares of GPA occurred in up to 75% of 
pediatric patients as treatment was weaned, and significant long-term renal impairment 
was observed in 17%−40% of patients across studies.  However, treatment-related 
morbidity (e.g., infections) and malignancies are less common compared with those 
observed in adults (Rottem et al. 1993; Frosch and Foell 2004). 
Data on the epidemiology of vasculitides in children are limited and difficult to interpret, 
owing to the varying nature of data (e.g., prospective vs. retrospective) and changing 
classifications over the past 20 years.  A recent apparent increase in incidence may in 
part be due to better case recognition after the introduction of ANCA testing.  Despite 
these limitations, the data clearly show that GPA and MPA are very rare conditions in 
children and adolescents, with estimated annual incidences of < 1 to 2.75 cases per 
million (Gardner-Medwin et al. 2002; Watts et al. 2009; Grisaru et al. 2010). 
Treatment recommendations in pediatric GPA and MPA are extrapolated from evidence 
and expert consensus in adults, and there are no guidelines for the dosage or duration 
of immunosuppressive therapy in children with these diseases.  Standard practice in 
severe disease is remission induction with CYC (in combination with glucocorticoids), 
followed by maintenance with azathioprine (AZA) or methotrexate (MTX) 
(Vanoni et al. 2010).  Twilt et al (2012) provide an overview of the current status of the 
epidemiology, pathogenesis, and treatment of childhood GPA. Reported rates of 
remission and relapse vary.  However, comparisons with adult disease are based on 
limited data and should be interpreted with caution because of the differing definitions of 
outcomes (e.g., remission) and length of follow-up in the few pediatric studies reporting 
outcomes. 
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The current mainstay of therapy, CYC, targets only proliferating cells (e.g., newly formed 
immune cells from the bone marrow).  Consequently, the expansion of pathogenic 
clones is blunted by CYC, but memory B and T cells are likely not affected.  The 
indiscriminate anti-proliferative effect of CYC causes dose-limiting adverse effects and 
might not eliminate pathogenic lymphocyte clones.  This failure may explain the 
chronically relapsing nature of GPA and MPA in patients treated with CYC. 
There is strong support for a crucial role for B cells in the pathogenesis of GPA and MPA 
(Fauci et al. 1971, 1974; Fauci and Wolff 1973; Wolff et al. 1974).  The number of 
activated B cells in the periphery has been shown to correlate with the extent of active 
disease (Popa et al. 1999).  There is also a significant body of evidence indicating that 
the loss of B-cell tolerance to PR3 and MPO plays a critical role in GPA and MPA.  
The rationale that B cells and ANCAs play a role in pathogenesis, together with the 
subsequent small studies of rituximab in GPA and MPA, generated the groundwork for 
the National Institutes of Health (NIH)-sponsored study ITN021AI (RAVE) with 
subsequent partial funding provided by the Immune Tolerance Network.  The results of 
this study provided the basis for submission of the supplemental Biologics License 
Application to the Food and Drug Administration (FDA) and for regulatory submissions 
worldwide, and they supported approval of rituximab for the treatment of severe GPA 
and MPA in adults. 
1.2 
BACKGROUND ON RITUXIMAB 
Rituximab (MabThera®/RITUXAN®) is a chimeric murine/human monoclonal antibody 
specific for the cluster of differentiation (CD) 20 antigen on the surface of B cells.  
Potential mechanisms of action for rituximab include complement-mediated toxicity and 
antibody-dependent cell-mediated cytotoxicity, as well as the inhibition of B-cell 
proliferation and the induction of apoptosis (Reff et al. 1994).  Treatment with rituximab 
induces a rapid and sustained depletion of CD20-positive B lymphocytes.  Short-lived 
plasma cells are thought to be the primary source of pathogenic autoantibodies such as 
ANCAs.  Because short-lived plasma cells are the terminally differentiated progeny of 
antigen-specific B-cell precursors, they disappear after approximately 2 weeks when the 
precursor cells are no longer available (Reff et al. 1994).  Thus, rituximab may be used 
to disrupt B-cell pathogenic mechanisms to disease and suppress autoantibody 
production. 
Clinical studies have been completed or are being undertaken by Roche in various 
disease areas, including rheumatoid arthritis (RA) and several other autoimmune 
disorders, including multiple sclerosis, pemphigus vulgaris, systemic lupus 
erythematosus (SLE), and AAV.  Rituximab is currently approved in more than 100 
countries for the treatment of relapsed or refractory non-Hodgkin’s lymphoma, chronic 
lymphocytic leukemia, and in combination with MTX for the treatment of RA patients who 
inadequately responded to one or more anti-tumor necrosis factor (anti-TNF) therapies. 
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Preliminary open-label, single-institution experience suggested that rituximab helped 
control AAV and could potentially help re-establish tolerance to ANCA-target antigens 
(Specks et al. 2001; Keogh et al. 2005).  This preliminary information generated interest 
in performing a multicenter trial to assess the ability of rituximab to induce remission in 
patients with severe AAV.  The pivotal double-blind, double-dummy, placebo-controlled 
randomized trial called RAVE (Stone et al. 2010) provided evidence of a positive 
benefit−risk for rituximab in GPA (WG) and MPA that resulted in the FDA’s approval of 
rituximab for the treatment of these conditions in 2011.  This indication has since been 
approved in a number of other markets worldwide, including the European Union, 
Canada, Switzerland, South Korea, and Israel. 
The safety and effectiveness of rituximab in pediatric patients have not been 
established. Off-label use of rituximab for a wide range of immune-mediated diseases in 
pediatric populations has been noted.  The most frequent reporting of adverse events 
(AEs) in autoimmune indications in children has been in SLE and immune 
thrombocytopenic purpura (ITP).  Controlled clinical trials for the pediatric population are 
difficult to conduct because of the small number of eligible patients.  Interpretation of the 
safety and efficacy of rituximab therapy in pediatric autoimmune diseases relies largely 
on analysis of retrospective case studies and extrapolation from adult populations. 
The data on the use of rituximab in pediatric patients with GPA and MPA are sparse and 
are based on case reports in off-label use.  The published case studies on 7 patients 
≤ 18 years old who were treated with rituximab are presented in Table 1.  Of the 
7 patients, 4 achieved remission, whereas another patient was reported as being 
successfully treated.  There was one fatal event:  pulmonary fibrosis in a 7-year-old male 
whose history included severe pulmonary fibrosis and an unclassified acute adenovirus, 
as well as treatment with multiple prior and/or concomitant immunosuppressant 
therapies.  There was no apparent difference in the pattern of AEs compared with the 
adult patients in the same trials. 


 
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Table 1 
Pediatric Patients with GPA or MPA Treated with Rituximab (Literature Reports) 
Reference 
Age (yr)/ 
Sex 
Organ 
Involvement 
Previous 
Treatment 
Rituximab 
Regimen 
Efficacy 
(BVAS 
before/after RTX) 
Safety 
17/M 
Kidney and skin 
CYC and MTX 
375 mg/m2 
weekly × 4 
BVAS/WG 
7/0 
None 
Keogh et al. 2005
14/F 
ENT and lung 
CYC and MTX 
375 mg/m2 
weekly × 4 
BVAS/WG  
3/0 
Mild angioedema (during 
first infusion); polyarthritis 
following fourth infusion 
that responded to 
short term treatment 
with GC 
Aries et al. 2006
4/M 
ENT and eye 
CYC, GC, and 
IFX 
RTX 375 mg/m2 
q4w × 4; 
CYC 100 mg od;
PRD 10 mg od 
BVAS 10/7; active 
scleritis persisted 
NR 
Smith et al. 2006
18/F 
Lung, kidney, and 
eye 
Six prior IS 
agents, 
including CYC 
and MMF 
375 mg/m2 
weekly × 4 
Remission 
achieved by 
5 months 
NR 
(no deaths or serious 
IRRs in the study) 
Di Maria et al. 2008
13/M 
Lung, kidney 
CYC 
700 mg 
weekly × 4 
Successful 
treatment 
NR 
Brunner et al. 2009
14/F 
Lung, kidney 
CYC and MMF 
375 mg/m2 
weekly × 2 
Remission 
NR 
Jones et al. 2009
7/M 
Lung (NOS) 
NR 
RTX (regimen 
not specified) 
NR 
Death due to vasculitis 
(pulmonary fibrosis) 
8 months after RTX 
BVAS = Birmingham Vasculitis Activity Score; CYC = cyclophosphamide; ENT = ear, nose, and throat; F = female; GC = glucocorticoid; 
GPA = granulomatosis with polyangiitis; IFX = infliximab; IRR = infusion-related reaction; IS = immunosuppressant; M = male;  MMF = mycophenolate 
mofetil; MPA = microscopic polyangiitis; MTX = methotrexate; NOS = not otherwise specified; NR = not reported; od = oral;  q4w = every 4 weeks; 
RTX = rituximab; yr = year; WG = Wegener’s granulomatosis. 
 


 
Additional published data include information on single cases or limited case series in 
pediatric patients treated with rituximab for a range of malignant and non-malignant 
hematologic diseases, including, for example, post-transplant lymphoproliferative 
disorder, graft-versus-host disease, autoimmune hemolytic anemia, chronic ITP, 
thrombotic thrombocytopenic purpura (TTP), and congenital and acquired hemophilia.  
Some of the data in pediatric autoimmune cytopenias have been reviewed 
(Singer and Scalzi 2004). 
There are several reports of rituximab treatment in children with a range of other 
autoimmune conditions, including juvenile idiopathic arthritis (JIA), SLE, Type I diabetes 
mellitus, juvenile dermatomyositis, opsoclonus−myoclonus syndrome, and childhood 
pemphigus vulgaris.  The following is a brief summary of these publications. 
SLE:  Recent studies have shown that children with SLE (Marks et al. 2005) and lupus 
nephritis caused by childhood-onset SLE (Barillas-Arias et al. 2006) respond well to a 
combination of rituximab and CYC.  Therapy was well tolerated, with no reported serious 
adverse events (SAEs). 
JIA:  Alexeeva et al. (2011) reported a significant reduction in systemic manifestations in 
a case series of 55 patients with JIA refractory to infliximab and standard 
immunosuppressive therapy following treatment with repeat courses of rituximab.  
Consistent with data from adult populations, the most frequent AE was infusion 
reactions, which decreased with repeated courses.  The incidence of infections and 
neutropenia increased as serum concentrations of immunoglobulin M (IgM) and 
immunoglobulin G (IgG) decreased, highlighting the need for careful monitoring of 
children who are receiving rituximab for treatment of JIA. 
Other Autoimmune Diseases:  El Hallak (2007) presented findings from a retrospective 
study in which 10 patients were treated with rituximab for a range of severe, refractory 
autoimmune diseases, including SLE, Evans syndrome, vasculitis, and 
insulin-dependent diabetes mellitus.  Of the 10 patients, 9 experienced clinical 
improvements after rituximab therapy and treatment was associated with a decrease in 
mean corticosteroid dose.  Rituximab was well tolerated in this population, and the 
number and severity of infections did not change significantly after B-cell depletion. 
Fuertes et al. (2010) reported long-term clinical remission in 7 children and adolescents 
treated with rituximab for childhood pemphigus vulgaris, with no clinically relevant 
side effects. 
Pranzatelli et al. (2006) evaluated whether rituximab (plus corticotropin and/or 
intravenous [IV] immunoglobulins [IVIgs]) reduces cerebrospinal fluid B-cell expansion in 
opsoclonus−myoclonus syndrome and results in clinical improvement in 16 children.  
Following rituximab treatment, a significant proportion of patients experienced improved 
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outcomes, and the authors concluded rituximab is effective and safe as adjunctive 
therapy for opsoclonus−myoclonus syndrome. 
Chiu and Co (2011) reviewed the use of rituximab in juvenile dermatomyositis  
and reported the use of rituximab in 12 children (8−22 years old).  Most patients received 
375 mg⁄m2 weekly for 4 weeks.  Cutaneous or muscle disease was improved in 
9 patients (75%) following rituximab treatment, and 5 patients (42%) achieved remission 
of disease with one course of rituximab.  Only minor side effects were reported. 
Pescovitz et al. (2009) conducted a randomized, double-blind study in which 87 patients 
between 8 and 40 years old (median age:  16 years in the rituximab group, 14 years in 
the placebo group) with newly diagnosed Type 1 diabetes received four infusions of 
rituximab or placebo.  At 1 year, the mean area under the concentration−time curve 
(AUC) for the level of C peptide was significantly higher in the rituximab group than in 
the placebo group.  More patients in the rituximab group relative to the placebo group 
had AEs, mostly Grade 1 or 2, after the first infusion.  The reactions appeared to be 
minimal with subsequent infusions.  There was no increase in infections or neutropenia 
with rituximab treatment.  The authors concluded that a four-dose course of rituximab 
partially preserved B-cell function over a period of 1 year in patients with 
Type 1 diabetes. 
In general, the safety of rituximab infusions in children is consistent with the profile 
observed in adults.  However, data are limited, especially for rituximab treatment in 
children < 2 years old.  
1.2.1 
Efficacy and Safety of Rituximab in Adult Patients with GPA 
and MPA 
RAVE was a multicenter, randomized, double-blind, placebo-controlled trial conducted to 
assess whether treatment with rituximab (375 mg/m2 IV weekly × 4) was not inferior to 
CYC (2 mg/kg/day by mouth [PO]) for inducing remission in severe GPA and MPA 
(Stone et al. 2010).  Once remission was achieved, CYC was replaced by AZA between 
Months 3 and 6 (AZA placebo for patients in the rituximab group).  All patients received 
the same glucocorticoid treatment according to the protocol:  1−3 g of 
IV methylprednisolone followed by 1 mg/kg/day PO of prednisone, which was reduced to 
40 mg/day by Month 1, then tapered and discontinued completely by Month 6.  The 
6-month remission induction phase was followed by a 12-month remission maintenance 
phase (Months 6−18).  The primary endpoint was disease remission in the absence of 
prednisone therapy at 6 months.  Remission was defined as a Birmingham Vasculitis 
Activity Score for WG (BVAS/WG) of 0. 
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Efficacy in RAVE 
Results of the RAVE study support the conclusion that rituximab is non-inferior to oral 
CYC over 6 months of treatment; a higher percentage of patients in the rituximab group 
(64%) achieved a complete remission at 6 months compared with patients in the CYC 
group (55%).  The lower limit of the 95.1% confidence interval (CI) for the absolute 
difference was −4.3% and met the predefined protocol-specified non-inferiority criterion.  
Similar rates of severe and limited disease flares and similar mean BVAS/WG AUC 
values were observed over the first 6 months in the two treatment groups, suggesting 
comparable control of disease activity over the 6-month period.  The cumulative 
prednisone dose from randomization to 6 months was numerically lower in the rituximab 
group (p = 0.055), supporting the conclusion that the efficacy results seen in the 
rituximab group were not due to increased prednisone exposure compared with the CYC 
group.  Non-inferiority to CYC was observed consistently across subgroups defined by 
demographic and disease characteristics. 
At 18 months, efficacy findings were similar to those observed at 6 months.  The 
proportion of patients who maintained their complete remission at 12 months and 
18 months was similar between treatment arms after a single cycle of rituximab.  Rates 
of remission (BVAS/WG of 0) for patients on a prednisone dose of < 10 mg/day, as well 
as rates of remission irrespective of prednisone dose, were similar across treatment 
groups.  The rates of remission were similar across groups despite a numerically lower 
cumulative steroid dose and lack of AZA maintenance therapy in the rituximab group.  
Over 18 months, the overall rates of severe and limited flares were comparable between 
treatment groups.  However, after 6 months, slightly more flares occurred in the 
rituximab group than the CYC group. 
Safety in RAVE 
Overall tolerability was similar between the rituximab and CYC groups at 6 months, and 
the proportion of patients experiencing any AE, any severe (Grade ≥ 3) AE, or any SAE 
was comparable, as was the rate of AEs and SAEs.  The proportion of patients with AEs 
leading to a permanent discontinuation of study drug was slightly higher in the CYC 
group (13.3%) than in the rituximab group (8.1%). 
The prespecified secondary analysis of safety of rituximab relative to CYC focused on 
the following selected events, which were considered key safety outcomes associated 
with underlying disease or treatment:  
• 
Deaths 
• 
Bone marrow suppression 
• 
Infections 
• 
Hemorrhagic cystitis 
• 
Malignancies 
• 
Venous thromboembolic events 
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• 
Hospitalizations as the result of disease activity or treatment, according to 
investigator assessment 
• 
Cerebrovascular accidents 
• 
Infusion-related reactions (IRRs) leading to cessation of further infusions  
 
The proportion of patients who experienced at least one of the above selected AEs was 
numerically lower in the rituximab group (22.2%) than in the CYC group (34.7%).  
However, the rates of selected AEs were similar between the two treatment groups 
(0.78 events/patient-year in the rituximab group vs. 0.96 events/patient-year in the CYC 
group; p = 0.250).  The difference in the proportion was due largely to the greater number 
of CYC-treated patients with National Cancer Institute (NCI) Common Toxicity Criteria 
(CTC) Grade ≥ 2 leukopenia, although this did not translate into a higher number of 
infections during the first 6 months in the CYC group.  More patients in the rituximab 
group (10 patients; 10.1%) than in the CYC group (4 patients; 4.1%) required 
hospitalization that was considered by the investigator to be related to disease activity or 
study therapy.  The incidence of events of special interest for rituximab, such as serious 
infections, serious cardiac AEs, and malignancies, was similar across the two treatment 
groups over the 6-month treatment period.  A similar proportion of patients experienced 
infusion reactions in each group, and no serious reactions were reported.  
The long-term safety of rituximab was evaluated on the basis of the 18-month data 
post-randomization.  Overall safety, including the incidence and rate of any AE, selected 
AEs, Grade ≥ 3 AEs, SAEs, and serious infections, was comparable between the 
rituximab and CYC groups.  The overall profile of AEs reported over 18 months of follow-
up in RAVE was similar to that observed over the study’s first 6 months. 
1.2.2 
Overall Safety of Rituximab in Rheumatoid Arthritis 
Safety data have been collected in clinical trials in a variety of indications, particularly 
oncology and RA, following IV administration of rituximab. 
Safety data are available from 3194 patients with RA who were exposed to rituximab in 
clinical trials.  The total duration of observation is approximately 12,000 patient-years, 
with 627 patients followed for > 5 years, as of September 2010.  The long-term safety 
profile of rituximab is similar to that observed in the pooled placebo population 
(the placebo control groups from the randomized RA studies).  The rates of infection, 
myocardial infarction, stroke, and malignancies were consistent with those observed in 
other RA cohorts.  Key findings were as follows (see the Investigator’s Brochure for 
more details): 
• 
Adverse events:  The overall rate of AEs (263.1/100 patient-years; 95% CI:  260.21, 
266.02), SAEs (14.4/100 patient-years; 95% CI: 13.73, 15.09), and deaths 
(0.5/100 patient-years; 95% CI:  0.39, 0.65) has remained stable across multiple 
courses and over time.  The most common SAEs were infections (most frequently 
pneumonia). 
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• 
IRRs:  In total, 23% of all rituximab-treated patients with RA experienced an IRR 
following the first infusion.  Subsequent infusions were better tolerated.  
Premedication with an IV corticosteroid reduced the proportion of affected patients 
and severity of events.  Most events were mild or moderate and resolved without 
complication.  Less than 1% of patients (16 of the 3194 patients) experienced a total 
of 18 serious IRRs, none of which was fatal.  Of the 18 events, 10 occurred with 
Course 1 (8 with the first infusion), 5 with Course 2, and 1 each with the 
first infusions with Courses 4, 5, and 6.  The events were variable in nature and 
included rash, headache, blood pressure changes, anaphylactic or anaphylactoid 
reactions, and edema.  Severe IRRs with fatal outcome have been reported in 
patients with RA treated with rituximab in the postmarketing setting. 
• 
Infections:  The overall rates of infections (81.64/100 patient-years; 95% CI:  80.04, 
83.27) and serious infections (3.94/100 patient-years; 95% CI:  3.60, 4.31) have 
remained stable across multiple treatment courses.  There was no evidence of 
increased rates of serious infection following the use of other biologic agents, 
including TNF inhibitors, subsequent to rituximab treatment.  No cases of hepatitis B 
reactivation or atypical mycobacterium infections were reported in clinical trials.  
Opportunistic infections were rare.  One case of progressive multifocal 
leukoencephalopathy (PML) was observed in RA clinical trials.  Other cases of PML 
and hepatitis B reactivation have been reported in the postmarketing setting, outside 
of clinical trials. 
• 
Malignancy:  The incidence of malignancy did not increase with multiple courses of 
rituximab.  No difference was observed in the overall rate or pattern of malignancy in 
patients treated with rituximab compared with other patients with RA described in 
epidemiologic studies. 
 
