Clinical trial NCT02112838
Conditions: IGA Nephropathy
Keywords: IGA Glomerulonephritis Nephritis, IGA Type
Sponsor: Rigel Pharmaceuticals
Start date: 2014-10-01; Completion date: 2018-11-12
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether fostamatinib is safe and effective in the treatment of IgA Nephropathy

Detailed description:

Arms: arm 1: Fostamatinib 150 milligram (mg) tablet twice daily by mouth, over the course of 24 weeks arm 2: Fostamatinib 100 mg tablet twice daily by mouth, over the course of 24 weeks arm 3: Placebo tablet twice daily by mouth, over the course of 24 weeks
Interventions: intervention 1: Fostamatinib 150 mg intervention 2: Fostamatinib 100 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Fostamatinib 150 milligram (mg) tablet twice daily by mouth, over the course of 24 weeks intervention 2: Fostamatinib 100 mg tablet twice daily by mouth, over the course of 24 weeks intervention 3: Placebo tablet twice daily by mouth, over the course of 24 weeks

Protocol documents:
Prot_000.pdf: 
 
 
 
CLINICAL PROTOCOL 
A Phase 2, Multi-Center, Randomised, Double-Blind, Ascending-Dose, Placebo-Controlled Clinical 
Study to Assess the Safety and Efficacy of Fostamatinib in the Treatment of IgA Nephropathy 
Protocol Number: 
C-935788-050 
EudraCT Number: 
2014-000331-16 
Study Sponsor: 
Rigel Pharmaceuticals, Inc. 
1180 Veterans Boulevard 
South San Francisco, CA 94080, USA 
Tel: +1.650.624.1100 
Sponsor Representative: 
Daniel Magilavy, MD 
Medical Monitor 
Tel.: +1.650.624.1372 
Mobile: +1.603.770.7216 
E-Mail: dmagilavy@rigel.com 
Principal Investigator 
(Frederick) Wai Keung Tam  MB BChir (Cantab) PhD FRCP FHEA 
Reader in Renal Medicine/ Hon. Consultant Nephrologist 
Imperial College Renal and Transplant Centre 
London W12 0NN, United Kingdom 
Tel: (44) 20 83 83 2354 
Email: f.tam@imperial.ac.uk 
Version 1.0: 
21 March 2014 
Version 2.0: 
26 February 2015 
 
Version 3.0: 
27 October 2015 
 
Version 4.0: 
05 October 2016 
 
Version 5.0: 
17 March 2017 
 
Confidentiality Obligation 
The information contained in this protocol and all information and data related to R935788 ("Drug") are the 
confidential and proprietary information of Rigel Pharmaceuticals, Inc. ("Rigel") and may not be disclosed to others 
without prior written permission of Rigel.  The Investigator may, however, disclose information about this protocol and 
Rigel’s Drug to individuals under his/her supervision who are working on the protocol, provided such individuals are 
bound by written agreement to maintain the confidentiality of such information.  The Investigator may disclose 
information about the Drug as required by applicable law, provided he/she promptly notifies Rigel. 




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Signature of Agreement for Clinical Protocol C-935788-050 
I agree to the following: 
• To conduct the study in strict accordance with this protocol and the contract with the 
Sponsor, Rigel Pharmaceuticals, Inc. (Rigel), and all applicable national and international 
laws, rules, and regulations, including the principles of the International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) Good Clinical Practice and the Declaration of Helsinki. 
• To maintain adequate and accurate records and make those records available for inspection 
by Rigel (or its authorized representative), or any other Regulatory Agency authorized by 
law. 
• To report to Rigel (or its authorized representative) any adverse events (AEs) or serious 
adverse events (SAEs) that occur in the course of the study, as specified in the protocol. 
• To promptly report to the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) and Rigel all changes in research activity and all unanticipated problems 
involving risks to subjects or others and not make any changes in the protocol without 
approval from Rigel and the IRB/IEC, except when necessary to eliminate hazards to the 
subjects. 
• To personally conduct or supervise the study and ensure that all associates, colleagues, and 
employees assisting in the conduct of the study are also duly qualified, have adequate 
understanding of the study, are informed about their obligations and commitments, and are 
provided adequate training on how to conduct their delegated tasks. 
• To ensure that the IRB/IEC responsible for initial and continuing review and approval of this 
study complies with applicable laws and the requirements for obtaining informed consent and 
IRB/IEC review and approval are met. 
• To comply with all other requirements regarding the obligations of Investigators as described 
in this protocol and in applicable laws. 
• That this protocol and all data and information generated in connection with this study are 
the exclusive property of Rigel. 
I have read and understood the Investigator’s Brochure, including potential risks and side effects 
of the study drug. 
I represent that I am a licensed medical practitioner in good standing under applicable law and 
that I am qualified and duly authorized to conduct the study.  I acknowledge that Rigel has the 
right to terminate the study at any time. 
 
 
 
Investigator’s Signature 
 
Date 
 
 
 
Print Investigator’s Name and Title 
 
 


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TABLE OF CONTENTS 
1.0 
PROTOCOL SYNOPSIS ....................................................................................................8 
2.0 
ABBREVIATIONS AND TERMS ...................................................................................15 
3.0 
INTRODUCTION .............................................................................................................17 
3.1 
Background ........................................................................................................................17 
3.2 
Rationale for Development of Fostamatinib for IgAN ......................................................18 
3.3 
Fostamatinib Safety and Pharmacokinetics .......................................................................18 
3.3.1 
Single Ascending Dose Safety and Pharmacokinetics ......................................18 
3.3.2 
Multiple-dose Pharmacokinetics .......................................................................19 
3.3.3 
Metabolism ........................................................................................................19 
3.3.4 
Renal Impairment Population ...........................................................................19 
3.3.5 
Drug-Drug Interactions .....................................................................................20 
3.4 
Efficacy ..............................................................................................................................21 
3.5 
Safety .................................................................................................................................21 
3.5.1 
Blood Pressure Elevation ..................................................................................21 
3.5.2 
Liver Function Test Abnormalities ...................................................................22 
3.5.3 
Neutropenia .......................................................................................................22 
3.5.4 
Gastrointestinal (GI) Effects .............................................................................22 
3.5.5 
Rare Adverse Events .........................................................................................23 
3.5.6 
Safety Summary ................................................................................................23 
4.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................24 
4.1 
Objectives ..........................................................................................................................24 
4.2 
Primary Efficacy Endpoint ................................................................................................24 
4.3 
Secondary Efficacy Endpoints ...........................................................................................24 
4.4 
Safety Endpoints ................................................................................................................25 
4.5 
Pharmacokinetic Endpoints ...............................................................................................25 
4.6 
Exploratory Histologic Endpoints......................................................................................25 
5.0 
STUDY DESIGN...............................................................................................................26 
5.1 
Summary of Study Description ..........................................................................................26 
5.2 
Rationale for Proposed Dosing ..........................................................................................27 
5.3 
Study Treatment .................................................................................................................28 
5.3.1 
Randomisation ..................................................................................................28 


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5.4 
Safety Monitoring ..............................................................................................................28 
5.5 
Safety Review Committee .................................................................................................28 
5.6 
Administrative Structure ....................................................................................................28 
6.0 
SUBJECT SELECTION ....................................................................................................30 
6.1 
Inclusion Criteria ...............................................................................................................30 
6.2 
Exclusion Criteria ..............................................................................................................31 
7.0 
STUDY PROCEDURES ...................................................................................................33 
7.1 
Screening (Visits 1a and 1b) ..............................................................................................36 
7.1.1 
Screening Visit 1a .............................................................................................36 
7.1.2 
Screening Visit 1b .............................................................................................36 
7.2 
Treatment Period Visits 2-9 ...............................................................................................37 
7.2.1 
Baseline/First Dose (Visit 2) .............................................................................37 
7.2.2 
Treatment Visits 3-9 ..........................................................................................37 
7.3 
Study Follow-Up (Visit 10) ...............................................................................................38 
7.4 
Dose Adjustments Due to Adverse Events ........................................................................38 
7.4.1 
Non-Diarrhoea Gastrointestinal Toxicity ..........................................................39 
7.5 
Definition of Study Procedures ..........................................................................................39 
7.5.1 
Medical History .................................................................................................39 
7.5.2 
Histologic Assessment of Renal Biopsies .........................................................39 
7.5.3 
Physical Exam ...................................................................................................40 
7.5.4 
Vital Signs .........................................................................................................41 
7.5.5 
Clinical Laboratories .........................................................................................41 
7.5.6 
Pregnancy Tests ................................................................................................41 
7.6 
Concomitant Therapies ......................................................................................................42 
7.6.1 
Required Medications: Angiotensin Blockade..................................................42 
7.6.2 
Restricted IgA Nephropathy Medications .........................................................42 
7.6.3 
Restricted Medications Unrelated to IgA Nephropathy ....................................42 
7.7 
Pharmacokinetics Samples.................................................................................................42 
7.8 
Calculation of Blood Draws...............................................................................................42 
7.9 
Withdrawal from Study......................................................................................................43 
7.10 
Study Completion and Early Termination .........................................................................44 
7.11 
Post-Trial Access to Fostamatinib .....................................................................................44 
7.11.1 
Dose Modification During Extended Treatment Period ...................................45 


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8.0 
STUDY DRUG ..................................................................................................................46 
8.1 
Study Drug Description .....................................................................................................46 
8.1.1 
100 mg Tablets ..................................................................................................46 
8.1.2 
150 mg Tablets ..................................................................................................46 
8.2 
Storage ...............................................................................................................................46 
8.3 
How Supplied/Study Drug Dispensation ...........................................................................46 
8.4 
Study Drug Administration ................................................................................................47 
8.5 
Unblinding .........................................................................................................................47 
8.6 
Study Drug Accountability/Drug Compliance ...................................................................47 
9.0 
ADVERSE EVENTS .........................................................................................................49 
9.1 
Definitions..........................................................................................................................49 
9.2 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators .......................................................................................................................52 
9.2.1 
Adverse Event Reporting Period .......................................................................52 
9.2.2 
Assessment of Adverse Events .........................................................................52 
9.2.3 
Expedited Reporting Requirements for Serious Adverse Events .....................53 
9.2.4 
Reporting of Serious Adverse Events by Sponsor ............................................53 
9.3 
Pregnancy ...........................................................................................................................53 
10.0 
STATISTICAL METHODS ..............................................................................................55 
10.1 
General Considerations ......................................................................................................55 
10.2 
Analysis Populations ..........................................................................................................55 
10.3 
Analysis of Efficacy Endpoints .........................................................................................55 
10.3.1 
Primary Efficacy Endpoint ................................................................................56 
10.3.2 
Secondary Efficacy Endpoints ..........................................................................56 
10.4 
Analysis of Safety ..............................................................................................................57 
10.5 
Analysis of Pharmacokinetic Endpoints ............................................................................58 
10.6 
Analysis of Exploratory Endpoints ....................................................................................58 
10.7 
Determination of Sample Size ...........................................................................................58 
10.8 
Handling of Dropouts and Missing Data ...........................................................................58 
10.9 
Interim Analysis of Results from 100 mg bid Cohort........................................................59 
11.0 
ETHICAL AND LEGAL ISSUES ....................................................................................60 
11.1 
Confidentiality of Subject Personal Information ...............................................................60 
11.2 
Independent Ethics Committee/Institutional Review Board..............................................60 