Data received since 2010 are consistent with this profile.  See the Investigator’s 
Brochure for details about the nonclinical and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
The data from the RAVE trial in adults with GPA and MPA have demonstrated that 
patients with severely active GPA and MPA can achieve complete remission with an 
acceptable safety profile in the absence of conventional CYC and maintenance AZA 
treatment.  Given the adult data, the expectation is that rituximab treatment would be 
associated with a positive benefit−risk, providing at least equivalent efficacy to current 
treatments employed in children with severely active GPA or MPA. 
The overall safety profile of rituximab in adult GPA and MPA was consistent with the 
known safety profile of rituximab and the underlying disease, with no new safety signals 
identified during a mean follow-up period of 3 years in the RAVE study.  Longer-term 
safety data on rituximab in other indications do not suggest an association with the 
known long-term toxicities associated with conventional CYC treatment such as infertility 
or malignancies. 
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Rituximab treatment offers a therapy with a novel mode of action that may be associated 
with significant efficacy and safety benefits for children with severe GPA or MPA.  The 
safety and effectiveness of rituximab in pediatric patients with GPA and MPA have not 
been studied, with only limited data for 7 patients available in the published literature 
(see Section 1.2 and Table 1).  There are also no available pharmacokinetic (PK) and/or 
pharmacodynamic (PD) data on rituximab in pediatric patients with GPA and/or MPA.  
Therefore, the primary objectives of the present study are to evaluate the safety and 
pharmacokinetics of rituximab in pediatric patients with GPA or MPA.  Moreover, given 
that outcomes with current treatments such as CYC are unsatisfactory and are 
associated with high relapse rates and significant morbidity and toxicity, the present 
study will also include exploratory efficacy objectives.  Because this study represents the 
first global clinical trial investigating the use of rituximab in pediatric patients with GPA 
and MPA, a relatively small number of patients will be enrolled, and an open-label, 
single-arm design has been adopted. 
2. 
OBJECTIVES 
2.1 
SAFETY OBJECTIVES 
The primary safety objective for this study is to evaluate the safety and tolerability of 
rituximab in pediatric patients with severe GPA or MPA. 
2.2 
PHARMACOKINETIC OBJECTIVES 
The primary PK objective for this study is to evaluate the PK parameters of rituximab in 
pediatric patients with severe GPA or MPA. 
2.3 
EXPLORATORY EFFICACY OBJECTIVES 
 
 
2.4 
OTHER EXPLORATORY OBJECTIVES 
 
 
 
 
 
 
 
  
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview 
This is a Phase IIa, international, multicenter, open-label, single-arm study.  The primary 
objectives are to evaluate the safety and tolerability and the PK parameters of rituximab 
in pediatric patients with severe GPA or MPA.  At least 25 patients between 2 and 
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18 years of age will be enrolled across approximately 23 sites in France, Germany, Italy, 
Turkey, Canada, Serbia, the United Kingdom (UK), and the United States (US).   
The study comprises an initial 6-month remission induction phase, followed by a 
minimum 12-month follow-up phase.  The common closeout date will occur 18 months 
after the enrollment of the last patient (see Figure 1).   
At screening, all patients will be assessed for eligibility according to the inclusion and 
exclusion criteria (see Sections 4.1.1 and 4.1.2, respectively).  Screening assessments 
will be performed in accordance with the schedule of assessments (see Appendix 1).  
The screening visit may occur up to 28 days prior to the baseline visit.  If the patient is 
receiving treatment with an agent such as mycophenolate mofetil (MMF), the agent 
should be washed out prior to baseline according to local practice.  The recommended 
washout period for MMF is at least 48 hours.  Following screening, eligible patients will 
enter the remission induction phase of the study.   




 
3.1.2 
Remission Induction Phase 
Prior to the first rituximab infusion, patients must receive three doses of 
methylprednisolone at 30 mg/kg/day (up to 1 g/day) by IV infusion that can occur any 
time after screening, up to and including Day 1.  If clinically indicated, and at the 
discretion of the investigator, additional daily doses (up to three) of methylprednisolone 
(30 mg/kg, up to 1 g/day) can be given by IV infusion.  No more than six doses of 
methylprednisolone in total can be given.  All methylprednisolone doses must be 
completed prior to the first rituximab infusion.  The first rituximab infusion must occur no 
later than 14 days after the last dose of methylprednisolone infusion.  Subject to the 
investigator’s discretion, corticosteroid premedication with an IV infusion of 100 mg of 
methylprednisolone may be administered at least 30 minutes prior to the infusion of 
rituximab (but not prior to clinical assessments) if the patient has experienced an IRR 
with a previous rituximab infusion. 
Rituximab will be administered to patients as four weekly IV infusions of 375 mg/m2 on 
Days 1, 8, 15, and 22.  The dose will be calculated using a patient’s body surface area 
(BSA) at screening.  Infusions can be given in a day care or inpatient setting.  It is 
acceptable to hospitalize a patient as per local clinical practice.  All patients will receive 
concomitant oral prednisolone or prednisone (maximum, 1 mg/kg/day or up to 
60 mg/day, whichever is less), which will be tapered to a minimum of 0.2 mg/kg/day (or 
10 mg/day, whichever is lowest) no later than by Month 6.  Following completion of 
rituximab infusions on Day 22, patients will complete study visits at Months 1, 2, 4, and 
6 and will undergo assessments in accordance with the schedule of assessments 
(see Appendix 1).  For more details about rituximab administration, pre-infusion 
medications, and monitoring of patients during infusion, see Section 4.3.2.  
Patients who receive at least part of one IV infusion of rituximab but do not complete 
four weekly infusions should continue to receive protocol-defined concomitant oral 
prednisolone or prednisone and/or should receive treatment at the discretion of the 
investigator (local standard of care) but will remain in the study.  Patients who show 
some initial improvement but then, prior to Month 6, experience disease flare 
(Section 3.1.6) before remission that cannot be controlled by glucocorticoids should 
receive treatment at the discretion of the investigator (according to local standard of 
care) and will remain in the study.  Patients who, by Month 6, exhibit progressive 
disease before remission (see Section 4.5.9) will receive additional treatment as per 
local standard of care and will remain in the study.  
The schedule of assessments (Appendix 1) will be the same for all patients in the study. 
3.1.3 
Follow-Up Phase 
Following the remission induction phase, patients will be followed for a minimum of 
12 months with visits every 3 months, in accordance with the schedule of assessments 
(see Appendix 1).  The optimal treatment after rituximab induction for GPA or MPA has 
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not been established in adults or in pediatric patients.  After Month 6, patients who are 
protocol remission failures or experience disease flare that cannot be controlled by 
glucocorticoids alone should receive treatment in accordance with local standard of care 
at the discretion of the investigator and will remain in the study (see Section 4.4.2.1).  
After Month 6, if patients require retreatment with rituximab, additional courses will be 
provided by the Sponsor until the common closeout date.  Retreatment with rituximab is 
at the discretion of the investigator and may be considered based on disease activity, 
previous response to treatment, and the investigator’s assessment of the risks 
with rituximab.  
After Month 18, patients will be followed at study visits every 3 months until the common 
closeout date.  The procedures performed at the follow-up visits will be similar to those 
performed at the Month 18 visit.  After the common closeout date, patients whose B cells 
remain depleted and/or who have immunoglobulin levels below the lower limit of normal 
(LLN) for the population will enter extended follow up. 
The schedule of assessments is provided in Appendix 1. 
3.1.4 
Extended Follow-Up 
At the common closeout date, patients whose peripheral B cells remain depleted will 
continue to attend study visits every 3 months until their peripheral B-cell counts have 
returned to pre-rituximab baseline levels or to within the normal range for the 
population, whichever is lower.  Safety (adverse events), central laboratory and 
immunological parameters, including immunoglobulin, will continue to be assessed in 
extended safety follow-up (see Appendix 1).  
If a patient receives any B cell-depleting therapy (commercial or investigational) or any 
other agent that affects the return of B cells including, but not limited to, rituximab, CYC, 
and AZA, on or after the common closeout date, he or she will not be followed any 
further (although routine clinical follow up after the end of the study will continue, 
according to local practice). 
3.1.5 
Unscheduled Visits 
Patients may attend the clinic for unscheduled visits at any time for additional safety 
monitoring or disease surveillance at the discretion of the investigator. 
3.1.6 
Disease Relapse/Flare 
Relapse is defined as the recurrence or new onset of disease attributable to active 
GPA/MPA. 
By Pediatric Vasculitis Activity Score (PVAS), major relapse/flare is defined as the 
recurrence or new onset of potentially organ- or life-threatening disease (i.e., the 
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recurrence or new appearance of one or more major PVAS items listed in Table 2 or 
disease that is severe enough to require treatment with CYC). 
By PVAS, minor relapse/flare is defined as the recurrence or new onset of disease that 
is neither potentially organ- or life-threatening (i.e., the recurrence or new appearance of 
at least three minor PVAS items listed in Table 2). 
By BVAS/WG, major relapse/flare is defined as the recurrence or new onset of 
potentially organ- or life-threatening disease (i.e., the recurrence or new appearance of 
one or more major BVAS/WG items listed in Table 3 or disease that is severe enough to 
require treatment with CYC). 
By BVAS/WG, minor relapse/flare is defined as the recurrence or new onset of disease 
that is neither potentially organ- or life-threatening (i.e., the recurrence or new 
appearance of at least three minor BVAS/WG items listed in Table 3). 
Table 2 
PVAS Features of Limited and Severe AAV 
Severe (Major) PVAS Itemsa
Limited (Minor) PVAS Itemsb
 
Gangrene (extensive necrosis) 
Myalgia 
Significant proptosis 
Arthralgia or arthritis 
Red eye scleritis c
Fever ≥38°C 
Sudden visual loss 
Weight loss of ≥5% body weight  
Retinal vasculitis/retinal vessel 
thrombosis/retinal exudates/hemorrhages 
Polymorphous exanthema 
Subglottic stenosis/hoarseness /stridor 
Livedo 
Sensorineural hearing loss 
Panniculitis 
Massive hemoptysis/alveolar hemorrhage 
Purpura 
Respiratory failure 
Skin nodules 
Loss of pulses 
Infarct (nail edge lesion, splinter hemorrhage) 
Ischemic cardiac pain 
Ulcer (full-thickness necrosis) 
Cardiomyopathy 
Other skin vasculitis 
Congestive cardiac failure 
Mouth ulcers/granulomata 
Peritonitis 
Genital ulcers 
Bowel ischemia 
Adnexal inflammation 
Hematuria with red cell casts d
Red eye episcleritis c
Rise in creatinine >10% or creatinine clearance 
or GFR fall >25% 
Red eye conjunctivitis/blepharitis/keratitis 
Meningitis/encephalitis 
Uveitis 
Organic confusion/cognitive dysfunction 
Blurred vision 
Seizures (not hypertensive) 
Nasal discharge/crusts/ulcers/granuloma 
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Severe (Major) PVAS Itemsa
Limited (Minor) PVAS Itemsb
Stroke 
Paranasal sinus involvement 
Cord lesion 
Conductive hearing loss 
Cranial nerve palsy 
Wheeze or expiratory dyspnea 
Motor mononeuritis multiplex 
Endobronchial/endotracheal involvement 
 
Nodules or cavities 
 
Pleural effusion/pleurisy 
 
Infiltrate 
 
Bruits over accessible arteries 
 
Blood pressure discrepancy 
 
Caudication of extremities 
 
Valvular heart disease 
 
Pericarditis 
 
Abdominal pain 
 
Blood in stools or bloody diarrhea 
 
Hypertension >95th centile (for height) 
 
Proteinuria  >0.3 g/24h, creatinine  >20 
mg/mmol 
 
Hematuria ≥2+ or 5 rbc/hpf 
 
Headache 
 
Sensory peripheral neuropathy 
AAV = ANCA-associated vasculitis; ANCA = anti−neutrophil cytoplasmic antibody; 
PVAS = Pediatric Vasculitis Activity Score; GFR = glomerular filtration rate.  
a Any of these items must be attributable to the active underlying disease. 
b Minor items with a significant risk of morbidity may be classified as severe. 
c Ophthalmologist should be consulted to distinguish scleritis and episcleritis. 
d Presence of casts should be carefully examined. 
 
3.1.7 
Early Study Termination 
The investigator or the Sponsor may withdraw a participant from the study if the 
participant does not comply with study procedures or withdraws consent.  The 
participant will be asked to complete a withdrawal visit (see Appendix 1). 
3.1.8 
Early Study Drug Withdrawal 
The investigator may also withdraw a participant from study treatment if he or she judges 
that continuing on rituximab is no longer in the participant’s best interest.  These 
participants will remain in the study for follow-up, but will be asked to complete a 
withdrawal visit (see Appendix 1).  From the point of withdrawal, a patient may no 
longer receive rituximab as part of this protocol.  They will continue to be followed until 
the common closeout date.  At the common closeout date, patients whose peripheral B 
cells remain depleted, will continue to attend study visits every 3 months until their 
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peripheral B-cell counts have returned to pre-rituximab baseline level or to within the 
normal range for the population, whichever is lower (see Section 3.1.4). 
3.2 
END OF STUDY 
Follow up of all participants will continue until the common closeout date, when the final 
participant enrolled has completed his or her Month 18 study visit. 
At the time of the common closeout date for each patient, the scheduled study visit 
occurring before or at the common closeout date will represent the end of main study 
visit.  However, all participants with peripheral B-cell counts below the LLN or pre-
rituximab baseline value will enter extended follow up, as described in Section 3.1.4.  If 
the trial is stopped early, all participants will be withdrawn from the study at the time of 
the termination of the study. 
The end of the study will occur when the last participating patient completes the final 
scheduled visit (inclusive of extended follow up) or when the Sponsor decides to 
discontinue the study or development program.  
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Test Product Dosage 
Rituximab will be administered to patients as 4 weekly IV infusions (375 mg/m2). 
Currently, there are no guidelines for the dosage or duration of immunosuppressant 
therapy in children with GPA or MPA.  The recommended regimens in pediatric patients 
described in literature (see Section 1.2.2) are similar to those of adults. 
In the RAVE study, a rituximab regimen of weekly infusions of 375 mg/m2 for 4 weeks 
was given to adult patients with GPA or MPA.  The mean area under the rituximab 
plasma concentration−time curve from Time 0 to infinity (AUC0–inf) ranged from 
3.14 mg/mL/day to 24.5 mg/mL/day (mean ± standard deviation [SD], 
10.6 ± 3.93 mg/mL/day).  Inter-patient PK variability was 38%.  AUC0–inf was independent 
of either BSA (see Figure 2, Panel A) or body weight (Figure 2, Panel B) in 
adult patients. 
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Figure 2 Scatter Plots of AUC0−inf versus Body Surface Area (A) and 
AUC0−inf versus Body Weight (B) in the RAVE Study 
y = -20.993x + 11653
R2 = 0.0105
0
5000
10000
15000
20000
25000
40
60
80
100
120
140
Body Weight, kg
AUC0-inf, μg*day/mL
y = -2814.7x + 15364
R2 = 0.029
0
5000
10000
15000
20000
25000
1.5
2
2.5
Body Surface Area, m2
AUC0-inf, μg*day/mL
B
A
 
AUC0–inf = area under the rituximab plasma concentration−time curve from Time 0 to infinity. 
Note:  n = 97. 
 