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11.3 
Changes to the Study .........................................................................................................61 
11.4 
Protocol Deviations, Violations, Waivers and Exemptions ...............................................61 
11.5 
Informed Consent...............................................................................................................61 
11.6 
Liability, Insurance, and Financing ...................................................................................62 
12.0 
DATA COLLECTION, RETENTION, AND MONITORING ........................................63 
12.1 
Source Data ........................................................................................................................63 
12.1.1 
Source Documentation Requirements ...............................................................63 
12.2 
Electronic Case Report Forms ...........................................................................................63 
12.3 
Monitoring .........................................................................................................................63 
12.4 
Data Quality Assurance .....................................................................................................64 
12.5 
Data Collected by Contractors ...........................................................................................64 
12.6 
Availability and Retention of Investigational Records ......................................................64 
13.0 
SUPERVISION OF THE STUDY ....................................................................................66 
14.0 
DISCLOSURE/PUBLICATION OF DATA .....................................................................67 
15.0 
REFERENCES ..................................................................................................................68 
 
LIST OF APPENDICES 
Appendix 1: 
Guideline for Dose Modification for Possible Drug-Induced Liver Injury 
(DILI):  AST or ALT 3x ULN or TBL > 2xULN .................................................69 
Appendix 2: 
Guideline for Management of Neutropenia ...........................................................71 
Appendix 3: 
Guideline for Management of Diarrhoea ...............................................................72 
Appendix 4: 
Guideline for Management of Hypertension .........................................................74 
Appendix 5: 
Restricted Medications...........................................................................................76 
 
LIST OF TABLES 
Table 1: 
Double-Blind Treatment ........................................................................................28 
Table 2: 
Schedule of Study Procedures—Main Study (Visits 1 through 10) ......................34 
Table 3: 
Schedule of Study Procedures—Extended Treatment ...........................................35 
Table 4: 
Dose Adjustment ....................................................................................................39 
Table 5: 
Oxford Classification of Renal Biopsy Scoring.....................................................40 
Table 6: 
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Subject (Screening through Follow-Up, and Extended 
Treatment Period) ..................................................................................................43 
 
LIST OF FIGURES 
Figure 1: 
Study Design ..........................................................................................................27 


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1.0 
PROTOCOL SYNOPSIS  
Name of Finished Product(s): 
Fostamatinib (R788) 
Title of Study: A Phase 2, Multi-Center, Randomised, Double-Blind, Ascending-Dose, 
Placebo-Controlled Clinical Study to Assess the Safety and Efficacy of Fostamatinib in the 
Treatment of IgA Nephropathy 
Objectives: 
• To assess the efficacy of fostamatinib administered orally for 24 weeks to subjects with 
IgA nephropathy, as measured by change in renal function and histology. 
• To investigate the safety and tolerability of fostamatinib administered orally for 24 weeks 
to subjects with IgA nephropathy. 
Methodology: This is a Phase 2, multi-center, randomised, double-blind, ascending-dose 
placebo-controlled, proof-of-concept study to evaluate 2 dose regimens of fostamatinib in 
approximately 75 subjects.  The study will consist of 11 visits over 28 to 43 weeks.  
Subjects who meet all inclusion/exclusion criteria will be required to have completed at least 
90 days of treatment with an angiotensin converting enzyme inhibitor (ACEi) and/or 
angiotensin II receptor blocker (ARB) at a maximum approved (or tolerated) dose and to have 
had a pre-study renal biopsy no more than 180 days prior to the initial study visit.  The renal 
biopsy will be reviewed by a member of the central panel of renal pathologists to ensure 
subjects meet histological entry criteria. 
The enrollment plan for this study has been to randomise patients in an ascending dose 
fashion, with review and approval of safety, tolerability and renal function findings by the 
Safety Review Committee prior to enrollment into Cohort 2.  Once randomisation of the 
initial cohort of approximately 38 subjects (25 randomised to fostamatinib 100 mg bid, 13 to 
placebo) was complete, enrollment began for the second cohort of approximately 37 subjects 
(25 randomised to fostamatinib 150 mg bid, 12 to placebo).  Subjects will be randomised 2:1 
in each cohort so as to maintain 1:1:1 allocation for all 3 double-blind dosing groups (25 
subjects per group; Table 1).  Subjects will be stratified among the 3 treatment groups by 
presence or absence of endocapillary hypercellularity as determined by a member of the 
central panel of renal pathologists on the most recent renal biopsy obtained prior to 
randomisation. 
Table 1: 
Double-Blind Treatment 
Treatment Group 
Number of Subjects 
Dose  
A 
25 
Fostamatinib 100 mg bid  
B 
25 
Fostamatinib 150 mg bid 
C 
25 
Placebo bid 
During the 24-week double-blind treatment period, subjects should remain on the same dose 
of ACEi or ARB during the treatment period (Visits 2-9).  Subjects will be monitored by 


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routine safety assessments (vital signs, haematology, serum chemistries, urinalyses, and 
adverse event [AE] assessments) and for renal function (spot urine protein/creatinine ratio 
[sPCR], urine dipstick test for haematuria and estimated glomerular filtration rate [eGFR] 
using the MDRD equation).  At the end of the treatment period, subjects will be encouraged 
to have a renal biopsy. 
Brief Summary of Visit Schedule 
There will be 11 visits over the course of 28 to 43 weeks: 
• Visit 1a = Up to 120 days prior to Baseline (Visit 2) 
• Visit 1b = Up to 30 days prior to Baseline (Visit 2) 
• Visit 2 = Day 1, Baseline 
• Visit 3 = Week 1 ± 1 day, Treatment Week 1 
• Visit 4 = Week 2 ± 3 days, Treatment Week 2 
• Visit 5 = Week 4 ± 3 days, Treatment Week 4 
• Visit 6 = Week 8 ± 4 days, Treatment Week 8 
• Visit 7 = Week 12 ± 4 days, Treatment Week 12 
• Visit 8 = Week 18 ± 7 days, Treatment Week 18 
• Visit 9* = Week 24 ± 7 days, Treatment Week 24 
• Visit 10 = Week 26 ± 3 days, Post-treatment 
*Visit 9 procedures will be performed for subjects that withdraw early, with the 
exception that renal biopsy will not be required. 
Prior to the completion of this study (ie, before the clinical database is locked and unblinded, 
and top line efficacy results are available), subjects who have had at least a 40% decrease from 
Baseline in proteinuria at Visit 9 (or, in the judgment of the Rigel Medical Monitor, a 
clinically significant improvement in post-treatment biopsy score) and have tolerated study 
drug may be permitted to continue to receive extended treatment with study drug (fostamatinib 
or placebo) on the same double-blind treatment regimen until the results of this study are 
known.  
If the sPCR of a subject increases during the extended treatment period to more than 50% 
greater than the Week 24 value across 2 evaluations at least 2 weeks apart (whether analyzed 
at the local or central laboratory), the subject may be transitioned to 150 mg fostamatinib bid 
(whether previously receiving placebo, 100 mg fostamatinib bid, or 150 mg fostamatinib bid) 
if, in the Investigator’s judgment, the subject has not experienced safety or tolerability issues 
related to study drug. The subject’s original treatment during the 24-week main study and 
extended treatment period will remain double-blind until the end of the study.   
Additional safety visits will occur at 2, 4, and 8 weeks from the treatment transition to 150 mg 
bid before the subject re-assumes the standard 12-week visit interval.  
 


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Number of Subjects: Approximately 75 subjects at 25 sites in 8 countries in Europe, Asia, 
and North America will be enrolled in the study. 
Study Population: For the purpose of this study, the term ‘subject’ will refer to patients with 
IgA nephropathy (IgAN) participating in this study. 
Inclusion Criteria: 
1. Signed informed consent prior to any study specific screening procedures.   
2. Male or female between 18 to 70 years of age (Note: minimum age is 20 years in 
Taiwan and 21 years in Singapore).   
3. Females must be either post-menopausal for at least 1 year, surgically sterile, or, if of 
childbearing potential, must not be pregnant or lactating.  If sexually active, must agree 
to use a highly effective method of birth control throughout the duration of the trial and 
for 30 days following the last dose.   
4. A pre-study renal biopsy obtained within 180 days prior to the initial study visit 
(Visit 1a) will be reviewed by a member of the central panel of renal pathologists to 
ensure subjects meet the following histologic entry criteria:  
• Consistent with IgAN 
• Mesangial hypercellularity score of > 0.5 (M1) and/or presence of endocapillary 
hypercellularity (E1) on renal biopsy (using the Oxford Classification).  
Note: Subjects may be included with prior written permission from the Rigel 
Medical Monitor if the renal biopsy is graded M0 E0 but shows mesangial 
hypercellularity with a score of ≤ 0.5 or if there are less than 8 evaluable glomeruli 
on the submitted pre-study renal biopsy. 
• ≤ 50% of cortical area involved by tubular atrophy or interstitial fibrosis (T0 or T1) 
• < 50% glomerular crescents 
Note: biopsies obtained greater than 180 days prior to Visit 1a may be permitted with 
prior written permission from the Rigel Medical Monitor if, according to the 
Investigator, there has been no clinically significant change in renal status. 
5. Treatment with an ACEi and/or an ARB for at least 90 days at a maximum approved 
(or tolerated) dose prior to Screening (Visit 1b).  Subjects should remain on the same 
dose of ACEi or ARB during the treatment period (Visits 2-9). 
6. Proteinuria > 1 gm/day, sPCR > 100 mg/mmol (> 884 mg/g), or Spot 
Albumin/Creatinine Ratio > 70 mg/mmol at diagnosis of IgAN or any time prior to 
screening.  
7 Proteinuria > 0.50 gm/day [sPCR > 50 mg/mmol (> 442 mg/g)] at Screening (Visit 1b). 
For USA only: proteinuria > 1 gm/day [sPCR > 100 mg/mmol (> 884 mg/g)] at 
Screening (Visit 1b) for Cohort 2 (150 mg bid or placebo). 
 