The analysis of the rituximab exposure−response relationship (i.e., remission at 
6 months after the last rituximab infusion) indicated that there was no difference between 
patients with a lower AUC0–inf (less than the median value) and patients with a higher 
AUC0–inf (greater than or equal to the median value), with no correlation between 
achievement of complete remission at Month 6 and individual AUC0–inf, as indicated by a 
Spearman coefficient of correlation of −0.01.  Thus, 375 mg/m2 of rituximab weekly for 
4 weeks appeared to reach a plateau in the exposure−response curve.  Assuming that 
the disease process is similar in adults and pediatric AAV patients, the 
exposure−response relationship between adult and pediatric patients is expected to 
be similar. 
Given the therapeutic class (i.e., an IgG antibody), mechanisms of clearance (CL) and 
linear PK properties, the pharmacokinetics of rituximab in children are expected to be 
similar to those in adults.  Four weekly infusions of 375 mg/m2 of rituximab have 
been used off-label in pediatric patients with refractory autoimmune disease 
(i.e., SLE, vasculitis, JIA, ITP, idiopathic autoimmune hemolytic anemia), suggesting 
efficacy and acceptable tolerability (Jansson et al. 2011).  It is reasonable to assume 
that a comparable PK exposure using the same dosing regimen would produce similar 
effects in children and adults in the same indication.  
Because of the linear pharmacokinetics of rituximab, allometric scaling is the most 
appropriate method to predict human CL.  The following allometric scaling equation has 
been used for the estimation of CL in children: 
CLchildren = CLadult (BWchildren/BWadult)0.75
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in which age, body weight (BW), and BSA data are taken from reference 
(Eriksson 2005).  The AUC0−inf for children is predicted using the following equation, 
assuming a weekly dose of 375 mg/m2 for 4 weeks: 
AUC0–inf = [BSA (m2) × 375 (mg/m2)/CL_children] 
The AUC0 − inf for children is also predicted using the following equation assuming a 
9-mg/kg dose weekly for 4 weeks:  
AUC0–inf = [BW (kg) × 9 (mg/kg)/CL_children] 
The predicted mean ± SD AUC0–inf of this dosing regimen in children across an age range 
of 2−18 years is 9592 ± 272 μg • day/mL for boys and 9538 ± 279 μg • day/mL for girls, 
which is comparable to the adult exposure.  Importantly, based on allometric scaling, 
uniform exposure across ages 2−18 years is predicted in both boys (range:  
9081−9972 μg • day/mL) and girls (range:  9102−9915 μg • day/mL).  
Conversely, if a weight-based regimen of 9 mg/kg weekly for 4 weeks is given to 
children, the mean ± SD AUC0-inf is predicted to be 6550 ± 972 μg • day/mL for boys and 
6552 ± 965 μg • day/mL for girls, which is lower than the adult exposure. 
Therefore, 4 weekly infusions of 375 mg/m2 is the most appropriate dose for all children 
in the study, on the basis of the following: 
• 
Use of lower doses would be unproven in a condition that requires aggressive 
treatment with immunosuppressive therapies 
• 
In adult patients with GPA and MPA, a 375 mg/m2 dose regimen achieved uniform 
PK exposures across a wide range of body weights or BSA 
• 
The allometric scaling method indicated that 375 mg/m2 is adequate in children 
• 
In adult patients from the RAVE study, similar to RA patients, an 
exposure−response relationship for clinical efficacy endpoints indicated that the PK 
exposure reached a plateau for the exposure−response curve 
• 
A regimen of four weekly infusions of 375 mg/m2 has been shown to be effective in 
adults with GPA or MPA and has an acceptable benefit−risk profile in children with 
autoimmune conditions and hematologic disorders (Giulino et al. 2007; 
Jansson et al. 2011) 
• 
Currently, there are no guidelines for the dosage or duration of immunosuppressant 
therapies in children with GPA or MPA.  The recommended regimens described in 
the literature are similar to those used in adults 
 
3.3.2 
Rationale for Patient Population 
Children ages 2 to 11 years and adolescents ages 12 to < 18 years will be included in 
the trial, since the safety and effectiveness of rituximab in pediatric patients with GPA 
and MPA have not been studied.   
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Inclusion of patients < 2 years old is not considered appropriate on the grounds of safety 
with respect to the immaturity of the immune system of young children and the risks 
this could present following treatment with rituximab.  Although younger children 
(i.e., ages 2−6 years) may not have completed their childhood vaccination program, 
given the severity of GPA and MPA, the potential risk−benefit is considered appropriate 
so as to include this subset in the clinical trial.  Moreover, standard treatment of pediatric 
GPA and MPA is broadly similar to that in adults (immunosuppression with CYC followed 
by maintenance of remission with AZA or MTX), which in some cases could be in the 
context of non-completion of childhood vaccination programs.  
3.4 
OUTCOME MEASURES 
3.4.1 
Primary Outcome Measures 
3.4.1.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Frequency, nature, and severity of AEs 
• 
Frequency of laboratory abnormalities 
 
3.4.1.2 
Pharmacokinetic Outcome Measures 
The primary PK parameters will be CL and volume of distribution estimated from 
population PK model.  The secondary PK exposure parameters (AUC0-inf, maximum 
plasma concentration [Cmax]) derived from the primary PK parameters will be computed.  
The rituximab exposure−response relationship will be explored. 
3.4.2 
Exploratory Efficacy Outcome Measures 
The exploratory efficacy outcome measures for this study will include the following: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.4.3 
Other Exploratory Outcome Measures 
3.4.4 
Pharmacodynamic Outcome Measures 
The exploratory PD outcome measures for this study will include the following: 
 
 
 
 
 
 
 
3.4.5 
Patient-Reported Outcome Measures 
 
 
 
 
3.4.6 
 
 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
The target population for this study is pediatric patients ages ≥ 2 to < 18 years with 
severe GPA or MPA.  Newly diagnosed patients and patients with relapsed or refractory 
GPA or MPA will be eligible. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Written informed consent for study participation obtained from patient’s parents or 
legal guardian, with assent as appropriate by the patient, depending on the patient’s 
level of understanding 
• 
Age at screening between ≥ 2 and < 18 years  
• 
Diagnosis of GPA (EULAR/PRINTO/PRES 2008, Ankara criteria for childhood WG 
[Özen et al. 2010]; see Appendix 5) or diagnosis of MPA (according to the Chapel 
Hill Consensus Conference [Jennette 1994]; see Appendix 6) 
• 
Newly diagnosed patients or patients with relapsing disease according to the 
following definition: 
The recurrence or new onset of potentially organ- or life-threatening disease 
(i.e., one or more major BVAS/WG items listed in Table 3 or disease severe 
enough to require treatment with CYC). 
• 
For patients of reproductive potential (males and females), use of a reliable means 
of contraception (e.g., abstinence, hormonal contraceptive patch, intrauterine 
device, physical barrier) throughout their study participation 
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• 
For all eligible patients, mandatory prophylactic treatment for Pneumocystis jiroveci 
infection 
 
Table 3 
BVAS/WG Features of Limited and Severe AAV 
Severe (Major) BVAS/WG Items a
Limited (Minor) BVAS/WG Items b
Cutaneous gangrene 
Arthralgias/arthritis 
Scleritis 
Fever (> 38°C) 
Retinal exudates/hemorrhage 
Purpura 
Sensorineural hearing loss 
Skin ulcer 
Mesenteric ischemia 
Mouth ulcers 
Alveolar hemorrhage 
Conjunctivitis/episcleritis 
Red blood cell urinary casts 
Orbital mass/proptosis 
Rise in serum creatinine 30% over 
baseline value 
Uveitis 
Aseptic meningitis 
Bloody nasal discharge/nasal crusting 
Spinal cord lesions 
Sinus involvement 
Cerebrovascular accident caused by vasculitis 
Swollen salivary gland 
Cranial nerve palsy 
Subglottic inflammation 
Conductive deafness c
Sensory peripheral neuropathy 
Motor mononeuritis multiplex 
Pericarditis 
 
Pleurisy 
 
Pulmonary nodules or cavities 
 
Other pulmonary infiltrates secondary to 
vasculitis  
Endobronchial lesions 
Hematuria 
AAV = ANCA-associated vasculitis; ANCA = anti-neutrophil cytoplasmic antibody 
BVAS = Birmingham Vasculitis Activity Score; WG = Wegner’s granulomatosis.  
a Any of these items must be attributable to the active underlying disease. 
b Minor items with a significant risk of morbidity may be classified as severe (i.e., BVAS/WG 3). 
c Additional testing may be required to make the diagnosis. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Exclusions Related to GPA or MPA 
• 
Diagnosis of Churg-Strauss syndrome, as defined by the Chapel Hill Consensus 
Conference (Jennette 1994; see Appendix 6) 
• 
Limited disease that would not normally be treated with CYC 
• 
Severe disease requiring mechanical ventilation due to alveolar hemorrhage 
• 
Requirement for plasmapheresis or dialysis at screening 
 
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Exclusions Related to General Health 
• 
Incomplete recovery from recent surgery or < 12 weeks since surgery prior to 
baseline or planned within 24 weeks of baseline 
• 
Lack of peripheral venous access 
• 
Pregnancy or breastfeeding 
• 
Evidence of 1) other significant uncontrolled concomitant disease, including, but not 
limited to, cardiovascular disease, nervous system, pulmonary, renal disease 
(including anti-glomerular basement membrane [GBM] disease); or 2) hepatic, 
endocrine, or gastrointestinal disorders that, in the investigator’s opinion, would 
preclude or interfere with patient participation 
• 
Primary or secondary immunodeficiency (history of or currently active), including 
known history of human immunodeficiency virus (HIV) infection 
• 
Evidence of active tuberculosis (patients receiving chemoprophylaxis for latent 
tuberculosis infection are eligible for the study) (see Section 4.5.6.1) 
• 
Known active infection of any kind (excluding fungal infections of nail beds), or any 
major episode of infection requiring hospitalization or treatment with IV anti-infective 
agents within 4 weeks of baseline or completion of oral anti-infective agents within 
2 weeks prior to baseline 
Entry into this study may be reconsidered once the infection has fully 
resolved 
• 
History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 
24 weeks prior to baseline 
• 
History of serious recurrent or chronic infection 
• 
History of cancer, including solid tumors, hematologic malignancies, and carcinoma 
in situ (except basal cell and squamous cell carcinoma of the skin that have been 
excised and cured) 
• 
Currently active alcohol or drug abuse or history of alcohol or drug abuse 
 
Exclusions Related to Medications 
• 
History of a severe allergic or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of rituximab or to murine proteins 
• 
Treatment with rituximab or other biologic B cell−targeted therapy (e.g., anti-CD19, 
anti-CD20, anti-CD22, or anti-B-lymphocyte stimulator [BLys]/BAFF) within 6 
months prior to baseline visit 
• 
Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator 
• 
Previous treatment with other cell-depleting therapies, including, but not limited to, 
investigational agents (e.g., alemtuzumab [CAMPATH®], anti-CD4, anti-CD5, 
anti-CD3, and anti-CD11a) 
• 
Receipt of oral or IV CYC within the previous 4 months prior to the baseline visit 
• 
Receipt of infliximab within the previous 3 months prior to the baseline visit 
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• 
Receipt of adalimumab within the previous 2 months prior to the baseline visit 
• 
Receipt of etanercept within the previous 1 month prior to the baseline visit 
• 
Treatment with any investigational agent within 28 days of baseline or 5 half-lives 
of the investigational drug (whichever is longer) 
• 
Receipt of any live or attenuated vaccine within 28 days prior to baseline  
It is recommended that a patient’s vaccination record and the need for 
immunization should be carefully reviewed and updated prior to receiving 
rituximab (see Section 4.4.3). 
• 
Intolerance or contraindications to IV glucocorticoids 
 
In case of receipt of any other immunosuppressant therapy (apart from corticosteroids), 
contact the Sponsor. 
Exclusions Related to Laboratory Findings 
• 
Positive serum human chorionic gonadotropin measured at screening or a 
positive pregnancy test prior to the first rituximab infusion for participants of 
childbearing potential 
• 
Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), hepatitis B virus (HBV), or hepatitis C serology 
• 
Level of IgM below LLN of age-specific reference range  
• 
Level of IgG below 5.65mg/ml 
• 
Absolute neutrophil count (ANC) < 1.5 × 103/μL 
• 
Platelet count < 130 × 103/μL 
• 
Estimated GFR < 15 mL/min/1.73 m2 (calculated using the Schwartz formula; 
see Appendix 3) 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 
> 2.5 × the upper limit of normal (ULN) (for age and sex) that cannot be attributed to 
underlying GPA or MPA 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  All eligible patients will be assigned to receive 
rituximab treatment. 
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4.3 
STUDY TREATMENT  
 
Treatment 
Investigational medicinal products 
 
Test product 
Rituximab 
Comparator 
Not applicable 
Non-investigational medicinal products 
 
Comparator 
Not applicable 
Background therapy 
Prednisone, prednisolone, and 
methylprednisolone 
Premedication 
Paracetamol/acetaminophen and 
antihistamine cetirizine hydrochloride 
(or similar) 
 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Rituximab (Investigational Medicinal Product) 
The rituximab drug product is manufactured from bulk drug substance by Genentech 
(US License No. 1048).  Study drug packaging will be overseen by the Roche Clinical 
Trial Supplies Department and will bear a label with the identification required by local 
law, the protocol number, drug identification, and dosage. 
The packaging and labeling of the study drug will be in accordance with Roche 
standards and local regulations.  Study drug must be stored according to the details on 
the product label.  The drug label indicates the storage temperature.  Local packaging in 
some countries may be different. 
Upon arrival of investigational products at the site, site personnel should check for 
damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery. 
Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for 
IV administration.  The product is supplied at a concentration of 10 mg/mL in either  
100-mg (10-mL) or 500-mg (50-mL) single-use vials.  Rituximab is formulated for 
IV administration in sodium chloride 9 mg/mL, sodium citrate dihydrate 7.35 mg/mL, 
polysorbate-80 0.7 mg/mL, and sterile water for infusion.  The pH is adjusted to 6.5.  
The vials provided to the pharmacy will have study-specific investigational agent labels. 
Rituximab vials are stable at 2°C−8°C (36°F−46°F) and have a proposed shelf life of 
30 months.  Once reconstituted into IV bags, rituximab is chemically stable for up to 
24 hours at 2°C−8°C (36°F−46°F).  Rituximab vials should be protected from 
direct sunlight. 
4.3.1.2 
Background Therapy (Non-Investigational Medicine Product) 
For additional details, see the local prescribing information for IV methylprednisolone 
and oral prednisolone or prednisone.   
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4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Rituximab (Investigational Medicinal Product) 
4.3.2.1.1 
Dosage and Administration 
For this trial, rituximab will be given as an IV infusion of 375 mg/m2 once a week for 
4 consecutive weeks, starting at the baseline visit.  The dose for rituximab will be 
calculated according to the participant’s BSA at the screening visit after the participant’s 
eligibility has been established, and it will remain the same for all four infusions.  Each 
participant’s actual body height and weight, measured during the 28-day period before 
baseline (i.e., during the 28 days before the start of administration of open-label 
rituximab) will be used to calculate a patient’s BSA according to the Dubois formula 
(DuBois and Dubois 1916): 
BSA (m2) = [(Weight in kg)0.425
 × (Height in cm)0.725] × 0.00718 
Note:  Do not round until the end of the calculation. 
4.3.2.1.2 
Preparation 
Use appropriate aseptic technique in preparing rituximab for administration.  Withdraw 
the necessary amount of rituximab and dilute to a final concentration of 1–4 mg/mL into 
an infusion bag containing 0.9% sodium chloride USP or British Pharmacopoeia. The 
investigator may prescribe a concentration of 4 mg/mL for volume-sensitive participants.  
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 before administration.  Reconstituted rituximab is stable at 2°C−8°C 
(36°F−46°F) for 24 hours.  No incompatibilities between polyethylene bags have been 
observed.  However, because rituximab solution does not contain a preservative, diluted 
solution should be stored refrigerated (2°C−8°C). 
4.3.2.1.3 
Pre-Infusion Medication 
Patients should be medicated pre-infusion with paracetamol/acetaminophen and 
cetirizine hydrochloride (or similar antihistamine), both according to labeled age-related 
doses, to be given 1 hour (± 15 minutes) before each infusion of rituximab. Subject to 
investigator’s discretion, corticosteroid premedication with an IV infusion of 100 mg of 
methylprednisolone may be administered at least 30 minutes prior to infusion of 
rituximab (but not prior to clinical assessments) if the patient has experienced an IRR 
with a previous rituximab infusion. 
4.3.2.1.4 
Monitoring 
Facilities for immediate emergency intervention, including resuscitation in case of an 
anaphylactic reaction, must be available.  Vital signs (i.e., pulse rate, systolic and 
diastolic blood pressure, and temperature) will be taken pre-infusion.  During the 
infusions, vital signs will be assessed every 15 minutes for 1 hour, then every 
30 minutes, and at least 1 hour after the completion of the infusion.  A physician will be 
available on site.  Rituximab must not be administered as an IV push or bolus because 
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hypersensitivity reactions may occur.  After infusion, the IV line should remain in the 
participant for at least 1 hour to enable the administration of drugs, if necessary.  The 
participant’s vital signs must be checked 1 hour after the infusion.  For additional 
information, see Appendix 7. 
4.3.2.1.5 
Assessment of Compliance 
Accountability and patient compliance will be assessed by maintaining adequate drug 
dispensing and return records.  A call for drug administration to the interactive 
voice/web-based response system (IxRS) will also be used to assess compliance. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.2.3. 
4.3.2.1.6 
Destruction of the Investigational Medicinal Product 
Local or institutional regulations may require immediate destruction of used 
investigational medicinal product (IMP) for safety reasons.  In these cases, it may be 
acceptable for investigational site staff to destroy dispensed IMP before a monitoring 
inspection, provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned, and destroyed.  Written authorization must be obtained from the Sponsor at 
study initiation before destruction. 
If there are any issues with the drug, it should be returned to the appropriate Roche 
Clinical Trial Supplies Department for long-term storage and not be destroyed. 
Written documentation of destruction must contain the following: 
• 
Identity (batch numbers and patient identification numbers) of destroyed IMP 
• 
Quantity of IMP destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of responsible person who destroyed the 
investigational products 
 
4.3.2.2 
Methylprednisolone (Non-Investigational Medicinal Product) 
4.3.2.2.1 
Dosage, Administration, and Compliance 
Patients must receive three daily doses of 30 mg/kg of methylprednisolone 
(up to 1 g/day) or the equivalent dose of other glucocorticoids by IV infusion, which can 
occur at any time, up to and including Day 1.  If clinically indicated, and at the discretion 
of the investigator, additional doses (up to three) of methylprednisolone (30 mg/kg, up to 
1 g/day, or equivalent) can be given by IV infusion.  No more than six doses of 
methylprednisolone in total may be given.  All methylprednisolone doses must be 
completed prior to the first rituximab infusion.    
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The first rituximab infusion must occur no longer than 14 days after the final 
IV glucocorticoid dose; the final IV glucocorticoid dose may be given on Day 1 (prior to 
the first rituximab infusion). 
Compliance will be assessed according to completion of a glucocorticoid log. 
4.3.2.3 
Prednisolone or Prednisone (Non-Investigational Medicinal 
Product) 
4.3.2.3.1 
Dosage, Administration, and Compliance 
On Day 1 and following completion of IV glucocorticoids, all patients will receive 
concomitant oral prednisolone or prednisone (1 mg/kg/day or up to 60 mg/day or 
equivalent, whichever is lower), the dose of which will be tapered to a minimum of 
0.2 mg/kg/day (or 10 mg/day, whichever is the lowest) no later than Month 6. 
The general guidance on the suggested oral steroid dose-tapering schedule is to taper 
from 1 mg/kg/day (60 mg/day, maximum) at the start of treatment, to 0.8 mg/kg/day by 
Month 1, and then by 0.1−0.2 mg/kg/day each month to 0.2 mg/kg/day (or 10 mg/day, 
whichever is the lowest), which should be reached no later than Month 6. 
Oral prednisone (used in some non-UK sites) may be substituted for prednisolone at the 
same dose as long as there is no hepatic impairment. 
The steroid-tapering practice is specific to a particular patient and as such should be 
tailored individually for each patient at the time of study entry, at the discretion of 
the investigator. 
4.3.3 
Investigational Medicinal Product Accountability 
The IMP required for completion of this study (rituximab) will be provided by Roche.  The 
investigational site will acknowledge receipt of IMP, using the IxRS to confirm the 
shipment condition and contents.  Any damaged shipments will be replaced.  
IMP will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to Roche with the appropriate documentation.  
The site's method of IMP destruction must be agreed upon by Roche.  The site must 
obtain written authorization from Roche before any IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Retreatment with Rituximab 
After Month 6, if patients require retreatment with rituximab, further courses will be 
provided by the Sponsor until the common closeout date.  The dose of rituximab and the 
frequency of retreatment for the maintenance of remission will be at the discretion of the 
investigator. 
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Following administration of the first infusion the investigator should review the following 
safety criteria before administering subsequent infusions of rituximab. 
The following are absolute contraindications to receipt of further infusions of rituximab in 
this study: 
• 
An infusion reaction which necessitated complete discontinuation of the study 
infusions 
• 
Significant deterioration in patient’s general health status since inclusion into the 
study that results in the patient meeting the exclusion criteria related to General 
Health 
• 
Emergent primary or secondary immunodeficiency recognized during the study 
period, including new HIV infection, de novo hepatitis B, hepatitis C, or active 
tuberculosis infection 
 