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8. Blood pressure controlled to ≤ 130/80 with angiotensin blockade with or without other 
anti-hypertensive agents.  Subjects should be taking a maximum approved (or 
tolerated) dose of an ACEi or ARB before an additional anti-hypertensive agent is 
added.  If additional anti-hypertensive therapy is required, other agents (beta-blockers, 
calcium channel blockers, or diuretics) may be added.  Patients may be reassessed if 
BP < 140/90, but > 130/80. 
9. Otherwise in stable health as determined by the Investigator based on medical history 
and laboratory tests during the screening period.  See Exclusion Criteria for specific 
exclusions. 
10. In the Investigator’s opinion, has the ability to understand the nature of the study and 
any hazards of participation and to communicate satisfactorily with the Investigator. 
Exclusion Criteria: 
1. History of or active, clinically significant, respiratory, gastrointestinal (including 
pancreatitis), hepatic, neurological, psychiatric, musculoskeletal, genitourinary, 
dermatological, or other disorder that, in the Investigator’s opinion, could affect the 
conduct of the study or the absorption, metabolism or excretion of the study drug.  
2. Have had any major cardiovascular event within the 180 days prior to randomisation, 
including but not limited to: myocardial infarction, unstable angina, cerebrovascular 
accident, pulmonary embolism, or New York Heart Association Class III or IV heart 
failure. 
3. Diagnosis or history suggestive of Henoch-Schonlein purpura. 
4. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (using the MDRD 
equation) at the time of Screening (Visit 1b).  
Note: Values as low 25 mL/min/1.73 m2 may be permitted with prior written permission 
from the Rigel Medical Monitor if, according to the Investigator, there has been no 
clinically significant recent change in renal status. 
5. A 50% decrease in eGFR from most recent pre-study clinic visit to Visit 1b.  
6. An absolute neutrophil count of < 1,500/µL, Hgb < 9 g/dL, ALT or AST of > 1.5x 
ULN, total bilirubin > 2.0 mg/dL at Visit 1b.  The Investigator may reassess these 
laboratory abnormalities within 30 days after Screening (Visit 1b). 
7. Acute gastrointestinal symptoms (eg, nausea, vomiting, diarrhoea) at Baseline (Visit 2).  
The subject may be reassessed after full recovery from the acute gastrointestinal illness. 
8. Active bacterial or parasitic infections, including tuberculosis. 
9. Serologic results suggestive of active hepatitis B or hepatitis C (subjects may be 
included if confirmed hepatitis C recombinant immunoblot assay negative or hepatitis 
C virus RNA negative [qualitative]), or subjects with suspected human 
immunodeficiency virus (HIV). 
 


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10. Use within 6 months prior to pre-study renal biopsy of cyclophosphamide, 
mycophenolate mofetil, azathioprine, or Rituximab (or other anti-B cell therapies). 
Those subjects who had been treated with an anti- B cell therapy must have a normal 
CD19 count by Visit 1b. 
11. Use of > 15 mg/day prednisone (or other corticosteroid equivalent).  For those subjects 
taking corticosteroids for renal indication, the daily dose should not change from 
Baseline (Visit 2) to the end of the study drug treatment (Visit 9).  
12. Prior or current use of cyclosporine or tacrolimus. 
13. Have a clinically significant infection, or who are known to have an active 
inflammatory process (other than IgAN) at the time of Screening (Visit 1b) or Baseline 
(Visit 2).  The subject may be reassessed after recovery from an acute infection. 
14. Currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 30 days or 5 half-lives (whichever is longer) of 
Screening (Visit 1a). 
15. Are unable or unwilling to follow instructions, including participation in all study 
assessments and visits. 
16. Have a history of alcohol or substance abuse that, in the judgment of the Investigator, 
may impair or risk the subject’s full participation in the study. 
17. Have a condition or be in a situation that the Investigator feels may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject’s participation in the study. 
18. Have a known allergy and/or sensitivity to the study drug or its excipients. 
Investigational Product: Fostamatinib (100 mg and 150 mg tablets) and matching placebo 
Route of Administration:  Oral 
Dose:  
1 tablet PO or matching placebo 
Frequency of Dosing: 
bid 
Duration of Treatment: 24 weeks (extended treatment available to eligible subjects) 
Statistical Methods: 
Analysis Populations: 
• Intent-to-Treat Population 
The Intent-to-treat (ITT) population will include all randomised subjects.  All 
efficacy endpoints will be analyzed based on the ITT population, and subjects will 
be analyzed according to their randomised treatment assignment.  The efficacy 
analyses based on the ITT population will be considered the primary efficacy 
analyses. 


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• Per-Protocol Population 
The Per-Protocol (PP) population will include all subjects in the ITT population 
who had no major protocol violations.  Major protocol violations will include: 
• Not receiving any study treatment 
• Not receiving the correct study treatment 
• Not receiving sufficient treatment 
• Failing to meet eligibility criteria 
• Other major protocol violations, as determined by a blinded review of the data prior 
to database lock 
Baseline measurements will be the last measurement for the corresponding 
variable prior to the first randomised dose at Visit 2. For analysis of the primary 
efficacy endpoint, the main analysis will be performed with baseline defined as 
the average between Visit 2 and the most recent screening value prior to Visit 2 
(a secondary analysis, with the Visit 2 value alone as baseline, will be 
performed). 
• Safety Population 
The safety population will include all randomised subjects who received at least 1 
dose of the allocated study drug.  The safety population will be used for analysis of 
all safety assessments.  The subjects will be analyzed as treated.   
Primary Efficacy Endpoint: 
• Mean change from Baseline of proteinuria as measured by sPCR at 24 weeks 
(Visit 9) 
Secondary Efficacy Endpoints: 
• Mean change from pre-treatment to post-treatment in mesangial hypercellularity on 
renal biopsies.  
• Percentage of subjects with ≥ 50% reduction in sPCR from Baseline (Visit 2) at 
Week 24 (Visit 9). 
• Percentage of subjects with ≥ 30% reduction in proteinuria from Baseline (Visit 2) 
at 24 weeks (Visit 9) 
• Mean change from pre-treatment to post-treatment in endocapillary hypercellularity 
on renal biopsies. 
• Mean change from pre-treatment to post-treatment in segmental sclerosis/adhesion 
score on renal biopsies. 
• Mean change from pre-treatment to post-treatment in global glomerulosclerosis 
score on renal biopsies. 
• Mean change from pre-treatment to post-treatment in tubulointerstitial scarring on 


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renal biopsies. 
• Mean change from pre-treatment to post-treatment in cellular/fibrocellular crescent 
score on renal biopsies.  
• Mean change from Baseline (Visit 2) of eGFR at 12 weeks (Visit 7). 
• Mean change from Baseline (Visit 2) of eGFR at 24 weeks (Visit 9). 
• Mean change from Baseline (Visit 2) of proteinuria at 12 weeks (Visit 7). 
• Percentage of subjects with sPCR < 50 mg/mmol at 12 weeks (Visit 7). 
• Shift in haematuria (dipstick test) from Baseline (Visit 2) at 12 weeks (Visit 7). 
• Shift in haematuria (dipstick test) from Baseline (Visit 2) at 24 weeks (Visit 9). 
Sample Size Calculation: 
A sample size of 25 evaluable subjects in each of the 3 treatment groups will have an 
80% power to detect a 43% reduction in proteinuria from Baseline (Visit 2) to 
24 weeks (Visit 9) between the pooled fostamatinib and placebo groups, using a 
2-sided t- test with α = 0.05 and log-transformed data.  This calculation assumes that 
the 3 treatment groups have the same mean and standard deviations of urinary 
protein/creatinine ratio at baseline (130 mg/mmol ± 120 mg/mmol) and that the values 
for the placebo group remain constant over 24 weeks.  Treatment allocation ratio will 
be 1:2 for the placebo: combined fostamatinib groups. 
A detailed statistical analysis plan will be developed as a separate document and will 
be finalized prior to database lock 
Interim Analysis of Results from 100 mg bid Cohort 
An interim analysis of safety data was conducted for a portion of the subjects in the 
100 mg bid cohort prior to proceeding with the 150 mg bid cohort.  
An interim analysis of safety and efficacy data was conducted for all data collected 
through Week 26/Follow-Up from the 100 mg bid cohort. Statistical methods for the 
interim safety and efficacy analysis were specified in the Statistical Analysis Plan. 


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2.0 
ABBREVIATIONS AND TERMS 
ACEi 
Angiotensin Converting Enzyme inhibitor 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Counts 
ARB 
Angiotensin II Receptor Blocker 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
bid  
bis in die (twice daily) 
BP 
Blood pressure 
CBC 
Complete blood counts 
CFR 
United States Code of Federal Regulations 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
CLCR 
Creatinine Clearance 
CRO 
Contract Research Organization 
CYP 
Cytochrome P450 
DSUR 
Development Safety Update Report 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FcR 
Fc receptor 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
H 
Hour 
HEENT 
Head, eye, ear, nose, and throat 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IgAN 
Immunoglobulin A Nephropathy 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 


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IV 
Intravenous 
IVIg 
Intravenous immunoglobulin 
IWRS 
Interactive web response system 
kg 
Kilogram 
L 
Liter 
LFT 
Liver function tests 
LOCF 
Last observation carried forward 
µg 
Microgram 
µL 
Microliter 
µM 
Micromolar 
MDRD 
Modification of Diet in Renal Disease 
mg 
Milligram 
OATP 
Organic anion transporting peptide 
PD  
Pharmacodynamic 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PO 
per os (by mouth) 
PP 
Per protocol 
qd 
quaque die (once daily) 
R406 
Rigel compound R940406 
R788 
Rigel compound R935788 (fostamatinib) 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
sPCR 
Spot urine protein/creatinine ratio 
SRC 
Safety Review Committee 
Syk 
Spleen tyrosine kinase 
T½ 
Half life 
Tmax 
Time of maximum plasma concentration 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 
WHO 
World Health Organization 
X ULN 
Multiple of upper limit of normal 


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3.0 
INTRODUCTION 
3.1 
Background 
Rigel Pharmaceuticals, Inc. (Rigel) is developing fostamatinib (R788) for the treatment of IgA 
nephropathy (IgAN).  Fostamatinib is a prodrug that is rapidly converted in vivo to R940406 
(R406), a potent, relatively selective Syk inhibitor.  For the past 5 years, Rigel and AstraZeneca 
focused their clinical investigation efforts with fostamatinib on a large program in rheumatoid 
arthritis (RA), comprising over 3,000 patient-years of treatment.  The results of those studies 
showed that fostamatinib was effective in reducing the signs and symptoms of RA, improving 
functional outcome in RA, but ineffective in slowing bone destruction and joint erosion.  As a 
consequence of not demonstrating radiographic improvement, AstraZeneca decided to cease 
development in RA and return the drug to Rigel.  Based upon the extensive clinical experience, 
the safety profile of R788 is very well understood in RA.  The most common side effects are 
diarrhoea and related gastrointestinal (GI) disturbances, and elevated blood pressure, which 
usually responds to conventional anti-hypertensive therapies.  Refer to the Investigator’s 
Brochure for descriptions of the safety reports from these studies.  
Immunoglobulin A nephropathy (IgAN) is the most common form of primary 
glomerulonephritis in developed countries and a major cause of end-stage kidney disease.  The 
natural course of IgAN is variable and ranges from asymptomatic microscopic haematuria to 
progressive kidney failure culminating in the need for dialysis and kidney transplantation.  A 
higher risk of loss of kidney function is associated with persistent proteinuria (> 1 gram/day), 
sustained hypertension (> 140/90 mm Hg), impaired glomerular filtration rate (GFR), and 
histologic lesions based on glomerular, vascular, tubular and interstitial features as defined by 
the pathological classification.  
The defining hallmark of IgAN is the deposition of IgA in the glomerular mesangium.  The 
deposited IgA is exclusively of the IgA1 subclass and it is deficient in its galactose modification.  
In IgAN patients, excess amounts in the serum of this abnormal poorly-galactosylated IgA1 
appear to be the trigger for the production of glycan-specific IgG and IgA autoantibodies.  These 
autoantibodies lead to the formation of circulating immune complexes containing IgA1 that 
accumulate in the glomeruli and activate mesangial cells to produce and release a variety of 
mediators that include angiotensin II, aldosterone, proinflammatory and profibrotic cytokines 
and growth factors.  Over a prolonged period of time, the unrelenting action of these mediators 
cause renal injury resulting in hypertension, proteinuria, haematuria and reduced renal function. 
Currently, therapeutic options for IgAN are limited.  The sole recommendation by the 2012 
Kidney Disease: Improving Global Outcomes (KDIGO) guidelines is for the use of renin-
angiotensin blocking agents to control blood pressure and reduce proteinuria.  For the significant 
fraction of patients that fail to lower the proteinuria target to < 0.5-1 g/day despite maximal 
amounts of ACEi or ARB, treatment modalities including glucocorticoids and 
immunosuppressive agents are limited by side effects or inconclusive efficacy. 