Patients who have any of the absolute contraindications to receipt of study infusions with 
rituximab will be withdrawn from the study and should be encouraged to enter Follow 
Up. 
Patients who develop malignancy during the study will not be able to receive further 
courses of treatment with the study medication.  However, patients with basal cell 
carcinoma, squamous cell carcinoma of the skin or melanoma in situ (Clarke’s Level I), 
or cervical carcinoma in situ with no stromal invasion (stage 0), which have been 
completely excised and can be considered as cured, may be retreated with study 
medication at the discretion of the investigator. 
4.3.5 
Post-Trial Access to Rituximab 
Roche does not intend to provide rituximab or other study interventions to patients after 
conclusion of the study or for any early patient withdrawal. 
4.4 
CONCOMITANT THERAPY 
Prophylactic treatment for Pneumocystis jiroveci should be in accordance with local, 
routine clinical practice. Any concomitant medications (including over-the-counter 
medications, herbal medications, preventive vaccines, Pneumocystis jiroveci 
prophylactic medications, vitamins, and food supplements) and procedures considered 
clinically relevant by the investigator must be recorded on the appropriate electronic 
Case Report Form (eCRF).  A description of the type of drug or procedure, the amount, 
duration, reason for administration of drug, and the outcome of any procedure must be 
documented.  AEs that are judged by the investigator to be related to the administration 
of a concomitant medication or the performance of a procedure must also be 
documented on the appropriate Adverse Event eCRF.  It is important that dosages of 
medications received by patients during the remission induction phase (up to Month 6) 
remain stable.  However, changes in treatment will be allowed as clinically required for 
safety reasons.  
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4.4.1 
Glucocorticoids 
Glucocorticoids other than those specified per protocol are permitted.  This includes, but 
is not limited to, the use of inhaled glucocorticoids for participants with documented 
asthma and for participants with large airway involvement of GPA, as documented on 
bronchoscopy.  Local injections of glucocorticoid into subglottic GPA lesions are also 
permitted.  Doses of glucocorticoids other than those specified in the protocol should, 
whenever possible, remain stable.  All use of additional glucocorticoids for all indications, 
including GPA and MPA, must be documented accurately on the Glucocorticoid Log. 
4.4.2 
Plasmapheresis (Plasma Exchange) 
Patients requiring plasmapheresis at screening are not eligible to enter the study.  
Patients requiring plasmapheresis prior to entering the study must have completed the 
process 28 days prior to screening.  During the study, plasmapheresis is permitted if 
absolutely necessary in the opinion of the investigator, to treat the patient.  
Plasmapheresis will alter the pharmacokinetics of rituximab, if it occurs during the initial 
four infusions it may reduce efficacy and should therefore be used with caution.   
4.4.2.1 
Treatment of GPA and MPA after Month 6 
The optimal treatment after rituximab induction for GPA or MPA has not been 
established in adult or in pediatric patients.  After Month 6, treatment for maintenance of 
remission should be in accordance with clinical judgment of the investigator and can 
include glucocorticoids, AZA, CYC, MMF, MTX, rituximab, or other therapy. 
Recommended non-mandatory treatment for relapse: 
Major relapse:  
• 
Treat with CYC, rituximab, or MMF therapy, and with methylprednisolone and/or 
plasma exchange according to investigator’s discretion, or 
• 
Increase prednisolone or prednisone to 1 mg/kg/day; reduce to 20 mg/day by 4  
weeks, and return to baseline steroid dose when remission is achieved 
 
Minor relapse: 
• 
Increase prednisolone or prednisone to 0.5 mg/kg/day then reduce to baseline 
steroid dose over 1 month 
Relapsing patients will remain in the study and all changes in drugs and doses are to be 
recorded in the eCRF.  
Patients who are protocol remission failures or experience disease flare that cannot be 
controlled by glucocorticoids alone should receive treatment in accordance with local 
standard of care at the discretion of the investigator and will remain in the study, with all 
changes in drugs and doses to be recorded in the eCRF.  
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4.4.3 
Vaccinations 
4.4.3.1 
Passive Antibody Titers to Specific Antigens 
Review of long-term safety data from patients with RA exposed to rituximab shows that 
rituximab does not appear to have an effect on specific humoral immunity to several 
common bacterial and viral antigens over the observation period, including repeat 
treatment courses.  The proportions of patients with positive antibody titers against 
mumps, rubella, varicella, tetanus toxoid, influenza, and Streptococcus pneumoniae, 
post-rituximab were similar to the proportions at baseline. 
4.4.3.2 
Immunization and Humoral Responses to Clinically Relevant 
Vaccines 
In a randomized, controlled study of immunization responses (SIERRA) (Bingham et al  
2008), patients with RA who were peripherally depleted of B cells and receiving 
rituximab + MTX had effective humoral responses to recall antigen (tetanus toxoid) 
administered 6 months after rituximab, similar to the responses observed in patients 
receiving MTX alone. Some rituximab-treated patients mounted T-cell–independent 
responses to the 23-valent pneumococcal polysaccharide vaccine but responses were 
decreased overall compared with those in patients receiving MTX alone.  Because 
polysaccharide vaccines elicit a T-cell–independent response, and rituximab targets 
peripheral CD20+ B cells, decreased responses to polysaccharide vaccines are 
consistent with the mechanism of action of rituximab. Although responses to the 23-
valent pneumococcal polysaccharide vaccine were decreased, a significant number of 
patients were able to mount positive responses. For example, a total of 57% and 43% of 
patients had at least a 2-fold increase in titers to at least one or two pneumococcal 
serotypes, respectively. 
It is recommended that a patient’s vaccination record and the need for immunization be 
carefully investigated in all patients prior to entering the study or receiving a further 
course of rituximab.  If vaccination is necessary, it is recommended that any required 
vaccination or booster be given at least 28 days prior to the first infusion of rituximab.  
The use of live or attenuated vaccines (i.e., measles, mumps, rubella, oral polio, Bacille 
Calmette Guerin [BCG], typhoid, yellow fever, vaccinia, some forms of influenza 
[e.g., FluMist®] or any other live vaccines not yet licensed but belonging to this category) 
are specifically prohibited during the study and while the patient’s peripheral B-cells are 
depleted. 
The use of killed or inactivated vaccine (e.g., some forms of influenza) is not prohibited 
during the study; however, the efficacy of certain vaccines during or following periods of 
B-cell depletion has not been studied in this patient population. 
Patients who are eligible for yearly influenza vaccine or who require other non-live 
booster vaccinations can receive vaccination with killed or toxoid vaccines in accordance 
with normal clinical practice.  
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There is no planned analysis of antibody titers to common vaccinations.  If clinically 
indicated, additional analysis of the immune status of patients may be considered using 
serum samples already collected for other protocol-defined analyses. 
4.4.4 
Prohibited Therapy 
Treatment with any investigational agent, cell-depleting therapy (except for CYC and 
rituximab), or biologic agents such as TNF antagonists, anti−alpha 4 integrin antibody, or 
co-stimulation modulator, is prohibited during the main study (until common closeout 
date). Any patients who do receive a prohibited therapy or any GPA or MPA treatment 
other than protocol-defined glucocorticoids will remain in the study for follow-up.  
Thereafter (i.e., at time points after the receipt of prohibited therapy or any GPA or MPA 
treatment other than protocol-defined glucocorticoids), patients will be considered to 
have failed to meet the protocol-defined remission endpoints, irrespective of BVAS/WG 
and PVAS scores. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.2.3. 
4.5 
STUDY ASSESSMENTS 
The sequence of assessments at each visit will be standardized as follows 
(at visits required by the schedule of assessments) and should be performed prior to 
infusion, with the exception of the post-dose PK sample. 
1. 
PRO assessments:  
  
2. 
Efficacy assessments:  
, and per schedule of assessments  
(see Appendix 1) 
3. 
Laboratory samples:  All samples (including for safety and efficacy) must be 
obtained prior to study drug treatment, except for some samples for PK analysis, 
which will be obtained after study drug treatment.  The laboratory samples can be 
drawn either at least 30 minutes before or at any time after the nurse or investigator 
assessments. 
4. 
Safety assessments:  review of AEs, vital signs, concomitant medications, and 
laboratory data 
5. 
Post-dose PK sample (at scheduled visits, where indicated). The post-infusion PK 
sample should be taken from the opposite arm to that into which the rituximab 
infusion was administered. 
 
4.5.1 
Medical History and Demographic Data 
Medical history includes life-long clinically significant diseases, surgeries, birth and 
developmental history, cancer history (including cancer therapies and procedures), 
smoking history, use of alcohol and drugs of abuse, immunization history, and all 
previous and current clinically relevant concomitant medications (e.g., prescription 
drugs, over-the-counter drugs, herbal/homeopathic remedies, nutritional supplements) 
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4.5.2.3 
 
 
  
 
 
 
 
 
 
 
 
 
 
4.5.2.4 
 
 
 
 
 
4.5.2.5 
Patient-Reported Outcomes 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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4.5.3 
Safety Assessments 
4.5.3.1 
Vital Signs 
Vital signs (i.e., pulse rate, systolic and diastolic blood pressure, and temperature) will 
be taken at the times indicated in the schedule of assessments (see Appendix 1).  
Assessments will be taken after the patient has been in a semi-supine position for at 
least 5 minutes.  Blood pressure measurements should be obtained using a child-
appropriate cuff size. 
4.5.3.2 
Electrocardiograms 
Twelve-lead electrocardiograms (ECGs) should be performed according to the schedule 
of assessments (see Appendix 1) and reviewed by the investigator or his or her 
designee.  Whenever possible, the same machine should be used for each patient.  
To minimize variability, it is important that patients be in a resting position for 
≥ 10 minutes prior to each ECG evaluation.  Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording.  ECGs should be performed prior to receipt of 
study drug, any scheduled vital sign measurements, and blood draws.  For safety 
monitoring purposes, the investigator or his or her designee must review, sign, and date 
all ECG tracings.  Paper copies will be kept as part of the patient's permanent study file 
at the site.  Digital recordings will be stored at study sites. ECG outcomes of “normal” or 
“abnormal” should be reported on the eCRF.  New or worsened abnormalities should be 
recorded as AEs on the Adverse Event eCRF. 
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4.5.3.3 
Chest X-Rays and Computed Tomography Scans 
Posterior–anterior chest X-rays (or chest X-ray in accordance with local requirements) 
should be obtained at screening and, if normal, only if indicated thereafter.  If chest X-ray 
is abnormal, it should be repeated at Month 1 and as indicated thereafter. 
At screening, if a chest X-ray has been obtained within the past 90 days that shows no 
clinically significant abnormality and if the patient exhibits no signs or symptoms 
suggestive of pulmonary disease that would exclude the patient, then an additional chest 
X-ray is not required. 
A chest computed tomography (CT) scan is to be completed only if indicated and at the 
discretion of the investigator. 
4.5.3.4 
Physical Examinations 
A complete baseline physical examination will be performed at screening and should 
include an evaluation of the head, eyes, ears, nose, and throat and of the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits, limited, symptom-directed physical examinations should be 
performed.  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened abnormalities should be recorded as AEs on the Adverse Event 
eCRF. 
4.5.3.5 
Laboratory Assessments 
The following laboratory tests will be recorded at the time points indicated in the 
schedule of assessments (see Appendix 1).  Whenever possible, laboratory samples 
should be drawn in the morning.  Unscheduled laboratory assessments for safety issues 
are permitted at any time.  
With the exception of samples for rituximab and HACA levels (for PK/PD assessments) 
obtained according to the schedule of assessments, all laboratory assessments 
requiring a blood sample are to be performed as part of routine clinical care.  
The total volume of blood loss for laboratory assessments (including all safety, efficacy, 
PK/PD, and immunologic assessments) does not exceed the per-visit and 
per-cumulative visit recommendations made by the University of Pittsburgh’s Institutional 
Review Board (IRB) and the NIH for the expected average weights of the patient.  
However, if the enrolled patient weighs  < 13 kg, please check with the Roche Medical 
Monitor for planning the blood draws.  This weight is based on acceptable blood draw 
limits of 2 mL/kg (blood draw in a day) or 4 mL/kg (blood draw in a month) at Children’s 
Hospital Seattle. 
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The procedures for the collection, handling, and shipping of laboratory samples are 
specified in the Sample Handling and Logistics Manual supplied to sites.  
The samples for this study should be classified, packed, and shipped as 
UN3373 Biological Substance, Category B. 
Local Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis: 
• 
Serum ANCA sample:  ANCA testing performed at the screening visit may be 
performed locally or centrally.  All other ANCA testing should be performed centrally. 
• 
Acute-phase reactants:  erythrocyte sedimentation rate and C-reactive protein 
• 
Urinalysis:  dipstick for blood, protein, and glucose, and albumin to creatinine ratio 
• 
Pregnancy test:  urine dipstick test for all females of childbearing potential 
 
Central Laboratory Assessments 
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor for analysis.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
• 
Serum ANCA sample:  ANCA testing performed at the screening visit may be 
performed locally or centrally.  All other ANCA testing should be performed centrally. 
• 
Hematology or complete blood count:  hemoglobin, hematocrit, red blood cells and 
indices (mean corpuscular volume, mean cell hemoglobin, mean corpuscular 
hemoglobin concentration), white blood cells, absolute differential, and platelet 
counts 
• 
Serum chemistry:  AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total 
bilirubin (direct and indirect will be performed if total bilirubin is greater than the 
ULN), urea, uric acid, creatinine, potassium, sodium, chloride, calcium, phosphate, 
and glycosylated hemoglobin (HbA1c). 
• 
Urinalysis:  microscopic examination if abnormal and applicable 
• 
Pregnancy test:  A serum pregnancy test will be performed at screening for all 
females of childbearing potential 
• 
Hepatitis serology:  HBcAb, HBsAg, and hepatitis C antibody (HCV Ab) at screening 
only or if clinically indicated during the trial 
 
4.5.3.6 
Immunologic Assessments 
Determination of B- and T-cell populations will be performed by fluorescence-activated 
cell sorter (FACS) analysis, including, but not limited to, CD3, CD4, CD8, CD16/56, 
CD19, CD27, CD4/45RA/45RO, and CD8/45RA/45RO.  In addition, quantitative 
immunoglobulin levels (including total immunoglobulin, immunoglobulin A [IgA], IgG, and 
IgM isotype levels). 
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4.5.4 
Pharmacokinetic Assessments 
During the remission induction phase of the study, each patient will provide serum 
samples for PK analysis (rituximab levels) prior to the first, second, third, and 
fourth doses; after completion of the first and fourth infusions; and subsequently on 
Days 29 (Month 1), 60 (Month 2), 120 (Month 4), and 180 (Month 6).  The post-infusion 
PK sample should be taken from the opposite arm to that into which the rituximab 
infusion was administered.  
4.5.5 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
4.5.6 
Timing of Study Assessments 
4.5.6.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  It will be obtained from 
parents or patient’s legal guardian, with assent as appropriate by the patient, depending 
on the patient’s level of understanding.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.  
Screening tests and evaluations will be performed at the screening visit and should be 
completed within 28 days of the baseline visit.  Results of standard of care tests or 
examinations performed prior to obtaining informed consent and within 14 days prior to 
the screening visit may be used and do not need to be repeated for screening, at the 
discretion of the investigator.  All screening evaluations must be completed and 
reviewed to confirm that patients meet all eligibility criteria before study enrollment.  
Please see Appendix 1 for the schedule of screening assessments. 
For entry into this study, patients will be screened for tuberculosis according to 
local/national guidelines.  Results of screening tests will be reported on the eCRF. 
The investigator will maintain a screening log to record details of all patients screened. 
Patients who fulfill all the inclusion criteria and meet none of the exclusion criteria will be 
accepted into the study.  The investigator or designated person will inform the IxRS and 
the patient will be allocated a patient number. 
Any new information arising during the study that may affect the willingness of the 
patient to continue in the trial will be provided to the investigator and the patient as soon 
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as possible.  Any changes to the protocol procedures will be subject to additional 
explanation and reconfirmation of consent to continue participation in the study. 
4.5.6.1.1 
Retesting for Laboratory Inclusion and Exclusion Criteria 
If a patient does not meet laboratory criteria for a third time, he or she will be considered 
a screen failure.  
It will not be considered retesting if blood samples have to be redrawn because of 
sample handling problems, breakage, or sample integrity. 
4.5.6.1.2 
Rescreening 
At the discretion of the Sponsor and the investigator, a patient may be rescreened. 
Rescreening refers to repeating the whole screening process.  Rescreening is required if 
a patient has not met all the eligibility criteria within 28 days of the original 
screening visit.  
Patients are only permitted to be rescreened once.  Each patient must be reconsented 
before rescreening occurs. 
It will not be considered rescreening if blood samples have to be redrawn because of 
sample handling problems, breakage, or sample integrity.  In the case of a protocol 
amendment, potential patients may be reassessed for eligibility according to any 
updated inclusion and exclusion criteria. 
4.5.6.2 
Baseline Assessments (Day 1) and Remission Induction Phase 
Patients must receive three doses of methylprednisolone at 30 mg/kg/day (up to 1 g/day) 
or the equivalent dose of other glucocorticoids by IV infusion, which can occur at any 
time, up to and including Day 1.  If clinically indicated, and at the discretion of the 
investigator, additional daily doses (up to three) of methylprednisolone (30 mg/kg, up to 
1 g/day) can be given by IV infusion.  No more than six doses in total may be given.  All 
doses of methylprednisolone must be completed prior to the first rituximab infusion.  
The first rituximab infusion (baseline visit) must occur no longer than 14 days after the 
final IV glucocorticoid dose; the final IV glucocorticoid dose may be given on Day 1 
(prior to the first rituximab infusion). 
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the schedule of assessments (see Appendix 2).  Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments.  PRO assessments should be performed prior to the completion of other 
study assessments. 
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Please see Appendix 1 for the schedule of assessments performed during the 
treatment period. 
4.5.6.3 
Follow-Up Visits 
Following the remission induction phase, which ends at Month 6, patients will be 
followed up for a minimum of 12 months at visits conducted every 3 months.  Patients 
who are protocol remission failures or who experience disease flare that cannot be 
controlled by glucocorticoids alone should receive treatment according to local 
standard of care, at the discretion of the investigator and will remain in the study 
(see Section 4.4.2.1).  After Month 18, patients will be followed at study visits every 
3 months until the common closeout date.  The procedures performed at the follow-up 
visits will be similar to those performed at the Month 18 visit.  The schedule of 
assessments for the follow-up phase is provided in Appendix 1.   
4.5.6.4 
Extended Follow-Up Visits 
At the common closeout date, patients whose peripheral B cells remain depleted, will 
continue to attend study visits every 3 months until their peripheral B-cell counts have 
returned to pre-rituximab baseline levels or to within the normal range for the 
population, whichever is lower.  Safety, (adverse events), central laboratory and 
immunologic  parameters, including immunoglobulins, will continue to be assessed in 
extended safety follow-up (see Appendix 1).  If a patient receives any B cell−depleting 
therapy (commercial or investigational) or any other agent that affects the return of 
B cells, including, but not limited to, rituximab, CYC and AZA, on or after the common 
closeout date, he or she will not be followed any further (although routine clinical follow-
up after the end of the study will continue, according to local practice). 
4.5.7 
Early Withdrawal Visit 
Patients who discontinue from the study early because of non-compliance or withdrawal 
of consent will be asked to return to the clinic to attend an early withdrawal visit and will 
be encouraged to enter follow up. 
If the investigator judges that continuing rituximab is no longer in the participant’s best 
interest, the participant will be asked to complete a withdrawal visit and will remain in the 
study for follow-up (see Section 3.1.8).  From the point of withdrawal, a patient may no 
longer receive rituximab as part of this protocol.  A schedule of assessments for the 
withdrawal visit is provided in Appendix 1.   
4.5.8 
Unscheduled Visits 
Patients may attend the clinic for unscheduled visits at any time for additional safety 
monitoring or disease surveillance at the discretion of the investigator.  If a patient has 
an unscheduled visit during the study that falls outside of a scheduled visit window, 
assessments will be performed at the discretion of the investigator.  If a patient has an 
unscheduled visit within a scheduled visit window, it is at the discretion of the 
investigator to perform the scheduled assessments indicated for the scheduled visit.  
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4.5.9 
Progressive Disease Before Remission 
Progressive disease before remission by PVAS is defined as: 
1. 
Persistence or worsening of a major PVAS item present at entry, and/or 
2. 
A new major PVAS item that is not present at entry 
 