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FcγR receptor signaling in monocytes, macrophages, and dendritic cells plays an important role 
in the initiation and propagation of antibody-mediated inflammatory responses.  The activating 
FcγR receptor complexes have a signaling subunit, referred to as the FcRγ chain, whose 
phosphorylation subsequent to receptor activation results in the recruitment and activation of the 
Syk kinase.  Syk kinase is an important component of the signaling system of activating Fc 
receptors and the B-cell receptor, ultimately culminating in the production and release of 
mediators of the inflammatory response.  Positive immunostaining for both “total” Syk and for 
“activated” phosphorylated-Syk in the glomeruli of kidney biopsies from IgAN patients suggest 
the involvement of Syk in the pathogenesis of IgAN.  R406, the active ingredient of 
fostamatinib, is a potent inhibitor of Syk activity and therefore has the potential to ameliorate 
renal injury induced by autoantibody-containing immune complexes. 
3.2 
Rationale for Development of Fostamatinib for IgAN 
In several rodent models of antibody-mediated glomerulonephritis, inhibition of Syk by 
treatment with fostamatinib or its active metabolite R406 can both prevent renal injury and 
reverse established renal pathology.  These models include Wistar-Kyoto rats in which nephritis 
was induced either by the intravenous injection of nephrotoxic serum (1) or immunizing with the 
recombinant rat protein non-collagenous domain of the α3 chain of type IV collagen, a model of 
Goodpasture’s (2); and in 2 inbred mouse strains that spontaneously develop glomerulonephritis: 
NZB/NZW F1 (3) and MRL/lpr. (4) In both of the murine strains, fostamatinib treatment reduced 
proteinuria, azotemia, kidney pathology (including glomerular crescents, mesangial proliferation, 
and interstitial fibrosis), and prolonged survival. 
Moreover, the effect of R406 on the activation by IgA1 of primary human mesangial cells 
(HMC) was investigated. (5) IgA1 purified from IgAN patients, but not IgA1 from healthy 
subjects, significantly stimulated HMC to produce the mRNA and protein of the mediator 
chemokine monocyte chemotactic protein-1 (MCP-1).  This production was inhibited by R406 in 
a dose-dependent manner.  R406 treatment also reduced the IgA1-induced production from 
primary HMC of other multiple cytokines and chemokines tested (IL-6, IL-8, IP-10, RANTES 
and PDGF-BB).  Similarly, R406 inhibited the proliferation of HMC stimulated with heat-
aggregated IgA1 purified from IgAN patients.  Corresponding effects were obtained using Syk 
mRNA knockdown with small interfering RNA.  Together, the results suggest that R406 blocks 
the action of pathogenic IgA1 on human mesangial cells by inhibiting the signaling controlled by 
Syk. 
3.3 
Fostamatinib Safety and Pharmacokinetics 
3.3.1 
Single Ascending Dose Safety and Pharmacokinetics 
R406 appeared rapidly in the systemic circulation after fostamatinib dosing, with median Tmax 
ranging between 1 and 3 hours.  Negligible levels of R788 were found in plasma.  The terminal 
half-life of R406 ranged from 12 to 19 hours.  Increasing the doses of fostamatinib tablets from 
100 to 300 mg resulted in approximately dose-proportional increases in R406 exposure. 
The geometric mean absolute bioavailability of R406 was estimated to be 54.6% (90% CI 42.5 to 
70.3%) in a bioavailability study in which 10 healthy volunteers were given a single oral dose of 


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150 mg fostamatinib and a 100 mcg IV dose of radiolabeled R406.  Following the IV dose of 
R406 the volume of distribution at steady state (Vss) was determined to be 256 L and total 
clearance (CL) of R406 was determined to be 15.7 L/h.  
In healthy Japanese subjects, mean AUC and Cmax were approximately dose-proportional 
between 50 and 200 mg single-doses.  Following single-dose administration of fostamatinib 
150 mg, higher Cmax (~45% higher) and AUC (~27% higher) values were observed in Japanese 
subjects compared with white subjects (of European ethnicity), however, exposure in Japanese 
generally tended to be comparable to other studies in which white subjects were enrolled. 
3.3.2 
Multiple-dose Pharmacokinetics 
A 2- to 2.5-fold increase in R406 exposure (AUC) was seen at 160 mg bid, when Day 7 exposure 
was compared with Day 1.  At 250 mg bid, a 3.3-fold increase in R406 AUC was observed on 
Days 7 and 20 over Day 1.  The higher than unity accumulation ratio is, to a large extent, due to 
bid dosing for a compound with a relatively long half-life.  A 3-fold increase in dose (from 100 
to 300 mg bid) resulted in approximately 4-fold increase in steady-state exposure.  Platelet 
aggregation studies were performed in the single and multiple dose PK studies; no effect on 
collagen or ADP-induced platelet aggregation at the highest doses tested were observed. 
In Japanese healthy subjects, steady-state AUC and Cmax were approximately dose-proportional 
between subjects administered 50 mg and 100 mg twice daily, and more than dose-proportional 
between 100 mg and 200 mg twice daily based on comparison of data across Japanese and 
Western studies.  R406 exposure was similar in Western and Japanese subjects with considerable 
overlap in exposure between groups. 
3.3.3 
Metabolism 
R406 was found to undergo both oxidation and direct glucuronidation in humans.  No unique 
metabolite was found in humans and there were no major circulating metabolites (> 10% of 
R406) in plasma.  Renal elimination of parent drug was ~20%. 
3.3.4 
Renal Impairment Population 
The conclusion from a 24 subject, single dose PK study with fostamatinib conducted in subjects 
with either moderate impairment in renal function (CLCR ≥ 30 to < 50 mL/min), end-stage renal 
disease (ESRD) requiring dialysis, or normal renal function (CLCR ≥ 80 mL/min), was that renal 
impairment did not affect the PK of R406 to an extent that would be considered clinically 
relevant.  Compared to subjects with normal renal function, R406 AUC was lower for moderate 
renal impairment (RI) and ESRD groups, with geometric least squares mean (glsmean) ratios of 
78.36% and 73.83%, respectively.  However, unbound AUC was similar between groups.  Cmax 
was lower for the moderate RI and ESRD groups, with glsmean ratios of 57.74% and 61.94%, 
respectively.  Geometric mean t1/2 was similar across groups and ranged from 19.6-23.8 hours.  
There were no statistically significant relationships between R406 PK and CLCR.  Renal 
clearance of R406 was negligible for all groups, with < 0.1% of the administered dose recovered 
in urine as unchanged R406.  The amount of R406 N-glucuronide recovered in urine decreased 
with decreasing renal function, at 14.7 mg, 7.56 mg, and 0.518 mg for normal, moderate, and 
ESRD groups, respectively.  Exposure was lower when fostamatinib was administered after 


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completion of a dialysis session compared to administration 2 hours before the start of dialysis.  
The amount of R406 cleared by dialysis, 0.216 mg (< 1% of the dose) was negligible. 
3.3.5 
Drug-Drug Interactions 
3.3.5.1 
Effect of Other Drugs on R406 Exposure 
• A strong CYP3A4 inhibitor, ketoconazole, produced ~2-fold increase in exposure to 
R406, while a moderate inhibitor, verapamil, caused ~1.4-fold increase in R406 
exposure.  The magnitude of these interactions suggests that fostamatinib is not a 
sensitive CYP3A4 substrate and that there are alternate in vivo pathways of R406 
metabolism in humans. 
• A strong inducer of multiple CYP enzymes, rifampicin, decreased exposure to R406 to 
about 25% of that observed when fostamatinib is administered alone. 
• Ranitidine, which increases gastric pH, did not have a clinically relevant effect on the PK 
of R406. 
• Single dose of rosuvastatin and simvastatin did not have a clinically relevant effect on the 
PK of R406.   
3.3.5.2 
Effect of Fostamatinib on Exposure of Other Drugs 
• Co-administration of fostamatinib increased mean exposure to both rosuvastatin (by 
2.0-fold for AUC and 1.9-fold for Cmax) and simvastatin acid (by 1.7-fold for AUC and 
1.8-fold for Cmax). [preliminary data] R406 and R788 are substrates for and/or inhibitors 
of transporters (P-gp and BCRP), cytochrome P450 (CYP3A4) and other enzymes 
(UGT1A1).  R406 is a weak inhibitor of OATP1B1 in vitro; however, it is predicted as 
unlikely to have relevant effects in vivo.  Adverse findings in a mouse transgenic model 
suggested the possibility of an interaction between R406 and rosuvastatin resulting in 
increased plasma and liver rosuvastatin levels in an animal model sensitive to 
rosuvastatin.  An analysis of serious adverse events in the clinical safety data base from 
the completed and ongoing fostamatinib Phase 2 - 3 clinical studies was conducted, 
focusing on patients concomitantly using a statin, including rosuvastatin.  The analysis 
included data from 3,048 patients in the long-term extension studies in RA, as well as 
from the Phase 2 oncology program (studies in B- or T-cell lymphoma, diffuse large 
B-cell lymphoma, solid tumours and immune thrombocytopenia) up to 19 April 2012.  In 
total, 389 patients were on a statin, (41 on rosuvastatin) while participating in a study.  
The analysis of SAEs did not reveal a new or emerging signal, nor did liver function 
differ from that observed in the general patient population.  There is no evidence to date 
to suggest that there is a difference in the safety risk for patients on a statin. 
• Digoxin geometric mean AUCss and Cmax,ss increased by 37% and 70%, respectively, 
when co-administered with fostamatinib.  This increase in exposure is likely due to 
R788’s inhibition of intestinal P-gp, resulting in an increase in the oral bioavailability of 
digoxin.  Therefore, it is recommended that the subject’s blood digoxin level be 
monitored throughout the treatment period. 