Major (and minor) PVAS items are defined in Table 2.  
Progressive disease before remission by BVAS/WG is defined as: 
1. 
Persistence or worsening of a major BVAS/WG item present at entry, and/or 
2. 
A new major BVAS/WG item that is not present at entry 
Major (and minor) BVAS/WG items are defined in Table 3.  
Patients with progressive disease before remission by Month 6 will receive additional 
treatment as per local standard of care and will be considered a ‘treatment failure’ 
however, data collection should continue within the trial. 
4.6 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients may withdraw early from the study for the following reasons: 
• 
Withdrawal of informed consent 
• 
Loss to follow-up 
• 
Death 
 
Parents or guardians have the right to withdraw their child from the study at any time for 
any reason.  In the case that a patient prematurely discontinues from the study, the 
parents/guardians should be asked whether they can be contacted for further 
information.  The outcome of that discussion should be documented in both the medical 
records and on the eCRF.  If the patient is lost to follow-up, the investigator should 
contact the patient’s parents/guardian or a responsible relative by telephone followed by 
registered mail or through a personal visit to establish as completely as possible the 
reason for the withdrawal.  A complete final evaluation at the time of the patient’s 
withdrawal should be made with an explanation as to why the patient is withdrawing from 
the study. 
4.6.2 
Criteria for Premature Study Drug Termination or 
Study Withdrawal by Investigator or Sponsor 
The investigator and Sponsor have the right to discontinue a patient from study drug or 
withdraw a patient from the study at any time.  Reasons for discontinuation of study drug 
or withdrawal from the study may include, but are not limited to, the following: 
• 
Non-compliance with the requirements of the study 
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• 
Any AE that in the opinion of the investigator or the Sponsor precludes further study 
participation 
• 
The best interest of the patient  
 
When applicable, parents/guardians should be informed of circumstances under which 
their child’s participation may be terminated by the investigator without the 
parent’s/guardian’s consent.  The investigator may withdraw patients from the study in 
the event of intercurrent illness, AE, treatment failure after a prescribed procedure, lack 
of compliance with the study and/or study procedures (e.g., dosing instructions, study 
visits), cure, or any reason where it is felt by the investigator that it is in the best interest 
of the patient to be discontinued from the study.  Any administrative or other reasons for 
withdrawal must be documented and explained to the patient. 
All patients who permanently discontinue infusions of rituximab but have not terminated 
study participation (withdrawn consent or have been withdrawn by the investigator or 
Sponsor according to the above examples) will have safety evaluations, including all 
withdrawal visits, as shown in the schedule of assessments (see Appendix 1).  If the 
reason for withdrawal of a patient from the study drug is an AE, the principal specific 
event will be recorded on the eCRF.  If possible, the patient should not be withdrawn 
from the study but only from study drug and, if possible, should be followed until the AE 
has resolved (see Section 5.5.1).  An excessive rate of withdrawals can render the study 
non-interpretable; therefore, unnecessary withdrawal of patients should be avoided.  
Should a patient decide to withdraw, all efforts will be made to complete and report the 
observations prior to withdrawal as thoroughly as possible. 
4.6.3 
Documentation at Withdrawal from Study 
Every effort should be made to obtain information about patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw from the study will not be replaced. 
4.6.4 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program.  The Sponsor has the right to 
replace a site at any time.  Reasons for replacing a site may include, but are not limited 
to, the following: 
• 
Excessively slow recruitment 
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• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording of AEs, SAEs, and 
non-serious AEs of special interest; measurement of protocol-specified safety laboratory 
assessments; measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2 
CLINICAL ADVERSE EVENTS 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.6.4 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present 
at baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g.,  invasive screening procedures such 
as biopsies) 
 
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.  AEs not listed in the NCI CTCAE 
will be graded using the following criteria: 
• 
Grade 1:  mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• 
Grade 2:  moderate; minimal, local or non-invasive intervention indicated 
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• 
Grade 3:  severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated 
• 
Grade 4:  life-threatening consequences; urgent intervention indicated 
• 
Grade 5:  death related to an AE 
 
5.2.1 
Serious Adverse Events (Immediately Reportable to Roche) 
An SAE is any AE that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death).  (Note:  Death is an outcome, 
not an event.  The term “sudden death” should only be used when the cause is of a 
cardiac origin as per standard definition.  The terms “death” and “sudden death” are 
clearly distinct and must not be used interchangeably.) 
• 
Is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
(see Section 5.3.6.5) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe, or according to NCI CTCAE criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor within 24 hours after 
learning of the event (see Section 5.4.2 for reporting instructions). 
5.2.2 
Relationship to Study Drug 
The relationship of the AE or SAE to the rituximab study treatment must be assessed by 
the investigator or his or her designee. 
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5.2.3 
Management of Specific Adverse Events 
Adherence to the planned dosing schedule with rituximab infusions is required unless an 
adjustment is necessary for safety reasons.  The following risk mitigation and dose 
modification rules apply.  Recommendations for vigilance with signs and symptoms of 
particular safety events of interest are summarized in the following sections.  During 
study visits when the rituximab infusion is interrupted for toxicity, all other study 
assessments should be performed as per the schedule of assessments 
(see Appendix 1). 
5.2.3.1 
Infusion-Related Reactions following Rituximab Administration 
Rituximab is associated with IRRs, including, but not limited to, headache, pruritus, 
throat irritation, flushing, rash, urticaria, hypertension, hypotension, and pyrexia, which 
may be related to release of cytokines and/or other chemical mediators.  Participants will 
receive at least three doses of IV methylprednisolone, followed by oral prednisolone or 
prednisone (see Section 4.3.2.1.3).  IV glucocorticoids may help prevent severe infusion 
reactions potentially associated with rituximab.  Medication, consisting of an 
analgesic/anti-pyretic drug and an anti-histaminic drug, should always be administered 
prior to each infusion of rituximab (see Section 4.3.2.1.3). Healthcare professionals 
administering the rituximab infusions must be trained in the appropriate administrative 
procedures and be able to recognize the symptoms associated with potential 
anaphylactic or hypersensitivity reactions.  
For patients with RA, GPA, and MPA, most infusion-related events reported in clinical 
trials were mild to moderate in severity.  Severe IRRs with fatal outcome have been 
reported in the postmarketing setting in RA patients.  Patients with pre-existing cardiac 
conditions and those who experienced prior cardiopulmonary adverse reactions must be 
closely monitored.  In general, the proportion of patients experiencing any infusion 
reaction was higher following the first infusion of any treatment course than following the 
second infusion.  Subsequent rituximab infusions were better tolerated by patients than 
the initial infusion.  Less than 1% of patients experienced serious IRRs, with most of the 
events reported during the first rituximab infusion.  The reactions reported were usually 
reversible with a reduction in rate or interruption of the infusion and with administration of 
an anti-pyretic medication, an antihistamine, and occasionally oxygen, IV saline, 
bronchodilators, or glucocorticoids, as required.  Depending on the severity of the IRR 
and the required interventions, treatment with rituximab should be temporarily or 
permanently discontinued.  In most cases, the infusion can be resumed at a 
50% reduction in rate when symptoms have completely resolved. 
Anaphylactic and other hypersensitivity reactions have been reported following the 
IV administration of proteins to patients.  Medicinal products for the treatment of 
hypersensitivity reactions (e.g., epinephrine, antihistamines, and glucocorticoids) must 
be available for immediate use in the event of an allergic reaction during administration 
of rituximab.  If a patient has symptoms of anaphylaxis or serious hypersensitivity, or 
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requires an interruption of the study drug because of symptoms of anaphylaxis or 
hypersensitivity, administration of rituximab must be discontinued permanently.  
Patients will be asked to complete a withdrawal visit but will remain in the study 
(see Section 3.1.8).  A schedule of assessments for the withdrawal visit is provided in 
Appendix 1.   
5.2.3.2 
Cardiovascular Events 
Because hypotension may occur during a rituximab infusion, consideration should be 
given to withholding anti-hypertensive medications 12 hours prior to the 
rituximab infusion. 
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure, 
and myocardial infarction have occurred in patients treated with rituximab.  Therefore, 
patients with a history of cardiac disease should be monitored closely. 
5.2.3.3 
Infections 
Given the mechanism of action of rituximab and the knowledge that B cells play an 
important role in maintaining normal immune response, patients may have an increased 
risk of infection following rituximab therapy.  Rituximab should not be administered to 
patients with an active infection or to severely immunocompromised patients (e.g., those 
in whom levels of CD4 or CD8 are very low).  Physicians should exercise caution when 
considering the use of rituximab in patients with a history of recurring or chronic 
infections or with underlying conditions that may further predispose patients to serious 
infection.  Patients who develop infection following rituximab therapy should be promptly 
evaluated and treated appropriately.  If a patient experiences a new infection during the 
intervening time between any of the four rituximab infusions, the subsequent infusion 
should be delayed (up to a maximum of 14 days) until the infection has completely 
resolved and treatment with any anti-infective medications has been completed.  Receipt 
of further rituximab infusions is at the discretion of the investigator.  Remaining infusions 
should be scheduled so that they are given 1 week apart. 
5.2.3.4 
Hepatitis B Infections 
Cases of hepatitis B reactivation, including those with a fatal outcome, have been 
reported in patients with RA, GPA, and MPA treated with rituximab. 
Screening for HBsAg, HBcAb, hepatitis C serology, and HBV DNA must be performed in 
all patients before initiation of treatment with rituximab.  Patients with positive hepatitis 
serology will be excluded from the study.  Any patient who experiences active hepatitis B 
disease during the study will be immediately withdrawn from rituximab study therapy and 
will be followed until the common closeout date or, if required, for longer in extended 
follow-up (see Section 3.1.4). 
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5.2.3.5 
Progressive Multifocal Leukoencephalopathy 
Cases of fatal PML have been reported following use of rituximab for the treatment of 
autoimmune diseases, including RA and GPA.  Several, but not all, of the reported 
cases had potential risk factors for PML, including the underlying disease, long-term 
immunosuppressive therapy, or chemotherapy.  PML has also been reported in patients 
with autoimmune disease not treated with rituximab.  Physicians treating patients with 
autoimmune diseases should consider PML in the differential diagnosis of patients 
reporting neurologic symptoms, which may include clumsiness, progressive weakness, 
visual, speech, and sometimes, personality changes.  If PML is considered, then a 
neurologic consultation should be obtained.  If PML is diagnosed in a patient receiving 
rituximab, no additional infusions of rituximab should be administered; reductions in 
concomitant immunosuppressive therapy and appropriate treatment, including antiviral 
therapy, should be considered.  There are no known interventions that can reliably 
prevent PML or adequately treat PML should it occur.  Additional information is provided 
in the Investigator’s Brochure. 
5.2.3.6 
Neutropenia 
Decreases in neutrophils have been observed in adult patients with GPA and MPA 
following treatment with rituximab.  Neutropenia was not associated with an observed 
increase in serious infection in such patients.  Patients with an ANC < 1.5 × 103/μL at 
screening will not be enrolled in the study.   
5.2.3.7 
Hypogammaglobulinemia 
Decreases in IgA, IgG, and IgM have been observed in adult patients with GPA and 
MPA following treatment with rituximab.  No increased rate in overall infections or 
serious infections was observed after the development of low IgA, IgG, or IgM levels.  
Assessment of the Roche safety database and published literature reveals that 
development of hypogammaglobulinemia after rituximab treatment in pediatric patients 
with various underlying disease has been observed, and, in some cases, this has been 
reported as severe and long term requiring long-term IVIg treatment.  However, 
attribution of these events to rituximab is limited by potential alternate etiologies, such as 
common variable immunodeficiency disease, severity of underlying diseases, use of 
rituximab as a last resort after exposure to other immunosuppressive agents, and limited 
clinical data including lack of randomized clinical trials, retrospective data collection, and 
lack of detailed safety data reporting.  Importantly, the majority of these cases were not 
reported to have been associated with serious infections. 
Patients with IgG and IgM levels below the exclusionary levels per section 4.1.2, at 
screening will not be enrolled in the study.  The investigator should closely monitor the 
patient’s immunoglobulin levels during the study.  If immunoglobulin levels decrease 
following rituximab treatment, and require specific medical care or management, repeat 
dosing can be considered at the discretion of the investigator, based on the assessed 
benefit/risk.  IVIg (restricted to replacement dosing for hypogammaglobulinemia) may be 
given at the discretion of the investigator.  
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5.2.3.8 
Skin Reactions 
Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and 
Stevens–Johnson syndrome, some with fatal outcome, have been reported.  In such 
cases, treatment should be permanently discontinued. 
5.2.3.9 
Pregnancy 
IgGs are known to cross the placental barrier. 
Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence 
of embryotoxicity in utero.  Newborn offspring of maternal animals exposed to rituximab 
were noted to have depleted B-cell populations during the postnatal phase.  
B-cell levels in human neonates following maternal exposure to rituximab have not been 
studied in clinical trials.  There are no adequate and well-controlled data from studies in 
pregnant females; however, transient B-cell depletion and lymphocytopenia have been 
reported in some infants born to mothers exposed to rituximab during pregnancy.  For 
these reasons, rituximab should not be administered to pregnant females unless the 
possible benefit outweighs the potential risk. 
Female patients in Tanner stages ≥ 2 (see Appendix 4) or post-onset of menarche 
should employ effective contraceptive methods during and for up to 12 months after 
treatment with rituximab. 
Additional information about rituximab is given in the Investigator’s Brochure. 
5.2.3.10 
Collection of Additional Data for Certain Adverse Events 
The Sponsor requires that additional data be collected for certain AEs that are presently 
closely monitored by the Sponsor.  This additional data collection will be performed 
using dedicated eCRFs.  The events are as follows: 
• 
Malignancies 
• 
Hepatitis B 
• 
PML 
• 
Posterior reversible encephalopathy syndrome  
 
5.2.4 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to Roche) 
Non-serious AEs of special interest are required to be reported by the investigator to the 
Sponsor within 24 hours after learning of the event (see Section 5.4.2 for reporting 
instructions).  AEs of special interest for general drug development include the following: 
• 
Cases of elevated ALT or AST levels in combination with either an elevated bilirubin 
level or clinical jaundice, as defined in Section 5.3.6.1 
• 
Suspected transmission of an infectious agent by the study drug  
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Section 5.4−5.6. 
For each AE recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.1 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported (e.g., SAEs related to 
invasive procedures, such as biopsies). 
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until the common closeout date and during extended follow-up (if applicable).  
After this time, investigators should report any deaths, SAEs, or other AEs of concern 
that are believed to be related to prior treatment with study drug (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation time points.  Examples of non-directive questions 
include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity. Table 4 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 
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Table 4 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
Life-threatening consequences or urgent intervention indicated d
4 
Death related to adverse event d
5 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the NCI CTCAE (v4.0), which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.1. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.1. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating “yes” or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions 
AEs that occur during or within 24 hours after study drug infusion should be captured as 
individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction. 
Other Adverse Events 
For AEs other than IRRs, a diagnosis (if known) should be recorded on the Adverse 
Event eCRF 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, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by one AE 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment, only vomiting 
should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by a mild, non-serious infection, only neutropenia 
should be reported on the eCRF. 
• 
If neutropenia is accompanied by a severe or serious infection, both events should 
be reported separately on the eCRF. 
 