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• The effect of fostamatinib on midazolam, a selective CYP3A4 substrate sensitive to 
interaction with CYP3A4 inhibitors, suggests that fostamatinib is a weak CYP3A4 
inhibitor and clinically important interactions between fostamatinib and CYP3A4 
substrates are unlikely. 
• There appears to be an interaction between fostamatinib and ethinyl estradiol resulting in 
a modest increase in ethinyl estradiol exposure.  There does not appear to be an 
interaction between fostamatinib and levonorgestrel. 
• Fostamatinib did not affect the PK or PD of warfarin to a clinically relevant degree. 
• Fostamatinib did not have a clinically relevant effect on the primarily CYP2C8 mediated 
metabolism of pioglitazone and does not appear to induce CYP2C8 in vivo. 
3.3.5.3 
Food Effect 
A high-fat/calorie meal increased R406 AUC up to 23% with variable effects on Cmax depending 
upon the formulation studied (-39% to +15%).  This modest food effect is not considered 
clinically important. 
3.4 
Efficacy 
No efficacy trials have been conducted in patients with IgAN. 
3.5 
Safety 
Phase 2 and 3 studies of fostamatinib have been conducted in several indications including ITP, 
RA and B- and T-cell lymphomas.  Doses of fostamatinib have ranged from 50 to 250 mg PO 
bid, depending on the indication being treated.  The majority of patients have been treated at 
doses ranging from 50-150 mg PO bid. 
The overall pattern of adverse effects of fostamatinib in these various clinical settings (patients 
with RA, severely ill patients with lymphoma and advanced solid tumours, chronically ill 
patients with ITP, and in healthy subjects), has been consistent, and includes dose-dependent 
effects on BP, neutrophil counts, dizziness, GI complaints and liver function test abnormalities, 
all of which are reversible and manageable with appropriate safety monitoring.  The ITP patients 
(on no anti-metabolites or chemotherapy) have not manifested neutropenia, despite receiving 
higher doses of fostamatinib than the RA patients.  The lymphoma patients have experienced 
more cytopenias, and infections, consistent with their extensive pre-treatment and underlying 
disease.  In patients with solid tumours, the overall pattern of reported AEs was consistent with a 
population of heavily pretreated, relapsed patients with solid tumours of varying histologies. 
3.5.1 
Blood Pressure Elevation 
Blood pressure elevation, a well described adverse effect of treatment with fostamatinib, may 
reflect off-target inhibition of vascular endothelial growth factor receptor-2 (VEGFR-2). 
In RA clinical trials, increases in blood pressure (mean ~2-4 mmHg) generally occurred early 
and were responsive to anti-hypertensive treatment.  Patients with a history of hypertension 


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appeared to be at greater risk of developing an increase in blood pressure and experienced higher 
mean increases (~5-9 mmHg).  A few patients have experienced severe elevated blood pressure 
(≥ 180 systolic and ≥ 110 diastolic).  In these studies the blood pressure effect has been reduced 
or eliminated over time by timely and effective anti-hypertensive treatment. 
3.5.2 
Liver Function Test Abnormalities 
Mild to moderate increases in liver enzymes (ALT and AST) have been observed in 
fostamatinib-treated patients.  A very small number of patients have experienced elevations 
> 10 x ULN.  LFT abnormalities can occur at any time during the course of treatment.  Mild 
increases in total and indirect bilirubin have also been observed in some fostamatinib treated 
patients and it has been determined that R406, the primary metabolite of fostamatinib, inhibits 
the enzyme UGT1A1 at fairly low concentrations (500 nM, concentrations regularly achieved 
clinically).  While this effect is clinically innocuous, it requires consideration when interpreting 
liver function test results. 
A total of 5 patients across the fostamatinib program have met the criteria for potential drug-
induced liver injury but have not met the formal Hy’s law criteria.  Two patients had alternative 
explanations for the abnormalities, one did not have simultaneous elevation of bilirubin and 
transaminases, and two patients had the UGT1A1*28 polymorphism upon genotyping. 
3.5.3 
Neutropenia 
Dose-dependent decreases in neutrophil counts have been observed in the majority of studies 
with fostamatinib.  Transient neutropenia (typically resolving within 5 to 7 days of 
discontinuation of fostamatinib) has been observed in RA patients receiving fostamatinib at 
doses ranging from 50 to 150 mg bid.  Neutropenia was not observed to any significant degree in 
the Phase 2 and 3 ITP trials.  Dose reduction has generally resulted in resolution of the 
neutropenia and permitted patients to remain on study drug for prolonged periods.  To date there 
is no clear association between neutropenia and an increased risk of infection, and no evidence 
that treatment with fostamatinib increases the risk of opportunistic infection. 
3.5.4 
Gastrointestinal (GI) Effects 
GI adverse effects have been reported in patients receiving fostamatinib.  Diarrhoea is the most 
commonly reported and can generally be managed with loperamide and/or study drug 
interruption or dose reduction.  Abdominal pain and nausea have also been amongst the 
commonly reported AEs. 
There have been 12 SAE reports consistent with pancreatitis in the completed clinical trials.  
Factors confounding the ability to determine relationship to fostamatinib have included gall 
bladder disease, and other medications such as anti-hypertensives and NSAIDs.  All but 1 
episode resolved.  The 1 unresolved episode involved a subject who had dyslipidemia and was 
using NSAIDs and had a fatal outcome.  The relationship between fostamatinib and pancreatitis, 
if any, remains unclear. 


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3.5.5 
Rare Adverse Events 
As of the finalization date of this version of the protocol, 1 confirmed case of Posterior 
Reversible Encephalopathy Syndrome (PRES) and another case of a patient with malignant 
hypertension and seizures whose MRI showed subtle signs of PRES had been reported.  In 1 
patient, onset of the event was 5 days after stopping drug.  In the other patient, it was less than 1 
week after starting drug.  Both patients recovered.  In addition, a single SAE report for a 
suspected case of Toxic Epidermal Necrolysis (TEN) was received from the Phase 3 clinical trial 
program.  Symptoms began 18 days after stopping the drug; the patient had a complicated course 
and did not survive.  Concomitant medications prior to the start of the event included 
methotrexate, folic acid, diclofenac and deflazacort. 
3.5.6 
Safety Summary 
Fostamatinib has been extensively studied and a large safety database is available.  Fostamatinib 
is generally well tolerated when administered at doses of 100-150 mg bid, as planned in the 
current study.  The most common adverse effects observed with fostamatinib treatment include 
increased blood pressure, transaminase and bilirubin elevations, neutropenia, dizziness, and GI 
adverse effects such as diarrhoea, nausea, vomiting and abdominal pain.  For additional 
information on the safety of fostamatinib, see the Investigator’s Brochure. 


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4.0 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
• To assess the efficacy of fostamatinib administered orally for 24 weeks to subjects with 
IgA nephropathy, as measured by change in renal function and histology.  
• To investigate the safety and tolerability of fostamatinib administered orally for 24 weeks 
to subjects with IgA nephropathy. 
4.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change from Baseline of proteinuria, as measured by 
sPCR at 24 weeks (Visit 9). 
4.3 
Secondary Efficacy Endpoints 
• Mean change from pre-treatment to post-treatment in mesangial hypercellularity on renal 
biopsies. 
• Percentage of subjects with ≥ 50% reduction in sPCR from Baseline (Visit 2) at Week 24 
(Visit 9). 
• Percentage of subjects with ≥ 30% reduction in proteinuria from Baseline (Visit 2) at 
24 weeks (Visit 9). 
• Mean change from pre-treatment to post-treatment in endocapillary hypercellularity on 
renal biopsies. 
• Mean change from pre-treatment to post-treatment in segmental sclerosis/adhesion on 
renal biopsies. 
• Mean change from pre-treatment to post-treatment in global glomerulosclerosis score on 
renal biopsies. 
• Mean change from pre-treatment to post-treatment in tubulointerstitial scarring on renal 
biopsies. 
• Mean change from pre-treatment to post-treatment in cellular/fibrocellular crescent score 
on renal biopsies. 
• Mean change from Baseline (Visit 2) of eGFR at 12 weeks (Visit 7). 
• Mean change from Baseline (Visit 2) of eGFR at 24 weeks (Visit 9). 
• Mean change from Baseline (Visit 2) of proteinuria at 12 weeks (Visit 7). 
• Percentage of subjects with sPCR < 50 mg/mmol at 12 weeks (Visit 7). 
• Shift in haematuria (dipstick test) from Baseline (Visit 2) at 12 weeks (Visit 7). 
• Shift in haematuria (dipstick test) from Baseline (Visit 2) at 24 weeks (Visit 9). 


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4.4 
Safety Endpoints 
The safety endpoints will assess the safety and tolerability of fostamatinib as assessed by the 
incidence of adverse events, clinical laboratory results (haematology, serum chemistry, and 
urinalysis), vital signs, and physical examinations.  Safety parameters of particular interest will 
include increases in blood pressure, adverse effects on liver function tests including transaminase 
elevations, diarrhoea, other GI symptoms and neutropenia. 
4.5 
Pharmacokinetic Endpoints 
The PK endpoint of this study will be a preliminary assessment of the kinetics of fostamatinib in 
subjects with IgAN.  Plasma concentrations of R406 will be summarized by visit using 
descriptive statistics including the number of subjects, arithmetic mean, standard deviation, 
geometric mean, median, minimum, maximum, and coefficient of variation for each treatment 
group. 
4.6 
Exploratory Histologic Endpoints 
Change from pre-treatment to post-treatment of macrophage subsets, Syk, Phospho-Syk, Smad 6, 
and Smad 7. 


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5.0 
STUDY DESIGN 
5.1 
Summary of Study Description 
This is a Phase 2, multi-center, randomised, double-blind, ascending-dose, placebo-controlled, 
proof-of-concept study to evaluate 2 dose regimens of fostamatinib in approximately 75 subjects.  
The study will consist of 11 visits over 28 to 43 weeks.  Subjects may be eligible for extended 
treatment with study drug as described in Section 7.11. 
For the purpose of this study, the term ‘subject’ will refer to patients with IgAN participating in 
this study. 
Subjects who meet all inclusion/exclusion criteria will be required to have completed at least 
90 days of treatment with either an ACEi or ARB at a maximum approved (or tolerated) dose, 
and to have had a pre-study renal biopsy no more than 180 days prior to the initial study visit.  
The renal biopsy will be reviewed by a member of the central panel of renal pathologists to 
ensure subjects meet histological entry criteria (complete scoring by the full panel will occur 
following randomisation).  
The enrollment plan for this study has been to randomise subjects in an ascending dose fashion 
with review and approval of safety, tolerability and renal function findings by the Safety Review 
Committee prior to enrollment into Cohort 2 (see Section 5.5).  Once randomisation of the initial 
cohort of approximately 38 subjects (25 randomised to fostamatinib 100 mg bid, 13 to placebo) 
was complete, screening began for the second cohort of approximately 37 subjects (25 
randomised to fostamatinib 150 mg bid, 12 to placebo).  Subjects will be randomised 2:1 in each 
cohort so as to maintain 1:1:1 allocation for all 3 double-blind dosing groups (25 subjects per 
group: Table 1).  Subjects will be stratified among the 3 treatment groups by presence or absence 
of endocapillary hypercellularity, as determined by a member of the central panel of renal 
pathologists on the most recent pre-study renal biopsy obtained prior to randomisation (see 
Figure 1). 
During the 24-week double-blind treatment period, subjects should remain on the same dose of 
ACEi or ARB during the treatment period (Visits 2-9).  Subjects will be monitored by routine 
safety assessments (vital signs, haematology, serum chemistries, urinalyses, and AE 
assessments) and for renal function (sPCR, urine dipstick test for haematuria and eGFR using the 
MDRD equation).  At the end of the treatment period, subjects will be encouraged to have a 
renal biopsy. 
 
 


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Figure 1: 
Study Design 
After Visit 9 has been completed, subjects may be eligible for extended treatment with study 
drug (see Section 7.11). 
5.2 
Rationale for Proposed Dosing 
Biomarker data from early studies of R940406 (R406), the active moiety of fostamatinib 
disodium, demonstrated that the EC50 for its pharmacodynamic effects on the Syk pathway was 
496 ± 42.2 ng/mL (~1.06 μM), roughly equivalent to a daily AUC of ~ 12,000 ng•h/mL.  
In Phase 2 and 3 trials of fostamatinib in RA, multiple dose levels including 50 mg PO bid, 
100 mg PO bid and 150 mg PO qd or bid were studied.  Doses ranging from 100 mg to 150 mg 
PO bid were effective in ameliorating the signs and symptoms of RA, while 50 mg PO bid was 
not effective.  The average R406 exposure at 100 mg PO bid ranged from 4,400 to 
7,020 ng•h/mL per dose interval, with daily exposures ranging from 8,800 to 14,000 ng•h/mL.  
These exposures are consistent with the levels needed to affect the Syk pathway, as defined in 
the biomarker assays described above, and support the 100 mg PO bid starting dose for this 
study. 


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5.3 
Study Treatment 
After qualifying during the screening period of the study, the initial cohort of subjects will be 
randomised in a 2:1 ratio to either fostamatinib 100 mg PO bid (see Table 1) or matching 
placebo.  Screening may then begin at the next cohort in which subjects will be randomised in a 
2:1 ratio to either fostamatinib 150 mg PO bid (see Table 1) or matching placebo. 
Table 1: 
Double-Blind Treatment 
Treatment Group 
Number of Subjects 
Dose  
A 
25 
Fostamatinib 100 mg bid  
B 
25 
Fostamatinib 150 mg bid 
C 
25 
Placebo bid 
 
5.3.1 
Randomisation 
An Interactive Web Response System (IWRS) will be used to randomise subjects to 1 of 
2 groups in each cohort.  The IWRS will assign a blister pack number of study drug to each 
subject who is eligible for the double-blind treatment period of the study.  Subjects will be 
stratified at randomisation by the presence or absence of endocapillary hypercellularity on pre-
study renal biopsy.  An individual subject can only be randomised once for the entire study.  
5.4 
Safety Monitoring  
The Rigel Medical Monitor and representatives will monitor the safety of study drug on an 
ongoing basis by assessing reported adverse events, vital signs, clinical laboratory values 
(haematology, serum chemistry, and urinalysis), and physical exams.  In addition, subjects will 
be monitored for renal function (sPCR, and eGFR).  Safety parameters of particular interest will 
include increases in blood pressure, adverse effects on liver function tests including transaminase 
elevations, diarrhoea, other GI symptoms and neutropenia. 
5.5 
Safety Review Committee 
An independent Safety Review Committee (SRC) will monitor safety throughout the study. 
In addition, the SRC, including one member who has IgAN expertise, evaluated the safety, 
tolerability and renal function findings prior to making a decision to proceed with dosing of 
Cohort 2 (150 mg bid or placebo). 
5.6 
Administrative Structure 
This trial is sponsored by Rigel.  Approximately 75 subjects will be randomised at 25 sites in 8 
countries in Europe, Asia, and North America.   


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A clinical research organization (CRO) will be responsible for project management and team 
training, site activation, site monitoring and management, data management, biometrics, 
randomisation code assignment, and writing and preparation of the final clinical study report.  
An additional CRO will be responsible for electronic trial master file preparation and 
maintenance.  A financial services vendor will be used for clinical site contract negotiation and 
site payments, and collection of financial disclosure information.  A safety CRO will be 
responsible for safety database set-up, data entry and maintenance, coding of SAE data and SAE 
case processing and preparation of expedited safety reports. 
Data will be recorded in an electronic Case Report Form (eCRF) via an electronic data capture 
(EDC) system.  An IWRS will be used for study drug inventory management and to randomise 
subjects to study drug.  The central panel of renal pathologists will review renal biopsies to 
ensure subject eligibility, determine stratification (presence or absence of endocapillary 
hypercellularity) and evaluate endpoints with histologic criteria.  A central laboratory will be 
used for testing haematology, serum chemistry, urinalysis, and serum pregnancy and will store 
PK samples.  A bioanalytical laboratory will be used for testing pharmacokinetic (PK) samples.  


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6.0 
SUBJECT SELECTION 
6.1 
Inclusion Criteria 
1. Signed informed consent prior to any study specific screening procedures.   
2. Male or female between 18 to 70 years of age (Note: minimum age is 20 years in Taiwan and 
21 years in Singapore). 
3. Females must be either post-menopausal for at least 1 year, surgically sterile, or, if of 
childbearing potential, must not be pregnant or lactating.  If sexually active, she must agree 
to use a highly effective method of birth control throughout the duration of the trial and for 
30 days following the last dose.  
4. A pre-study renal biopsy obtained within 180 days prior to the initial study visit (Visit 1a) 
will be reviewed by a member of the central panel of renal pathologists to ensure subjects 
meet the following histologic entry criteria: 
• Consistent with IgAN 
• Mesangial hypercellularity score of > 0.5 (M1) and/or presence of endocapillary 
hypercellularity (E1) on renal biopsy (using the Oxford Classification)  
Note: Subjects may be included with prior written permission from the Rigel Medical 
Monitor if the renal biopsy is graded M0 E0 but shows mesangial hypercellularity 
with a score of ≤ 0.5 or if there are less than 8 evaluable glomeruli on the submitted 
pre-study renal biopsy. 
• ≤ 50% of cortical area involved by tubular atrophy or interstitial fibrosis (T0 or T1) 
• < 50% glomerular crescents 
Note: biopsies obtained greater than 180 days prior to Visit 1a may be permitted with 
prior written permission from the Rigel Medical Monitor if, according to the Investigator, 
there has been no clinically significant change in renal status. 
5. Treatment with an ACEi and/or an ARB for at least 90 days at a maximum approved (or 
tolerated) dose prior to Screening (Visit 1b).  Subjects should remain on the same dose of 
ACEi or ARB during the treatment period (Visits 2-9).   
6. Proteinuria > 1 gm/day, sPCR > 100 mg/mmol (> 884 mg/g), or Spot Albumin/Creatinine 
Ratio > 70 mg/mmol at diagnosis of IgAN or at any time prior to screening. 
7. Proteinuria > 0.50 gm/day [(sPCR > 50 mg/mmol (> 442 mg/g)] at Screening (Visit 1b). For 
USA only: proteinuria > 1 gm/day [sPCR > 100 mg/mmol(> 884 mg/g)] at Screening (Visit 
1b) for Cohort 2 (150 mg bid or placebo).  


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8. Blood pressure controlled to ≤ 130/80 with angiotensin blockade with or without other anti-
hypertensive agents.  Subjects should be taking a maximum approved (or tolerated) dose of 
an ACEi or ARB before an additional anti-hypertensive agent is added.  If additional anti-
hypertensive therapy is required, other agents (beta- blockers, calcium channel blockers, or 
diuretics) may be added.  Patients may be reassessed if BP < 140/90, but > 130/80. 
9. Otherwise in stable health as determined by the Investigator based on medical history and 
laboratory tests during the screening period.  See Exclusion Criteria for specific exclusions. 
10. In the Investigator’s opinion, has the ability to understand the nature of the study and any 
hazards of participation, and to communicate satisfactorily with the Investigator. 
6.2 
Exclusion Criteria 
1. History of or active, clinically significant, respiratory, gastrointestinal (including 
pancreatitis), hepatic, neurological, psychiatric, musculoskeletal, genitourinary, 
dermatological, or other disorder that, in the Investigator's opinion, could affect the conduct 
of the study or the absorption, metabolism or excretion of the study drug.  
2. Have had any major cardiovascular event within the 180 days prior to randomisation, 
including but not limited to: myocardial infarction, unstable angina, cerebrovascular 
accident, pulmonary embolism, or New York Heart Association Class III or IV heart failure. 
3. Diagnosis or history suggestive of Henoch-Schonlein purpura. 
4. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (using the MDRD 
equation) at the time of Screening (Visit 1b). 
Note: Values as low 25 mL/min/1.73 m2 may be permitted with prior written permission from 
the Rigel Medical Monitor if, according to the Investigator, there has been no clinically 
significant recent change in renal status. 
5.  A 50% decrease in eGFR from most recent pre-study clinic visit to Visit 1b.  
6. An absolute neutrophil count of < 1,500/µL, Hgb < 9 g/dL, ALT or AST of > 1.5x ULN, 
total bilirubin > 2.0 mg/dL at Visit 1b.  The Investigator may reassess these laboratory 
abnormalities within 30 days after Screening (Visit 1b). 
7. Acute gastrointestinal symptoms (eg, nausea, vomiting, diarrhoea) at Baseline (Visit 2).  The 
subject may be reassessed after full recovery from the acute gastrointestinal illness. 
8. Active bacterial or parasitic infections, including tuberculosis. 
9. Serologic results suggestive of active hepatitis B or hepatitis C (subjects may be included if 
confirmed hepatitis C recombinant immunoblot assay negative or hepatitis C virus RNA 
negative [qualitative]), or subjects with suspected human immunodeficiency virus (HIV). 