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All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens.  If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent AE is one that resolves between patient evaluation time points and 
subsequently recurs.  Each recurrence of an AE should be recorded separately on the 
Adverse Event eCRF. 
5.3.6 
Laboratory Test Abnormalities 
Any treatment-emergent abnormal laboratory result (i.e., a result that falls outside the 
laboratory reference range or is a substantial within-reference range change) that is 
clinically significant should be recorded as an appropriate clinical diagnosis on the 
Adverse Event eCRF. 
Clinically significant laboratory values are those that: 
• 
Are accompanied by a clinical symptom, in which case the symptom, not the 
laboratory parameter, is recorded as the adverse event term. 
• 
Lead to a change in study drug (e.g., dose modification, interruption, or permanent 
discontinuation). 
• 
Require a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication or therapy) 
 
This applies to any protocol-specified and non-protocol-specified safety and efficacy 
laboratory result from tests performed after the first dose of study drug, which meets the 
clinical significance criteria above. 
This does not apply to any abnormal laboratory result that does not meet the clinical 
significance criteria or those that are a result of an AE which has already been reported. 
Any laboratory result abnormality considered to be an SAE should be reported as such. 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × the ULN associated with cholecystitis), only 
the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.6.1 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × the ULN) in combination with either an 
elevated total bilirubin (> 2 × the ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × the ULN in combination with total bilirubin 
> 2 × the ULN 
• 
Treatment-emergent ALT or AST > 3 × the ULN in combination with clinical jaundice 
 
The most appropriate diagnosis (or, if a diagnosis cannot be established, the abnormal 
laboratory values) should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor within 24 hours after learning of the event, either as an SAE 
or a non-serious AE of special interest (see Section 5.4.2). 
5.3.6.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of GPA or MPA. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term “sudden death” should only be used for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
was stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
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cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. 
If the death is attributed to progression of MPA/GPA, MPA/GPA “progression” should be 
recorded on the Adverse Event eCRF. 
5.3.6.3 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
5.3.6.4 
Lack of Efficacy or Worsening of Granulomatosis with 
Polyangiitis (Wegener’s) and Microscopic Polyangiitis 
Medical occurrences or symptoms of deterioration that are anticipated as part of MPA 
and GPA should be recorded as an AE if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of MPA or GPA on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., “accelerated MPA/GPA”). 
5.3.6.5 
Hospitalization or Prolonged Hospitalization 
Any AE that results inpatient hospitalization or prolonged hospitalization should be 
documented and reported as an SAE (per the definition of SAE in Section 5.2.1), except 
as outlined as follows.   
The following hospitalization scenarios are not considered to be SAEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not suffered an AE. 
 
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5.3.6.6 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects.   
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.  
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated AE fulfills serious criteria, the 
event should be reported to the Sponsor within 24 hours after learning of the event 
(see Section 5.4.2). 
5.3.6.7 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data.  However, if any patient and/or 
parent/guardian’s responses suggestive of a possible AE are identified during site review 
of the PRO questionnaires, site staff will alert the investigator, who will determine if the 
criteria for an AE have been met and will document the outcome of this assessment in 
the patient’s medical record per site practice.  If the event meets the criteria for an AE, it 
will be reported on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The investigator must report the following events to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study drug: 
• 
SAEs 
• 
Non-serious AEs of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor within 24 hours after becoming aware of the information.  New significant 
information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/Ethics Committee (EC). 
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5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information  
Primary Contact 
Medical Monitor: 
, MD 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Secondary Contact 
Medical Monitor: 
, MD 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Alternative Medical Monitor Contact Information 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see “Protocol 
Administrative and Contact Information & List of Investigators”).  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of SAEs and non-serious AEs of special interest, investigators should record 
all case details that can be gathered within 24 hours of the Adverse Event eCRF and 
submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse Event/ 
Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet should be 
completed and faxed to Roche Safety Risk Management or its designee within 24 hours 
day after learning of the event, using the fax numbers provided to investigators 
(see “Protocol Administrative and Contact Information & List of Investigators”).  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or 90 days after the last dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator within 
24 hours after learning of the pregnancy and submitted via the EDC system.  A 
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pregnancy report will automatically be generated and sent to Roche Safety Risk 
Management.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Roche Safety Risk 
Management or its designee within 24 hours after learning of the pregnancy, using the 
fax numbers provided to investigators (see “Protocol Administrative and Contact 
Information & List of Investigators”). 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator within 24 hours after learning of the pregnancy and 
submitted via the EDC system.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event eCRF, and reported to the Sponsor within 24 hours after learning of the event 
(see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as an SAE, recorded on the 
Adverse Event eCRF, and reported to the Sponsor within 24 hours after learning of the 
event (see Section 5.4.2). 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered 
to be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a 
designee may follow-up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the study completion/early termination visit, the investigator should instruct each 
patient to report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures.   
The investigator should notify the Sponsor of any death, SAE, or other AE of concern 
occurring at any time after a patient has discontinued study participation if the event is 
believed to be related to prior study drug treatment or study procedures.  The Sponsor 
should also be notified if the investigator becomes aware of the development of cancer 
or a congenital anomaly/birth defect in a subsequently conceived offspring of a patient 
that participated in this study. 
The investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the investigator 
should report the event directly to Roche Safety Risk Management by telephone 
(see “Protocol Administrative and Contact Information & List of Investigators”). 
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Rituximab Investigator’s Brochure 
• 
Local prescribing information for rituximab 
• 
Rituximab Core Data Sheet 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is an exploratory, open-label, single-arm study, with the primary objective of 
evaluating safety and PK of rituximab in pediatric patients with GPA or MPA.  Therefore, 
there will be no formal statistical hypothesis testing.  An analysis will be conducted when 
the last patient enrolled reaches 6 months.  Full details of all planned tables, listings, 
graphs, and descriptive analyses will be provided in a Statistical Analysis Plan, which will 
be finalized prior to this analysis.  An outline of the proposed analyses is provided 
herein. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The planned sample size of 25 patients was determined on the basis of the 
epidemiology of pediatric AAV and information from existing patient cohorts.  This 
sample size takes into the account the number of pediatric patients that would be eligible 
for treatment with rituximab and that could be expected to be enrolled within a 
reasonable timeframe.  The primary objective of this study is to evaluate the safety and 
pharmacokinetics of rituximab in these patients.  The planned sample size would be 
sufficient to provide a reasonable estimate of variability for the mean PK parameters 
based on the observed intra-patient variability from the RAVE study.  It would also 
ensure 95% probability of observing at least one AE when the underlying incidence of 
that event is ≥ 11%. 
Given the exploratory nature of this study, there will be no formal statistical hypothesis 
testing.  The study will focus on exploratory estimation of the efficacy and PD endpoints.  
The planned sample size of 25 would allow estimation of the percentage of patients in 
remission at 6 months to within 20% of the point estimate (the distance from the point 
estimate to the upper or lower limit of a 95% CI). 
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6.2 
ANALYSIS POPULATIONS 
Safety Analysis Population 
All patients who received at least part of one infusion of rituximab will be included in the 
safety population.  Patients will be assigned to a single rituximab treatment group.  
Safety and efficacy analyses will be based on the safety population. 
PK Analysis Population 
The PK analysis population will include all patients in the safety population who provide 
at least one evaluable PK sample. 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
Any eligibility violations or major protocol deviations from the study will be summarized. 
6.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Patient demographics and baseline characteristics will be listed and summarized for the 
safety population.  
6.5 
PATIENT DISPOSITION AND TREATMENTS 
The following data will be listed and summarized for the safety population: 
• 
Patients who completed four IV infusions of rituximab study treatment 
• 
Patients withdrawn prematurely from rituximab study treatment 
• 
Cumulative exposure to rituximab study treatment 
• 
Patients who switched to local standard care 
• 
Details about non-study AAV treatments given over time 
• 
Concomitant medications received 
• 
Patients withdrawn prematurely from study follow-up 
 
6.6 
SAFETY ANALYSES 
The safety and tolerability of rituximab will be evaluated from AEs, laboratory tests, vital 
signs, ECGs, chest X-rays, and as defined by protocol.  Safety parameters will be 
summarized or listed for the safety population. 
6.7 
PHARMACOKINETIC ANALYSES 
In the PK analysis population, non-linear mixed-effects modeling technique (NONMEM®) 
will be used to analyze the PK data with the population PK model developed from adult 
patients with GPA and MPA in the RAVE study (Stone et al. 2010).  The primary PK 
parameters will be CL and volume of distribution.  The secondary PK parameters 
(AUC0-inf, Cmax) will be calculated for each patient.  PK concentrations will be summarized 
by visit.  PK parameters will be tabulated and summarized (i.e., by mean, SD, coefficient 
of variation, median, and minimum and maximum).  PK exposure and response 
relationships will be explored. 
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6.8 
EXPLORATORY EFFICACY ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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6.9 
EXPLORATORY PHARMACODYNAMIC ANALYSES 
 
  
 
6.10 
EXPLORATORY PATIENT-REPORTED OUTCOME ANALYSES 
 
  
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
Roche will be responsible for data management of this study, including quality checking 
of the data.  Data entered manually will be collected via EDC using eCRFs.  Sites will be 
responsible for data entry into the EDC system.  In the event of discrepant data, Roche 
will request data clarification from the sites, which the sites will resolve electronically in 
the EDC system. 
Roche will produce an EDC Study Specification document that describes the quality 
checking to be performed on the data.  Central laboratory data will be sent directly to 
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Roche, using Roche’s standard procedures to handle and process the electronic transfer 
of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at Roche and records retention for study data will be 
consistent with Roche’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and a have access to a manual for appropriate eCRF completion.  eCRFs will be 
submitted electronically to Roche and should be handled in accordance with instructions 
from Roche. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered onto the eCRFs must not be obliterated or destroyed and must be retained 
according to the policy for retention of records described in Section 7.5. 
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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB or EC review.  The investigational site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study, or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.   
No records may be disposed of without the written approval of Roche.  Written 
notification should be provided to Roche prior to transferring any records to another 
party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a US 
Investigational New Drug (IND) Application will comply with US FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union 
(EU)/EEA will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
Roche’s sample Informed Consent Form (and ancillary sample Informed Consent Forms 
such as a Child’s Assent or Parent or Caregiver’s Informed Consent Form, if applicable) 
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will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  Roche or its designee must review and approve any proposed 
deviations from Roche's sample Informed Consent Forms or any alternate consent forms 
proposed by the site (collectively, the “Consent Forms”) before IRB/EC submission.  The 
final IRB/EC-approved Consent Forms must be provided to Roche for health authority 
submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
Roche for health authority submission purposes. 
Patients must be reconsented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the US 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
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The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.5). 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC.  
Investigators may receive written IND safety reports or other safety-related 
communications from Roche.  Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.  
8.4 
CONFIDENTIALITY 
Roche maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number.  This means that patient 
names are not included in data sets that are transmitted to any Roche location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the US FDA and other national and local health authorities, Roche 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last 
visit). 
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9. 
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to the data. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by Roche or an authorized representative for inspection of 
study data, patients’ medical records, and eCRFs.  The investigator will permit national 
and local health authorities, Roche monitors, representatives, and collaborators, and the 
IRBs/ECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
9.3.1 
IxRS 
An IxRS will be used to manage the dispensing of study drug (rituximab). 
9.3.2 
Central Laboratory 
With the exception of ANCA (at screening only), C-reactive protein, erythrocyte 
sedimentation rate, urinalysis, and the urine dipstick pregnancy test 
(see Section 4.5.3.5), all laboratory tests will be analyzed by a central laboratory 
according to the Laboratory Manual. 
9.4 
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission.  This allows the Sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator. 
Roche will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, Roche will generally support publication of 
multicenter trials only in their entirety and not as individual center data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Roche personnel exceeded that of conventional 
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monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of Roche, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.  Approval must be obtained from the IRB/EC and regulatory 
authorities (as locally required) before implementation of any changes, except for 
changes necessary to eliminate an immediate hazard to patients or changes that involve 
logistical or administrative aspects only (e.g., change in Medical Monitor or 
contact information). 
10. 
INTERNAL MONITORING COMMITTEE  
Because this is an open-label study, an Internal Monitoring Committee (IMC) composed 
of a Clinical Scientist, a Statistician, a Statistical Programmer Analyst, and a safety 
representative will review safety data from patients participating in this study.  The IMC 
will be responsible for monitoring the overall safety of the patients in this study and will 
help to minimize patient exposure to unacceptable risk. From the time of its formation, 
the IMC will meet to review safety data as described in the IMC Charter.  
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11. 
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Barillas-Arias L, Adams AB, Angeles ST, et al. Combination of rituximab and 
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Brunner J, Freund M, Prelog M, et al. Successful treatment of severe juvenile 
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El Hallak E. Clinical effects and safety of RTX in refractory paediatric AI disease. 
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Eriksson P. Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis 
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Exley AR, Carruthers DM, Luqmani RA, et al. Damage occurs early in systemic 
vasculitis and is an index of outcome. QJM 1997;90:391−9. 
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Rituximab—F. Hoffmann-La Roche, Ltd 
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Rituximab
104
—F. Hoffmann-La Roche, Ltd 
/Protocol WA25615, Version 5 
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Appendix 1  
Schedule of Assessments 
Week 
Month 
Follow-Up 
Visit  a
Screen b
BL c
1 
2 
3 
1 
2 
4 
6 
9 
12 
15 
18 
Every 3 
Months  
after  
Month 18 d
WD 
Extended 
Follow-Up e
Day 
 
1 
8 
15 
22 
29 
60 
120 
180 
270 
365 
455 
545 
 
 
 
Medications 
 
 
Glucocorticoids IV f
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucocorticoids PO g
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pre-infusion medications h
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Rituximab IV infusion 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
General Assessments 
 
 
Informed Consent/  
Child’s Assent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum) i
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
(urine)  i
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
12-Lead ECG j
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs (pulse rate, 
systolic and diastolic blood 
pressure, and temperature) 
x 
x k
x k
x k
x k
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Rituximab—F. Hoffmann-La Roche, Ltd 
105/Protocol WA25615, Version 5 


 
Appendix 1  
Schedule of Assessments (cont.) 
 
Week 
Month 
Follow-Up 
Visit  a
Screen b
BL c
1 
2 
3 
1 
2 
4 
6 
9 
12 
15 
18 
Every 
3 Months  
after  
Month 18 d
WD 
Extended 
Follow-Up e
Day 
 
1 
8 
15 
22 
29 
60 
120 
180 
270 
365 
455 
545 
 
 
 
General Assessments (cont’d) 
 
 
 
Physical examination  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chest X-ray l or CT scan m
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Safety Assessments 
 
 
Adverse events  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x n
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Efficacy Assessments 
 
 
Acute-Phase Reactant Assessments 
 
 
C-reactive protein 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Erythrocyte sedimentation rate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Rituximab—F. Hoffmann-La Roche, Ltd 
106/Protocol WA25615, Version 5 


 
Appendix 1  
Schedule of Assessments (cont.) 
 
Week 
Month 
Follow-Up 
Visit  a
Screen b
BL c
1 
2 
3 
1 
2 
4 
6 
9 
12 
15 
18 
Every 
3 Months  
after  
Month 18 d
WD 
Extended 
Follow-Up e
Day 
 
1 
8 
15 
22 
29 
60 
120 
180 
270 
365 
455 
545 
 
 
 
Laboratory Assessments 
 
 
Hematology (CBC) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum chemistry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis with microscopy and 
albumin to creatinine ratio  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c
 s
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBsAg, HBcAb, and HCV Ab and 
HBV DNAt
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis screening 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunologic and Antibody Assessments 
 
 
Immunoglobulins 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CD19 B cells 
 
x q
 
x q
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FACS panel 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum HACA sample 
 
x 
 
 
 
 
 
x 
x 
x 
 
 
x 
x u
x 
x u
Serum ANCA sample v, w
x 
 
 
 
 
x 
 
 
x 
 
x 
 
x 
x u
x 
x u
Pharmacokinetic Assessments 
 
 
Sample for rituximab levels  
 
x x
x y
x y
x x
x 
x 
x 
x 
x 
 
 
x 
x u
x 
x u
ANCA = anti−neutrophil cytoplasmic antibody; CBC = complete blood count; 
 
; 
 
; CT = computed tomography; ECG = electrocardiogram; eCRF = electronic Case Report Form; FACS = fluorescence-activated cell sorter; 
GFR = glomerular filtration rate; GPA = granulomatosis with polyangiitis; HbA1c = glycosylated hemoglobin; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B 
surface antigen; HBV = hepatitis B virus; HCV Ab  = hepatitis C virus antibodies; IV = intravenous; LLN = lower limit of normal; MPA = microscopic polyangiitis; 
PK = pharmacokinetic; PO = by mouth; PVDI = Pediatric Vasculitis Damage Index; WD = withdrawal. 
Rituximab—F. Hoffmann-La Roche, Ltd 
107/Protocol WA25615, Version 5 




 
Appendix 2  
Study-Specific Visit Windows 
Visit 
Study Day 
Visit Window 
Screening 
Varies 
Before baseline visit (varies) 
IV methylprednisolone 1 
Varies 
Before baseline visit (varies) 
IV methylprednisolone 2 
At least 1 day after Dose 
1 
Before baseline visit (varies) 
IV methylprednisolone 3 a
At least 1 day after Dose 
2 
Before baseline visit (varies) 
Baseline:   
Rituximab Infusion 1 a
1 
Within 28 days of screening 
Rituximab Infusion 2 
8 
± 3 days of the targeted date 
Rituximab Infusion 3 
15 
± 3 days of the targeted date 
Rituximab Infusion 4 
22 
± 3 days of the targeted date 
Month 1 
29 
± 3 days of the targeted date 
Month 2 
60 
± 3 days of the targeted date 
Month 4 
120 
± 5 days of the targeted date 
Month 6 
180 
± 5 days of the targeted date 
Month 9 
270 
± 10 days of the targeted date 
Month 12 
365 
± 10 days of the targeted date 
Month 15 
455 
± 10 days of the targeted date 
Month 18 
545 
± 10 days of the targeted date 
Every 3 months until 
the common closeout date 
+ 3 months after the last 
visit 
± 10 days of the targeted date 
Extended follow-up 
+ 3 months after the last 
visit 
± 10 days of the targeted date 
IV = intravenous. 
a If clinically indicated and at the discretion of the investigator, additional daily doses (up to 
three) of IV methylprednisolone can be given.  No more than six doses of IV 
methylprednisolone in total can be given.  Each of these additional doses must be given at 
least 1 day after the previous dose.  The final IV methylprednisolone dose and rituximab 
Infusion 1 can be administered on the same day (although IV methylprednisolone must be 
given before the rituximab infusion).  Rituximab Infusion 1 must occur no later than 14 days 
after the last IV methylprednisolone dose. 
 