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10.  Use within 6 months prior to pre-study renal biopsy of cyclophosphamide, mycophenolate 
mofetil, azathioprine, or Rituximab (or other anti-B cell therapies).  Those subjects who had 
been treated with an anti- B cell therapy must have a normal CD19 count by Visit 1b. 
11. Use of > 15 mg/day prednisone (or other corticosteroid equivalent).  For those subjects 
taking corticosteroids for renal indication, the daily dose should not change from Baseline 
(Visit 2) to the end of the study drug treatment (Visit 9). 
12. Prior or current use of cyclosporine or tacrolimus. 
13. Have a clinically significant infection, or who are known to have an active inflammatory 
process (other than IgAN) at the time of Screening (Visit 1b) or Baseline (Visit 2).  The 
subject may be reassessed after recovery from an acute infection. 
14. Currently enrolled in an investigational drug or device study or have used an investigational 
drug or device within 30 days or 5 half-lives (whichever is longer) of Screening (Visit 1a). 
15. Are unable or unwilling to follow instructions, including participation in all study 
assessments and visits. 
16. Have a history of alcohol or substance abuse that, in the judgment of the Investigator, may 
impair or risk the subject's full participation in the study. 
17. Have a condition or be in a situation that the Investigator feels may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject’s participation in the study. 
18. Have a known allergy and/or sensitivity to the study drug or its excipients. 


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7.0 
STUDY PROCEDURES 
The study procedures to be performed at each visit are shown in Table 2 and Table 3. 


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Table 2: 
Schedule of Study Procedures—Main Study (Visits 1 through 10) 
Study Procedure 
Screening 
Double-Blinded Treatment Period 
Follow-Up 
Visit 1a 
Visit 1b 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9/ 
Withdraw 
Visit 10 
Up to 120 
days prior 
to Baseline 
Up to 30 
days prior 
to Baseline 
Day 1 
(Baseline) 
Week 1 
(±3 days) 
Week 2 
(±3 days) 
Week 4 
(±3 days) 
Week 8 
(±4 days) 
Week 12 
(±4 days) 
Week 18 
(±7 days) 
Week 24 
(±7 days) 
Week 26 
(±3 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
 
X 
 
 
 
 
 
 
 
 
 
Medical History1 
 
X 
X 
 
 
 
 
 
 
 
 
Submit pre-study renal biopsy 
to central path for assessment2 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam3 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
 
X 
X 
 
 
 
 
 
 
 
 
Vital Signs4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Serum Chemistry6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Plasma Pharmacokinetics  
 
 
 
X 
 
X 
 
X 
X 
 
 
Serum Pregnancy7 
 
X 
X 
 
 
 
 
 
 
 
 
Urine for Pregnancy7 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Urine for sPCR 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum IgA 
 
 
X 
 
 
 
 
X 
 
X 
 
Renal biopsy  
 
 
 
 
 
 
 
 
 
X11 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Evaluation9 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Study Drug 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
1 Medical History at Screening (Visit 1b) includes documentation of date of initial IgAN diagnosis, documentation of most recent renal biopsy, concomitant medications, documentation of angiotensin blockade 
treatment, prior medications for treatment of IgAN, and any other relevant medical condition. 
2 Histologic eligibility must be confirmed using the most recent biopsy obtained within 180 days prior to the initial study visit (Visit 1a) before performing any additional study specific screening procedures. 
3 Physical Examination includes HEENT, cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and neurological systems.  Baseline (Visit 2) will also include a measurement of height and weight. 
4 Vital Signs include blood pressure and heart rate measured as noted in Section 7.5.4. 
5 Haematology includes red blood cell count (RBC), white blood cell count (WBC), hemoglobin, hematocrit, WBC differential count (neutrophils, lymphocytes, eosinophils and basophils), MCHC, MCH, MCV, 
MPV, RDW, and platelet count. 
6 Serum Chemistry includes Na, K, Cl, CO2, Ca, P, BUN, creatinine, globulin, glucose, ALT, AST, LDH, alkaline phosphatase, total bilirubin, direct bilirubin, indirect bilirubin, total protein and albumin.  
7 Females of childbearing potential only.  Females who are either post-menopausal for at least 1 year or surgically sterile (documented by medical record) do not need to take pregnancy tests. In Austria only, at-
home urine pregnancy testing will be completed at Week 15 and Week 21, as described in Section 7.5.6. 
8  Urinalysis includes appearance, glucose, ketones, blood, protein, nitrite, bilirubin, specific gravity, pH, urobilinogen, and leucocyte esterase.  If positive for blood or protein trace, microscopy will be included. 
9 SAEs will be followed to resolution or stabilization unless the subject is lost to follow-up.   
10 Haematology, serum chemistry and urinalysis only performed at Week 26 (Visit 10) if there are clinically significant abnormalities identified at Week 24 (Visit 9). 
11 Visit 9 renal biopsy should be collected within 14 days of Visit 9, and is not required to be collected during this visit itself; Visit 9 biopsy will not be required for subjects that withdraw early. 


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Table 3: 
Schedule of Study Procedures—Extended Treatment 
Study Procedure 
Every 12 weeks  
(± 2 weeks)  
until study results available 
Dose Modification Visits 
Following transition of subject 
to 150 mg fostamatinib bid 1 
2, 4, and 8 weeks from dose modification 
Informed Consent 
X2 
 
Inclusion/Exclusion 
X2 
 
Blood Pressure 
X 
X 
Haematology3 
X 
X 
Serum Chemistry4, 5 
X 
X 
Urine for Pregnancy6 
X 
X 
Urinalysis5,7 
X 
X 
Urine for sPCR5 
X 
X 
Concomitant Medications 
X 
X 
Adverse Event Evaluation8 
X 
X 
Study Drug Accountability 
X 
X 
Dispense Study Drug9 
X 
 
1  If a subject transitions to 150 mg fostamatinib bid during the extended treatment period as defined in Section 7.11, visits will occur at 2, 4, and 8 weeks from the 
dose modification to confirm safety of the new treatment regimen. Starting 12 weeks after dose modification, the standard 12-week visit interval will resume.  
2   Prior to initiation of extended treatment, eligibility will be confirmed and eligible subjects will sign an informed consent addendum (see Section 7.11).   
3 Haematology includes red blood cell count (RBC), white blood cell count (WBC), hemoglobin, hematocrit, WBC differential count (neutrophils, lymphocytes, 
eosinophils and basophils), MCHC, MCH, MCV, MPV, RDW, and platelet count. 
4 Serum Chemistry includes Na, K, Cl, CO2, Ca, P, BUN, creatinine, globulin, glucose, ALT, AST, LDH, alkaline phosphatase, total bilirubin, direct bilirubin, 
indirect bilirubin, total protein and albumin.  
5 Local (ie, standard care) proteinuria, serum creatinine, AST, ALT, bilirubin (total, direct, and indirect), alkaline phosphatase, and haematuria values may be 
collected in during the extended treatment period as defined in Section 7.11. 
6 Females of childbearing potential only. At-home urine pregnancy testing will be completed monthly, as described in Section 7.5.6. Females who are either 
post-menopausal for at least 1 year or surgically sterile (documented by medical record) do not need to take pregnancy tests.  
7  Urinalysis includes appearance, glucose, ketones, blood, protein, nitrite, bilirubin, specific gravity, pH, urobilinogen, and leucocyte esterase.  If positive for blood 
or protein trace, microscopy will be included. 
8 SAEs will be followed to resolution or stabilization unless the subject is lost to follow-up. 
9  At dose modification visits, no new Study Drug will be dispensed; material from the prior 12-week interval visit will be re-dispensed following accountability. 


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7.1 
Screening (Visits 1a and 1b) 
Subjects must sign and date an Independent Ethics Committee/Institutional Review Board- 
(IEC/IRB) approved informed consent form (ICF) prior to participating in any study-specific 
screening procedure activities.   
Screening evaluations will be used to determine the eligibility of each subject for study 
enrollment.  Subjects who fail to meet eligibility criteria may be re-screened once if there is a 
reasonable expectation that the subject will be eligible after the repeat screen.  Before a subject 
can be re-screened, approval must be obtained from the Medical Monitor.  All screen and 
re-screen failures will be recorded in a Patient Screening Log.  Any reasons for exclusion from 
the study will be documented.  
7.1.1 
Screening Visit 1a 
After informed consent has been obtained (within 120 days prior to Baseline Visit 2), the most 
recent pre-study renal biopsy will be submitted to the central panel of renal pathologists to 
ensure subjects meet all histologic screening criteria and to determine stratification (presence or 
absence of endocapillary hypercellularity).  The biopsy must be within 180 days prior to the 
initial study visit (Visit 1a).  The site will be notified by the renal pathologists whether a subject 
meets histologic eligibility. 
7.1.2 
Screening Visit 1b 
After histologic eligibility is confirmed and subject has received a minimum of 90 days of 
angiotensin blockade, the following will be obtained within 30 days prior to Baseline (Visit 2): 
• Demographic information 
• Medical history 
• Concomitant medications 
• Physical examination 
• Vital signs 
• Serum pregnancy test (for females of childbearing potential) 
• Haematology 
• Serum chemistry  
• Urinalysis  
• Urine for sPCR 
• Evaluation of eligibility based on Inclusion/Exclusion criteria 


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7.2 
Treatment Period Visits 2-9 
7.2.1 
Baseline/First Dose (Visit 2) 
Baseline/First Dose (Visit 2) will occur within 30 days after Screening (Visit 1b).   
To be eligible for randomisation into the study, subjects must continue to meet all 
inclusion/exclusion criteria.  Females of childbearing potential must have a negative serum 
pregnancy test at Screening (Visit 1b) and Baseline (Visit 2).  Administration of study drug need 
not await results of the Baseline (Visit 2) labs including the serum pregnancy test.  A urine 
pregnancy will be obtained at Baseline (Visit 2) prior to randomisation to ensure female subjects 
of childbearing potential are not pregnant. 
The following assessments will be completed prior to study drug administration: 
• Interim medical history  
• Concomitant medications 
• Physical examination including height and weight 
• Vital signs  
• Haematology 
• Serum chemistry 
• Serum IgA 
• Urinalysis 
• Urine for sPCR 
The first dose of study drug should be administered in the clinic to ensure that the subject 
understands dosing instructions.  For all subjects, this dose will be considered the evening dose 
for this day no matter what time it is administered.  Study staff will instruct the subject to take 
the study drug bid beginning the following morning. 
7.2.2 
Treatment Visits 3-9 
All visits subsequent to the baseline visit are determined by the date of the baseline visit and 
should occur within the visit windows specified in Table 2.  Over the course of the 24 week 
treatment period, subjects will be expected to visit the clinic 8 times (including Baseline 
[Visit 2]).  Safety assessments and renal function tests will be performed at each visit to evaluate 
the safety and efficacy of fostamatinib/placebo, and to determine if a dose adjustment is required.  
At Week 24 (Visit 9), a percutaneous renal biopsy will be performed and submitted to the central 
panel of renal pathologists for assessment.  This end of treatment biopsy should be collected 
within 14 days of Visit 9, but is not required to be collected during the visit in which the rest of 
the Visit 9 procedures are performed.  Subjects who withdraw from the study prior to Week 24 
will, at discontinuation, have a withdrawal visit equivalent to the Week 24 (Visit 9) assessments 
(see Section 7.9), with the exception that the post-treatment biopsy will not be required. 