 
Rituximab—F. Hoffmann-La Roche, Ltd 
109/Protocol WA25615, Version 5 




 
Appendix 4  
Tanner Stages 
Sexual Maturity Stages in Boys and Girls 
Stage 
Male Genitalia 
Pubic Hair 
Female Breasts 
1 
Preadolescent⎯testes, 
scrotum, and penis are 
childlike in size 
None; may be 
vellus hair, as 
over abdomen 
Preadolescent⎯elevation of 
papilla only 
2 
Slight enlargement of scrotum 
with reddening of skin; little or 
no enlargement of penis 
Sparse growth of 
long, slightly 
pigmented, 
downy hair, 
straight or slightly 
curled, primarily 
at base of penis 
or along labia 
Breast bud stage; breast and 
papilla form a small mound; 
areolar diameter enlarge 
3 
Further enlargement of 
scrotum; penis enlarges, 
mainly in length 
Hair considerably 
darker, coarser, 
and more curled; 
spreads sparsely 
over junction of 
pubes 
Further enlargement of breast 
and areola with no separation 
of their contours 
4 
Further enlargement and 
darkening of scrotum; penis 
enlarges, especially in 
breadth; glans develops 
Adult-type hair 
that does not 
extend onto 
thighs, covering a 
smaller area than 
in adult 
Areola and papilla project to 
form a secondary mound 
above the contour of the 
breast; stage 4 development 
of the areolar mound does 
not occur in 10% of girls and 
is slight in 20%; when 
present, it may persist well 
into adulthood 
     5 
Adult in size and shape 
Adult in quantity 
and type with 
extension onto 
thighs but not up 
linea alba 
Mature female; papilla 
projects and areola recesses 
to general contour of breast 
Data derived from Tanner JM: Normal growth and techniques of growth assessment.  
Clin Endocrinol Metab 1986;15:436. 
 
In boys, if different scores are obtained for pubic hair and genitalia, the score for 
genitalia should be used. 
In girls, if different scores are obtained for pubic hair and breast development, the 
score for breast development should be used. 
Rituximab—F. Hoffmann-La Roche, Ltd 
111/Protocol WA25615, Version 5 


 
Appendix 5  
EULAR/PRINTO/PRES 2008 Ankara Childhood−Wegener’s 
Granulomatosis Criteria (with Glossary) and Classification 
Definition 
 
Histopathology 
Granulomatous inflammation within the wall of an 
artery or in the perivascular or extravascular area 
Upper airway involvement 
Chronic purulent or bloody nasal discharge or 
recurrent epistaxis/crusts/granuloma 
Nasal septum perforation or saddle nose deformity 
Chronic or recurrent sinus inflammation 
Laryngo-tracheo-bronchial involvement 
Subglottic, tracheal or bronchial stenoses 
Pulmonary involvement 
Chest X-ray or CT scan showing the presence of 
nodules, cavities, or infiltrates 
ANCA 
ANCA positivity by immunofluorescence or by 
ELISA (MPO/p or PR3/c ANCA) 
Renal involvement 
Proteinuria > 0.3 g/24 hr or > 30 mmol/mg of urine 
albumin/creatinine ratio on a spot morning sample 
Hematuria or RBC casts:  > 5 RBC/high-power field 
or RBC casts in the urinary sediment or ≥ 2+ on 
dipstick 
Necrotizing pauci-immune glomerulonephritis 
c-WG EULAR/PRINTO/PRES 
 Ankara 2008 classification 
definition 
At least three of the six following criteria: 
Histopathology 
Upper airway involvement 
Laryngo-tracheo-bronchial stenosis 
Pulmonary involvement 
ANCA positivity 
Renal involvement 
ANCA = anti−neutrophil cytoplasmic antibody; CT = computed tomography; c-WG = c-Wegener 
granulomatosis; ELISA = enzyme linked immunosorbent assay; EULAR = European League 
Against Rheumatism; MPO = myeloperoxidase; PRES = Pediatric Rheumatology European 
Society; PR3 = proteinase 3; PRINTO = Pediatric Rheumatology International Trials Organisation; 
RBC = red blood cell. 
 
Adapted from Özen et al. 2010. 
 
 
Rituximab—F. Hoffmann-La Roche, Ltd 
112/Protocol WA25615, Version 5 


 
Appendix 6  
Chapel Hill Consensus Conference 
In 1994, the Chapel Hill International Consensus Conference developed definitions for 
systemic vasculitides.  These definitions are useful in formulating the diagnostic criteria 
that will be applied to determine a participant’s eligibility for this clinical trial with respect 
to MPA or their exclusion with respect to Churg−Strauss syndrome. 
Chapel Hill Consensus Conference Definitions for Microscopic Polyangiitis 
• 
Necrotizing vasculitis with few or no immune deposits affects small vessels 
(i.e., capillaries, venules, or arterioles) 
• 
Necrotizing arteritis involving small and medium-sized arteries may be present. 
• 
Necrotizing glomerulonephritis is very common. 
• 
Pulmonary capillaritis often occurs. 
 
Chapel Hill Consensus Conference Definitions for Churg−Strauss Syndrome 
• 
Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and 
necrotizing vasculitis affecting small- to medium-sized vessels, and associated with 
asthma and eosinophilia 
 
Rituximab—F. Hoffmann-La Roche, Ltd 
113/Protocol WA25615, Version 5 


 
Appendix 7  
Procedures for the Intravenous Administration of Rituximab 
Rituximab should be given as a slow intravenous (IV) infusion 
(Great Ormond Street Hospital 2012).  It should not be administered as an IV push or 
bolus. 
Although rituximab may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Irrespective, rituximab 
should be administered in a hospital or clinic environment where full resuscitation 
facilities are immediately available, along with qualified resuscitative personnel and 
under close supervision of the investigator or designee. 
Dosage 
The dose of rituximab will be calculated by the physician on the basis of 375 mg/m² of 
body weight (no maximum dose).  
Preparation  
Use appropriate aseptic technique.  Dilute rituximab to a final concentration of 1 mg/mL 
to 4 mg/mL in 0.9% NaCI, or 5% Dextrose in Water (USP or British Pharmacopoeia) to a 
final concentration 1 mg/mL to 4 mg/mL.  Gently invert the bag to mix the solution.  Do 
not mix or dilute with other drugs. Discard any unused portion left in the vial.  Parenteral 
drug products should be inspected visually for particulate matter and discoloration prior 
to administration.  No incompatibilities between rituximab and polyvinylchloride or 
polyethylene bags have been observed. 
FOR ALL TREATMENT COURSES THE INFUSION RATES FOR THE FIRST AND 
SUBSEQUENT INFUSION MUST BE ADHERED TO AS FOLLOWS:  
Patients should be medicated pre-infusion with paracetamol/acetaminophen and 
cetirizine hydrochloride (or similar antihistamine), both according to labelled age-related 
doses, to be given 1 hour (± 15 minutes) before each infusion of rituximab. 
First Infusion  
Rituximab infusions should commence at a rate of 25 mg/h.  This may be escalated at a 
rate of 25 mg/h increments every 30 minutes to a maximum of 200 mg/h.  An example of 
an infusion schedule is presented below. 
Rituximab—F. Hoffmann-La Roche, Ltd 
114/Protocol WA25615, Version 5 


 
Appendix 7  
Procedures for the Intravenous Administration of Rituximab 
(cont.) 
Final Concentration = 1 − 4 mg/mL 
Infusion Rate                            
Minutes 
mg/ha  
mL/ha
 
25 
(………………) 
30 
50 
(………………) 
30 
75 
(………………) 
30 
100 
(………………) 
30 
125 
(………………) 
30 
150 
(………………) 
30 
175 
(………………) 
30 
200 
(………………) 
thereafter  
a For countries not able to set the infusion pump to an accuracy of 0.5 mL/h, the rate is to be 
rounded down to the nearest whole number.   
 
Subsequent Infusions  
Patients who have tolerated the first infusion of rituximab well may receive the second 
infusion.  Infusion schedule described for the first infusion should be used also for all 
subsequent infusions; the infusion rate can be adjusted if the first infusion was well 
tolerated. Subject to investigator’s discretion, corticosteroid premedication with an IV 
infusion of 100 mg of methylprednisolone may be administered at least 30 minutes prior 
to the infusion of rituximab (but not prior to clinical assessments) if the patient has 
experienced an infusion-related reaction with a previous rituximab infusion. 
In the event of the patient experiencing an infusion-related reaction during first or any 
subsequent infusions, the infusion should be stopped immediately. The patient should 
be clinically assessed and appropriate treatment should be given as per local policy. The 
principle investigator or sub-investigator(s) should also be informed as soon as possible 
and all adverse events should be reported as required in Section 5.2. Once the adverse 
event has resolved, infusion can be restarted at the previous tolerated rate and should 
be given at the previous reduced rate for 30 minutes.  If tolerated, the rate may be 
increased to the next closest rate on the patient’s infusion schedule. Further information 
is provided in Section 5.2.3.1. 
All rituximab infusions should be made through a dedicated line. After the end of each 
infusion, the IV line should remain in situ for at least 1 hour in order to be able to 
administer drugs intravenously if necessary.  If there are no adverse events during this 
period of time, the IV line may be removed.  
 
Rituximab—F. Hoffmann-La Roche, Ltd 
115/Protocol WA25615, Version 5 

SAP_001.pdf: 
 
Official Title: 
A Phase IIA, International, Multicenter, Open-Label, Uncontrolled 
Study to Evaluate the Safety and Pharmacokinetics of 4 × 375 
mg/m2 Intravenous Rituximab in Pediatric Patients With Severe 
Granulomatosis With Polyangiitis (Wegener’s) or Microscopic 
Polyangiitis 
NCT Number: 
NCT01750697 
Document Date: 
Data Analysis Plan, Module 2, Version 1.0, dated 10-Sep-2018 
 
 




Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA25615     Report Number 1087669
1423
Rituximab—F. Hoffmann-La Roche Ltd 
WA25615: DAP Module 2 
2 
TABLE OF CONTENTS 
1. 
BACKGROUND ...................................................................................................... 4 
2. 
STUDY DESIGN ..................................................................................................... 5 
2.1 
Outcome Measures .......................................................................... 5 
2.1.1 
Primary Safety Outcome Measures .................................................. 5 
2.1.2 
Primary Pharmacokinetic Outcome Measures .................................. 5 
2.1.3 
Secondary Pharmacokinetic Outcome Measures ............................. 5 
2.1.4 
Primary and Secondary Efficacy Outcome Measures ....................... 5 
2.1.5 
Secondary Safety Outcome Measures ............................................. 5 
2.1.6 
Exploratory Outcome Measures ....................................................... 6 
2.1.6.1 Exploratory Efficacy Outcome Measures ............................................ 6 
2.1.6.2  Exploratory Pharmacodynamic Outcome Measures .......................... 9 
2.2 
Determination of Sample Size .......................................................... 9 
2.3 
Analysis Timing ................................................................................ 9 
2.3.1 
Data Included in the Remission Induction Phase .............................. 9 
2.3.2 
Data Included in the Follow-up Phase ............................................ 10 
2.3.3 
Data Included in the Extended Follow-up Phase ............................ 10 
3. 
STATISTICAL METHODS OVERVIEW ................................................................. 11 
3.1 
Analysis Populations ...................................................................... 11 
3.1.1 
Safety Population ........................................................................... 11 
3.2 
Baseline Demographics and Baseline Information ......................... 11 
3.2.1 
Definition of Remission Induction Phase Baseline .......................... 11 
3.2.2 
Follow-up Phase Baseline .............................................................. 11 
3.2.3 
Extended Follow-up Phase Baseline .............................................. 11 
3.3 
Visit Windows ................................................................................. 12 
3.4 
Analysis Overview .......................................................................... 13 
4. 
BASELINE DEMOGRAPHICS AND BASELINE INFORMATION .......................... 14 
4.1 
Analysis of Study Conduct ............................................................. 14 
4.2 
Analysis Populations and Disposition ............................................. 15 
4.3 
Baseline Output Specifications ....................................................... 15 
5. 
EXPOSURE TO STUDY MEDICATION ................................................................ 29 
5.1 
Exposure Output Specifications ..................................................... 29 


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6. 
ADVERSE EVENTS .............................................................................................. 41 
Adverse Event Output Specifications..................................................................... 42 
7. 
SAFETY LABORATORY ANALYSES ................................................................... 50 
7.1 
Safety Laboratory Analyses............................................................ 50 
7.2 
Acute-phase Reactants .................................................................. 50 
7.3 
Immunologic and Antibody Assessments ....................................... 50 
7.4 
Laboratory Output Specifications ................................................... 51 
8. 
VITAL SIGNS OUTPUT SPECIFICATIONS .......................................................... 58 
8.1 
Vital Signs Output Specifications .................................................... 58 
9. 
EFFICACY ANALYSES ......................................................................................... 62 
9.1 
Efficacy Output Specifications ........................................................ 64 
10. PHARMACODYNAMIC ANALYSES ..................................................................... 81 
 
LIST OF TABLES 
Table 1 
Analysis Visit Time-point Windows ....................................................... 12 
 
LIST OF APPENDICES 
Appendix 1 
 Study Design ...................................................................................... 94 
Appendix 2 
  Schedule of Assessments .................................................................. 95 
 
 
 
 
  
 


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1. 
BACKGROUND 
This document provides specifications for the primary analysis including, remission induction phase, 
follow-up phase and extended follow-up phase, of the study WA25615. 
 
 Remission Induction Phase: Day 1 until end of month 6. 
 Follow-Up Phase: Post month 6 until common closeout date, where common closeout date is 
18 months after the enrolment of the last patient. 
 Extended Follow-Up Phase: Post common closeout date until CD19 B-cell counts have returned 
to baseline level or within normal range, whichever is lower. 
 


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2. 
STUDY DESIGN 
This is a Phase IIa, international, multicenter, open-label, single-arm study. The primary objectives 
are to evaluate the safety and tolerability and the PK parameters of rituximab in pediatric patients 
with severe GPA or MPA. 
The study comprises an initial 6-month remission induction phase; rituximab is administered on Days 
1, 8, 15 and 22 during this phase. The remission induction phase is followed by a minimum 12-month 
follow-up phase, after which patients are followed up 3-monthly until the common closeout date, 
which occurs when the final participant enrolled has completed his or her Month 18 study visit (see 
Appendix 2). 
Following the remission induction phase (month 6), if required for the maintenance of remission, 
further courses of rituximab may be given, with the dose and the frequency of retreatment at the 
discretion of the investigator. 
At the common closeout date, patients whose B cells remain depleted and/or have immunoglobulin 
levels below the LLN for the population, continue to attend study visits every 3 months until their B-
cell counts have returned to baseline level or to within the normal range for the population, whichever 
is lower, and until their immunoglobulin levels have returned to within normal limits for the population. 
Patients that receive any B-cell therapy or other agent that affects the return of B-cells including but 
not limited to rituximab, CYC, AZA, on or after the common closeout date, he or she will not be 
followed any further. 
The Study Schema is given in Appendix 1 and the Schedule of Assessments is given in Appendix 2. 
2.1 
Outcome Measures  
This section lists all of the study outcome measures that will be included in this analysis. 
2.1.1 
Primary Safety Outcome Measures 
The primary safety outcome measures are: 
x Frequency, nature, and severity of AEs 
x Frequency of laboratory abnormalities 
2.1.2 
Primary Pharmacokinetic Outcome Measures 
The primary PK parameters are: 
x Clearance (CL) and volume of distribution 
2.1.3 
Secondary Pharmacokinetic Outcome Measures 
The secondary PK parameters of interest are: 
x AUC0-inf and Cmax, derived from the primary PK parameters 
2.1.4 
Primary and Secondary Efficacy Outcome Measures 
None 
2.1.5 
Secondary Safety Outcome Measures 
The secondary safety outcome measures are: 
x Vital signs 


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x Electrocardiograms – new or worsened abnormalities are reported as adverse events 
x Chest x-ray and computed tomography (CT) scan – to be completed at month 1 if abnormal at 
baseline and as indicated otherwise at the discretion of the investigator. New or worsened 
abnormalities are reported as adverse events 
x Physical examinations – post-baseline examinations are to be symptom directed only, with new 
or worsened abnormalities reported as adverse events 
x Laboratory parameters (clinically relevant new or worsened abnormalities are reported as 
adverse events): 
o Hematology: hemoglobin, hematocrit, red blood cells and indices (mean corpuscular volume, 
mean cell hemoglobin, mean corpuscular hemoglobin concentration), white blood cells, 
absolute differential, and platelet counts 
o Serum chemistry: AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total bilirubin 
(direct and indirect if total bilirubin is greater than the ULN), urea, uric acid, creatinine, 
potassium, sodium, chloride, calcium, phosphate, and glycosylated hemoglobin (HbA1c) 
o Acute-phase reactants: erythrocyte sedimentation rate and C-reactive protein 
o Urinalysis: dipstick for blood, protein, and glucose, and albumin to creatinine ratio 
 microscopic examination if abnormal and applicable 
x Immunologic Assessments 
o B- and T-cell populations - by fluorescence-activated cell sorter (FACS) analysis, including, 
but not limited to, CD3, CD4, CD8, CD16/56, CD19, CD27, CD4/45RA/45RO and 
CD8/45RA/45RO 
o Quantitative immunoglobulin levels (including total immunoglobulin, immunoglobulin A [IgA], 
IgG, and IgM isotype levels) 
2.1.6 
Exploratory Outcome Measures 
2.1.6.1 Exploratory Efficacy Outcome Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  


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x 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
     
 
 
x 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
     
 
 
 
x 
 
 
 
 
 
 
 


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x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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2.1.6.2  Exploratory Pharmacodynamic Outcome Measures 
 
 
 
 
 
 
 
 
2.2 
Determination of Sample Size 
The planned sample size of 25 patients was determined on the basis of the epidemiology of 
pediatric GPA and MPA plus information from existing patient cohorts. This sample size takes into 
the account the number of pediatric patients that would be eligible for treatment with rituximab and 
that could be expected to be enrolled within a reasonable timeframe. The primary objective of this 
study is to evaluate the safety and pharmacokinetics of rituximab in these patients. The planned 
sample size would be sufficient to provide a reasonable estimate of variability for the mean PK 
parameters based on the observed intra-patient variability from the RAVE study (a rituximab in 
ANCA-associated vasculitis trial), protocol number ITN021AI. It would also ensure 95% probability 
of observing at least one AE when the underlying incidence of that event is ≥11%. 
Given the exploratory nature of this study, there will be no formal statistical hypothesis testing. The 
study will focus on exploratory estimation of the efficacy and PD endpoints. 
2.3 
Analysis Timing 
There is an interim analysis for this study where the study data for the remission induction phase 
(6-month time-point) is analyzed when the last patient has reached the 6 month visit and the data 
have been cleaned with the relevant parts of the database locked for editing. 
Primary analysis will be done once all of the data, up until the follow-up visit subsequent to the 
common closeout date (the Withdrawal visit), has been entered into the study database, cleaned 
and the database locked for editing. 
A final analysis will be reported once the extended follow-up for all appropriate patients has been 
completed, with all data entered into the database, cleaned and the database fully locked. 
2.3.1 
Data Included in the Remission Induction Phase  
The following data will be included in the analysis of the 6-month time-point: 
x 
Patients entering the follow-up phase: 
o All screening and post-baseline data with a clinical date (i.e., administration/
assessment/onset/start date) on or before the date of entry into the follow-up phase at 
Month 6 will be included. 
The only exceptions to this is: 
o Concomitant medications that begin on the date of entry to the follow-up phase will not 
be included. 
x 
Patients not entering the follow-up phase: 
All screening and post-baseline data with a clinical date on or before the date of the 
patient’s last study visit within Study Day 210 will be included; (Day 210 equals 180 days 
plus a 30-day window).  


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The data cut will include all data regardless of the type of study visit at which it was collected. This 
may include data collected at unscheduled visits, dosing termination visits, early termination visits, 
or safety follow-up visits, if the visit date was on or before the data cutoff date. 
 
2.3.2 
Data Included in the Follow-up Phase  
For patients who enter the Follow-up phase all of their screening data plus post Month-6 data with a 
clinical date on or before the date of entry into the Extended Follow-up Phase will be included in 
this analysis of the Follow-up phase. 
x 
Patients entering the extended follow-up phase: 
All screening and post-Month-6 data with a clinical date on or before the date of entry into 
the extended follow-up phase will be included. 
x 
Patients not entering the extended follow-up phase: 
All screening and post-Month-6 data with a clinical date on or before the date of the patient’s 
last study visit within common closeout date will be included. 
 
2.3.3 
Data Included in the Extended Follow-up Phase  
Patients whose peripheral B cells remain depleted at the common closeout date will enter the 
Extended Follow-up phase. For patients who enter this phase all of their screening data plus post 
Follow-up phase data will be included in this analysis. 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 


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3. 
STATISTICAL METHODS OVERVIEW 
As this is an open-label, single-arm study, with primary objectives regarding safety and PK there 
will be no formal statistical hypothesis testing. 
The day of enrollment (Day 1) will be considered the day the patient receives their first infusion, or 
part thereof, of rituximab. 
For binary endpoints the number and percentage of patients will be presented by visit. At key time 
points (Month 6, 12 and 18) two-sided 95% Confidence intervals (CIs) for the percentage of 
patients will be calculated. 
For continuous endpoints, the n, mean, median, standard deviation (SD), minimum and maximum 
values will be presented by visit with two-sided 95% CIs for the mean presented for the data at key 
time-points (Months 6, 12 and 18), unless stated otherwise. 
When we have 0 counts, please don't display 0.0% 
3.1 
Analysis Populations 
3.1.1 
Safety Population 
All patients who received at least part of one infusion of rituximab will be included in the safety 
population. 
Safety and efficacy analyses will be based on the safety population. 
 
3.2 
Baseline Demographics and Baseline Information 
Details of the analyses and outputs are given in Section 4. 
3.2.1 
Definition of Remission Induction Phase Baseline 
Baseline will be defined as the last available pre-treatment value taken on or before the initiation of 
rituximab (RTX) treatment on study treatment Day 1, and will be used for summary of demographic 
characteristics, as well as for all change-from-baseline analyses of efficacy, safety, and PD 
endpoints. 
Special rules apply for the determination of the PVDI baseline score to account for missing 
individual scores: see Section 10. 
For endpoints that are defined in terms of change from baseline, patients who do not have a pre-
treatment value reported for a particular assessment (if any) will be excluded from the change-from-
baseline analyses for that assessment. 
3.2.2 
Follow-up Phase Baseline 
The Follow-up phase will use the same baseline values as the Remission Induction phase for all 
analyses. 
3.2.3 
Extended Follow-up Phase Baseline 
Baseline will be defined as the last available value taken on or before the start of the Extended 
Follow-up phase, and will be used for all change-from-baseline analyses of safety and PD 


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endpoints. For B cell deplection (absolute CD19 count) we should use the baseline value prior to 
receiving study medication. 
For endpoints that are defined in terms of change from baseline, patients who do not have a pre-
treatment value reported for a particular assessment (if any) will be excluded from the change-from-
baseline analyses for that assessment. 
3.3 
Visit Windows 
For summarization by time-point data will be assigned to an analysis visit based on the date of the 
assessment relative to the date of study treatment Day 1 (treatment start). The visit assessment 
windows given in Table 1 will be used to assign data to planned study assessments:  
Table 1 
Analysis Visit Time-point Windows 
Assessment 
Month 
Planned 
Treatment Day (1) 
Day Number (1) 
Range 
Baseline 
1 
Day 1 
Week 1 
8 
Days 5 – 11 
Week 2 
15 
Days 12 – 18 
Week 3 
22 
Days 19 – 25 
Month 1 
29 
Days 26 – 44 
Month 2 
60 
Days 45 – 75 
Month 4 
120 
Days 105 – 135 
Month 6 
180 
Days 165 – 210 
Month 9 
270 
Days 240 – 300 
Month 12 
365 
Days 335 – 395 
Month 15 
455 
Days 425 – 485 
Month 18 
545 
Days 500 – 590 
Month 21  
or 
Follow-up 
month 3  
** 
Planned 
Treatment Day ± 
45 days 
Month 24  
or  
Follow-up 
month 6  
** 
Planned 
Treatment Day ± 
45 days 
… 
… 
… 
** Planned Treatment Day = Month 18 Planned Treatment Day + 92 × (number of follow-up month /3) 
Assessments made outside of these assessment windows will be listed but not used in by time-
point summaries. 
(1) For each patient, the day of the baseline visit will be defined as treatment day 1 and 
subsequent time-points will be assigned a treatment day calculated as: 
  
 
(date of assessment − date of baseline) + 1 


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For a given measurement and analysis visit the following rules will be used to decide which value to 
use in the analysis: 
x Protocol defined visit assessments will take priority over unscheduled visit data; that is, 
unscheduled visit data will only be used if there is no scheduled visit results within the same time 
window.  
x If more than one assessment falls within the same window, then use the measurement taken 
nearest to the planned day. In the case of a tie, use the earlier measurement. 
x Assessments made outside of these analysis visit windows will be listed but not used in by time-
point summaries. 
 
3.4 
Analysis Overview 
 
Safety Analyses 
All safety analyses will be done on safety population and by study phase.  
Abnormal electrocardiogram (ECG), chest X-ray and chest CT scan findings are to be reported.  
Details of the analyses and outputs are given in Section 5 to 9. 
Efficacy Analysis 
 
 
Pharmacodynamic Analyses 
 
Subgroup Analyses 
The sample size for this study is too small to permit subgroup analyses. 
 
 
 
 


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4. 
BASELINE DEMOGRAPHICS AND BASELINE INFORMATION 
Descriptive summaries of the following information will be produced to characterize baseline 
characteristics for the safety population: 
x Demographic characteristics, including: 
o age, both as descriptive summary and as counts and percentages falling into the following 
categories: 
 2 – 11 years 
 12 – 17 years 
o sex 
o race 
o ethnicity 
o height 
o weight 
o body surface area 
x Baseline disease characteristics: 
o GPA or MPA disease 
 ANCA result (C-ANCA, P-ANCA, Negative) 
o Duration of disease 
o Pediatric Vasculitis Damage Index (PVDI) 
x Previous and current treatment for GPA or MPA 
o A glossary showing the mapping of investigator verbatim terms to coded medications will be 
produced also 
x Immunization history 
x Patients’ medical history, grouped by preferred term within SOC 
o A glossary showing the mapping of investigator verbatim terms to coded diseases will be 
produced also 
x Alcohol, tobacco and substance use 
x Female reproductive status 
4.1 
Analysis of Study Conduct 
The following data will be summarized for the safety population, giving the number and percentage 
of patients who: 
x Had major protocol deviations occurring during the remission induction phase 
x Were withdrawn prematurely from the study 
x Entered extended follow-up (To be added later as CSR addendum) 
x Entered extended follow-up 
x Switched to local standard care during the study by study phase 
In addition, summaries will be provided of: 
x Non-study treatments given for GPA and MPA by study phase 
x Concomitant medications received by study phase 














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5. 
EXPOSURE TO STUDY MEDICATION 
 
 
The following data will be presented: 
x Number (%) of patients receiving 1, 2, etc. infusions of RTX 
x Cumulative dose of RTX by infusion number. 
x Total dose, and the number of doses of methylprednisolone prior to first dose of RTX 
x Oral corticosteroid treatment duration (months), summarized both descriptively and as number 
(%) of patients using the following duration categories: 
o Remission induction phase(1)  
 <1 month (<26 days) 
 1 month - <2 months (<45 days)  
 2 months - <4 months (<105 days) 
 4 months - <6 months (<165 days) 
 6 months (≥165 days) 
o Follow-up phase 
 6 months - <12 months (<335 days) 
 12 months - <18 months (<515 days) 
 18 months - <2 years (<699 days) 
 2 years - <3 years (<1067 days) 
 3+ years (≥1067 days) 
x Total dose of corticosteroid following first dose of RTX. 
x duration (months) in the study phases over all patients, summarized as for Methylprednisolone, 
above 
 
(1) Total duration will be calculated as: 
 
1  +  Study end date  -  Date rituximab first administered 
where “study end date” is defined as: 
1. For ealy discontinuation or completion patients: early withdrawal/discontinuation date or date 
patient completed study 
2. For the rest of patients: minimum of common closeout date and last known alive date 
 
 
 
 
 
 
 
 
5.1 
Exposure Output Specifications 
























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6. 
ADVERSE EVENTS 
Adverse events will be considered TE (defined in Section 4) irrespective of the length of time 
since the first RTX infusion. Only TE adverse events will be included in summary tables. The 
current sponsor data safety standards will be used where available. 
Summaries of TE adverse events will be produced by study phase. Summaries will be 
produced of the numbers of patients (%) experiencing the following TE adverse events: 
Summaries will be produced of the following TE adverse events: 
x Summary profile of TE adverse events 
x Overview of adverse events 
x All events 
x All events by most extreme toxicity grade(*) 
x Events other than IRR occurring during or within 24 hours of a RTX Infusion by 
relationship to treatment (count multiple occurrences as one event) 
x Events leading to death 
x SAEs 
x SAEs assessed as related to the study drug 
x Events leading to discontinuation of study medication 
x Events leading to a study medication dose modification 
o  Infections 
 MedDRA SOC infections and infestations 
o Serious Infections 
 serious events in MedDRA SOC infections and infestations (include non-serious 
infections treated with IV anti-infective) 
o Opportunistic Infection 
  from Roche standard AEGT Opportunistic Infections 
o Infusion Related Reactions (IRRs) 
 events that occur during or within 24 hours of an infusion and fall within Roche 
standard AEGT Infusion Related Reactions + Hypersensitivity 
 Count multiple symptoms as one IRR for each infusion. 
o Cardiac events 
 MedDRA SOC “Cardiac Events” MedDRA SOC “Cardiac Events” 
o Malignancies 
 preferred terms in the Malignant or Unspecified Tumors SMQ (Wide) 
x CTCAE grade 3 and grade 4 events 
x Non-serious events reported by ≥ 5% patients (CTg requirement, not for CSR) 
x 
 Common Adverse Events reported by ≥ 10% patients  
 
 (*) Most extreme toxicity grade is recorded on the eCRF. If most extreme toxicity grade is not recorded 
then initial toxicity grade will be used; if neither grade is given then an unknown category will be 
used. The grading is based on National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 4. 
 
 


















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7. 
SAFETY LABORATORY ANALYSES 
7.1 
Safety Laboratory Analyses 
Safety hematology and serum chemistry laboratory samples are taken during each planned 
study visit. 
Treatment-emergent clinically relevant laboratory test abnormalities are to be reported as 
adverse events on the Adverse Event eCRF and so will be reported as AEs. This is required 
for planned samples taken at study visits and also for any unscheduled samples taken. 
For hematology and chemistry parameters, following summaries will be produced: 
x 
Descriptive summaries, including changes from baseline, of values at baseline and 
throughout the study. 
x 
The number of patients with values outside the normal upper and lower limit at each visit.  
7.2 
Acute-phase Reactants 
Samples for measurement of erythrocyte sedimentation rate and C-reactive protein are taken 
during each study visit for analysis by the site’s local laboratory. The parameters values and 
their changes from baseline will be summarized descriptively by visit and study phase. 
7.3 
Immunologic and Antibody Assessments 
B- and T-cell populations are measured at baseline and each subsequent visit. 
Samples for measurement of IgA, IgG, IgM and total immunoglobulins are taken at screening, 
baseline and then at each visit from Month 1 onwards. These will be summarized 
descriptively by visit and study phase and as changes from baseline. 
 
 
 
 
 
 
 
 
 
 














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9.1 
Efficacy Output Specifications 
 
 
 
 
 
 
 
 


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10. PHARMACODYNAMIC ANALYSES 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 


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Appendix 2   
Schedule of Assessments 
Visit  a 
Screen b 
Week 
Month 
Follow-Up 
WD 
Extended 
Follow-Up e 
BL c 
1 
2 
3 
1 
2 
4 
6 
9 
12 
15 
18 
Every 3 
Months  
after  
Month 18 d 
Day 
 
1 
8 
15 
22 
29 
60 
120 
180 
270 
365 
455 
545 
 
 
 
Medications 
 
 
Glucocorticoids IV f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucocorticoids PO g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pre-infusion medications h 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Rituximab IV infusion 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
General Assessments 
 
 
Informed Consent/  
Child’s Assent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum) i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
(urine)  i 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
12-Lead ECG j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs (pulse rate, systolic 
and diastolic blood pressure, 
and temperature) 
x 
x k 
x k 
x k 
x k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


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Appendix 2 
Schedule of Assessments (cont.) 
Visit  a 
Screen b 
Week 
Month 
Follow-Up 
WD 
Extended 
Follow-Up e 
BL c 
1 
2 
3 
1 
2 
4 
6 
9 
12 
15 
18 
Every 
3 Months  
after  
Month 18 d 
Day 
 
1 
8 
15 
22 
29 
60 
120 
180 
270 
365 
455 
545 
 
 
 
General Assessments (cont’d) 
 
 
 
Physical examination  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chest X-ray l or CT scan m 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Safety Assessments 
 
 
Adverse events  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Efficacy Assessments 
 
 
Acute-Phase Reactant Assessments 
 
 
C-reactive protein 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Erythrocyte sedimentation rate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


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Appendix 2 
Schedule of Assessments (cont.) 
Visit  a 
Screen b 
Week 
Month 
Follow-Up 
WD 
Extended 
Follow-Up e 
BL c 
1 
2 
3 
1 
2 
4 
6 
9 
12 
15 
18 
Every 
3 Months  
after  
Month 18 d 
Day 
 
1 
8 
15 
22 
29 
60 
120 
180 
270 
365 
455 
545 
 
 
 
Laboratory Assessments 
 
 
Hematology (CBC) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum chemistry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis with microscopy and 
albumin to creatinine ratio  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c s 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBsAg, HBcAb, and HCV Ab and 
HBV DNAt 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis screening 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunologic and Antibody Assessments 
 
 
Immunoglobulins 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CD19 B cells 
 
x q 
 
x q 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FACS panel 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum HACA sample 
 
x 
 
 
 
 
 
x 
x 
x 
 
 
x 
x u 
x 
x u 
Serum ANCA sample v, w 
x  
 
 
 
 
x 
 
 
x 
 
x 
 
x 
x u 
x 
x u 
Pharmacokinetic Assessments 
 
 
Sample for rituximab levels  
 
x x 
x y 
x y 
x x 
x 
x 
x 
x 
x 
 
 
x 
x u 
x 
x u 
ANCA   antineutrophil cytoplasmic antibody; CBC   complete blood count; 
 
 
 
; CT   computed tomography; ECG   electrocardiogram; eCRF   electronic Case Report Form; FACS   fluorescence-activated cell sorter; GFR   glomerular filtration rate; 
GPA   granulomatosis with polyangiitis; HbA1c   glycosylated hemoglobin; HBcAb   hepatitis B core antibody; HBsAg   hepatitis B surface antigen; HBV   hepatitis B virus; HCV 
Ab    hepatitis C virus antibodies; IV   intravenous; LLN   lower limit of normal; MPA   microscopic polyangiitis; PK   pharmacokinetic; PO   by mouth; PVDI   Pediatric 
Vasculitis Damage Index; WD   withdrawal. 
a 
For visit windows, please refer to protocol Appendix 2. 
b 
The screening visit must be completed within 28 days of the baseline visit.  
c 
Assessments performed within 14 days of the baseline visit do not have to be repeated at the discretion of the investigator and if not clinically indicated. 
d 
Until the common closeout date. 


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e 
At the common closeout date, patients whose peripheral B cells remain depleted, will continue to attend study visits every 3 months until their peripheral B-cell counts have 
returned to pre-rituximab baseline levels or to within the normal range for the population, whichever is lower. 
f 
Three times daily IV infusions of 30 mg/kg of methylprednisolone (up to 1 g/day, or equivalent) may be administered at any time, up to and including Day 1 (prior to the first 
rituximab infusion).  If clinically indicated, and at the discretion of the investigator, an additional three daily doses of methylprednisolone (up to 1 g/day) can be given by IV 
infusion.  No more than six doses in total can be given. All doses must be completed prior to the first rituximab infusion.  The first rituximab infusion must occur no later than 
14 days after the last dose of methylprednisolone infusion. 
g 
All patients will receive concomitant oral prednisolone or prednisone (1 mg/kg/day; up to 60 mg/day, or equivalent), which will be tapered to a minimum of 0.2 mg/kg/day (or 
10 mg/day, whichever is lower) no later than Month 6. 
h 
Patients should be premedicated with paracetamol/acetaminophen and cetirizine hydrochloride (or similar antihistamine), both according to labeled age-related doses, to be 
given 1 hour (r 15 minutes) before each infusion of rituximab. 
i 
To be completed for female patients of childbearing potential. 
j 
After screening, only if clinically indicated. 
k 
Vital signs should be taken immediately prior to infusion.  During an infusion, record vital signs every 15 minutes for 1 hour; then every 30 minutes; and then at least 1 hour 
after the completion of the infusion. 
l 
To be completed at screening and, if normal, only if indicated thereafter.  If the chest X-ray is abnormal, repeat at Month 1 and as indicated thereafter. 
m 
CT scan to be completed only if indicated. 
n 
Within the last 365 days of the screening visit. 
o 
 
p 
 
q 
CD19 B-cell samples to be obtained prior to infusion of rituximab. 
r 
 
 
s 
Fasting is not required. 
t 
After screening, only if clinically indicated. 
u 
After the Month 18 visit, samples should be taken every 6 months thereafter. 
v 
ANCA testing performed at the screening visit to support a diagnosis of GPA or MPA may be performed locally or centrally.  All other ANCA testing to be performed centrally. 
w 
Also to be performed at time of flare. 
x 
PK samples to be obtained prior to infusion of rituximab and 30 minutes following infusion of rituximab. 
y 
PK samples to be obtained prior to infusion of rituximab. 
 
 
 
 
 
 
 
 
 
 


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