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In Austria only, at home urine pregnancy testing will be performed in Weeks 15 and 21 (see 
Section 7.5.6).  
7.3 
Study Follow-Up (Visit 10) 
Subjects will be instructed to return to the clinic 2 weeks following the last dose of study drug 
for Follow-up Study assessments.  Haematology, serum chemistry and/or urinalysis are to be 
performed only if there are clinically significant abnormalities identified in the corresponding 
panel at Week 24 (Visit 9).  If an SAE is present at the last visit, follow-up should occur as 
indicated in Section 9.2.1. 
7.4 
Dose Adjustments Due to Adverse Events 
Clinical testing to date has revealed adverse events that may require temporary interruption of 
the study drug and/or a reduction in study drug dose.  Modification of study drug administration 
may be required under the following circumstances:  
• Increases in ALT, AST, or bilirubin (refer to Appendix 1 for guidance regarding 
LFT-related dose adjustments). 
• ANC < 1000/mm3 or 1.0 x 109/L (refer to Appendix 2 for guidance regarding 
management of neutropenia).   
• Severe diarrhoea (refer to Appendix 3 for guidance regarding diarrhoea-related dose 
adjustments). (6)  
• Hypertension uncontrolled by oral antihypertensive medications (refer to Appendix 4 for 
guidance regarding hypertension-related dose adjustments). 
• Other severe or life-threatening adverse events considered related to study drug 
administration. 
Subjects who have their dose reduced will not have their dose increased for the remainder of the 
study.  When dose interruption or reduction is required, subjects and study staff will remain 
blinded to the original treatment allocation; however, subjects and study staff will be aware of 
the switch to a reduced dose level. 
Subjects for whom dose reduction results in a once daily dose of fostamatinib or matching 
placebo will take the daily study drug dose in the morning.  Table 4 details the strategy for dose 
adjustment in subjects who experience AEs requiring dose reduction. 


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Table 4: 
Dose Adjustment 
Starting Dose 
Dose Level 
-1 
Dose Level 
-2 
Dose Level 
-3a  
Dose Level 
-4a 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd 
Discontinue 
------- 
150 mg PO bid 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd 
Discontinue 
a 
The Sponsor’s Medical Monitor should be consulted prior to consideration of dose modification to 
levels -3 or -4. 
7.4.1 
Non-Diarrhoea Gastrointestinal Toxicity 
Nausea, vomiting and abdominal pain have been reported in association with fostamatinib 
treatment.  Symptomatic treatment (eg, omeprazole or ranitidine for gastric distress) should be 
initiated promptly.  In the event of significant upper abdominal pain/distress, consideration 
should be given to the possibility of pancreatitis, and serum amylase and lipase should be 
monitored. 
7.5 
Definition of Study Procedures 
7.5.1 
Medical History 
Medical/surgical history will be taken at Screening and Baseline (Visits 1b and 2) and will 
include documentation of the date of initial IgAN diagnosis, documentation of most recent renal 
biopsy, concomitant medications, documentation of angiotensin blockade treatment, prior 
medications for treatment of IgAN and any other relevant medical condition.  Any new relevant 
medical conditions between Screening and Baseline (Visits 1b and 2) will be documented as 
medical history. 
7.5.2 
Histologic Assessment of Renal Biopsies 
Confirmation of the histologic eligibility from the most recent pre-study renal biopsy will be 
reviewed by a member of the panel of central nephropathologists using the Oxford classification 
of IgAN (and as defined in inclusion criterion 4). (7) In addition, the central nephropathologists 
will determine the degree of mesangial hypercellularity and absence or presence of endocapillary 
hypercellularity (the latter for stratification purposes).  Biopsy slides will be prepared for 
shipment according to instruction in the Study Reference Manual and will be provided by sites to 
the central pathology panel with local pathology reports (with subject personal identifiers 
redacted).  Biopsies will be analyzed as described below. 
7.5.2.1 
Assessment of Biopsies 
The following data will be determined by the central pathology panel for each biopsy collected 
from a randomised subject: 
• Total number of glomeruli (a minimum of 8) 
• Number of glomeruli with global sclerosis 


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• Number of glomeruli with segmental sclerosis 
For each glomerulus in the biopsy the following will be assessed (see Table 5): 
• Mesangial hypercellularity  
• Endocapillary hypercellularity (absent, segmental or global) 
• Presence of crescents (cellular/fibrocellular or fibrous) 
From the above assessments a MEST score will be calculated (see Table 5). 
Slides will be stained immunohistochemically for CD68 and the number of positive cells in each 
glomerulus will be recorded, and from this the mean number of CD68 cells/glomerulus will be 
derived. 
In addition, staining for Syk, Phospho-Syk, Smad 6, Smad 7 may be done. 
Table 5: 
Oxford Classification of Renal Biopsy Scoring 
Variable 
Definition 
Score 
Mesangial hypercellularity 
<4 Mesangial cells/mesangial area=0  
------------------------------------------------- 
4–5 Mesangial cells/mesangial area=1  
6–7 Mesangial cells/mesangial area=2 
≥ 8 Mesangial cells/mesangial area=3 
------------------------------------------------- 
The mesangial hypercellularity score is the mean score 
for all glomeruli 
M0 
----- 
 
M1 
Segmental glomerulosclerosis 
Any amount of the tuft involved in sclerosis, but not 
involving the whole tuft 
or the presence of an adhesion 
S0-absent 
S1-present 
Endocapillary hypercellularity 
Hypercellularity due to increased number of cells 
within glomerular capillary lumina causing narrowing 
of the lumina 
E0-absent 
E1-present 
Tubular atrophy/interstitial 
fibrosis 
Percentage of cortical area involved by the tubular 
atrophy or interstitial fibrosis, whichever is greater 
T0-0-25% 
T1-26-50% 
T2->50% 
7.5.3 
Physical Exam 
A physical exam should include evaluation of the head, eye, ear, nose, and throat (HEENT), 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological 
systems.  Physical examinations will include height and weight at Baseline (Visit 2) only.  
Physical examinations will be performed as per the study schedule in Table 2.  Any new or 
worsened abnormalities should be recorded as medical history (prior to randomisation) or 
adverse events after randomisation (Baseline, Visit 2), if appropriate.  No rectal or pelvic 
examination is required. 


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7.5.4 
Vital Signs 
Vital signs (including blood pressure and heart rate) will be assessed at study visits 1b through 
10 and extended treatment period visits (blood pressure only).  All blood pressure (BP) 
determinations should be made using an electronic sphygmomanometer with the subject seated.  
To minimize the ‘white coat effect’, the subject should rest in a quiet room for at approximately 
10 minutes prior to taking the BP.  The blood pressure should be taken at least 3 times at 
approximately 5-10 minutes apart, and the lowest of the 3 measurements will be recorded. 
7.5.5 
Clinical Laboratories 
Laboratory samples will be obtained according to the schedule in Table 2.  The following tests 
are to be analyzed and collected for the study: 
• Haematology: red blood cell count (RBC); white blood cell count (WBC), hemoglobin, 
hematocrit, WBC differential count, (neutrophils, lymphocytes, eosinophils and 
basophils), MCHC, MCH, MCV, MPV, RDW, and platelet count. 
• Serum Chemistry: includes Na, K, Cl, bicarbonate (CO2), Ca, P, BUN, creatinine, 
globulin, glucose, LDH, AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin, 
indirect bilirubin, total protein, albumin.  
• Serum IgA 
• Urinalysis includes appearance, glucose, ketones, blood, protein, nitrite, bilirubin, 
specific gravity, pH, urobilinogen, and leucocyte esterase (leukocytes).  If positive for 
blood or protein trace, then include microscopy. 
• Spot urine for protein/creatinine ratio. 
Clinically significant abnormal findings identified during the screening period should be 
recorded on the medical history eCRF as a diagnosis rather than recording actual laboratory 
values. 
7.5.6 
Pregnancy Tests 
Serum pregnancy tests will be performed by the central laboratory for all female subjects of 
childbearing potential at the Screening and Baseline (Visits 1b and 2).  Subjects may be enrolled 
at Baseline (Visit 2) based on the urine pregnancy results.  Urine pregnancy tests (performed at 
the site) will be obtained at Baseline and Weeks 4, 8, 12, 15 (Austria only), 18, 21 (Austria only), 
24, and 26 (Visits 2, 5, 6, 7, 8, 9, and 10), and at each extended treatment period visit (see 
Section 7.11).  During the extended treatment period (and, in Austria only, at Weeks 15 and 21 
of the main study), female subjects of childbearing potential will also be provided with urine 
pregnancy test supplies to perform monthly self-testing between study visits, as permitted. 
Subjects who have a confirmed positive pregnancy test at any time during the study will be 
discontinued from the study and will be followed for safety (see Section 9.3). 


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7.6 
Concomitant Therapies 
Concomitant therapies will be recorded in the eCRF at Visits 1b through 10 and extended 
treatment period visits. 
7.6.1 
Required Medications: Angiotensin Blockade 
Subjects should be taking a maximum tolerated approved dose of an ACEi or ARB before an 
additional anti-hypertensive agent is added.  Subjects should remain on the same dose of ACEi 
or ARB during the dosing period (Visits 2-9).  If additional anti-hypertensive therapy is required, 
other agents (beta-blockers, calcium channel blockers, or diuretics) should be added. 
7.6.2 
Restricted IgA Nephropathy Medications 
Use of prednisone (or equivalent corticosteroids) is restricted to no more than 15 mg/day, and 
dosage should not change from Baseline (Visit 2) to the end of the study drug treatment (Visit 9). 
Mycophenylate mofetil, azathioprine, cyclophosphamide, cyclosporine, tacrolimus and 
Rituximab or other anti-B cell therapies are excluded during the course of this study. 
7.6.3 
Restricted Medications Unrelated to IgA Nephropathy 
Due to the potential for drug-drug interactions with fostamatinib, specific treatments are either 
not allowed or are restricted during the course of this study (see Appendix 5). 
7.7 
Pharmacokinetics Samples 
Blood samples for PK analysis will be drawn during the visits specified in Table 2.  Date and 
time of last dose will be recorded.  Samples will be shipped to and stored at the central 
laboratory during the course of the study.  Samples will then be transferred to and analyzed at the 
corresponding bioanalytical laboratory. 
After completion of the study, samples may be stored for an additional 5 years for future 
metabolite identification and/or further evaluation of the bio-analytical method.  This data will be 
used for internal exploratory purposes and will not be included in the clinical report.  All samples 
will be destroyed after analysis or expiration of the 5 year time period. 
7.8 
Calculation of Blood Draws 
The maximum amount of blood that will be collected during study Visits 1b through 10 for 
safety and PK assessments is shown in Table 6. 
For subjects that qualify for the extended treatment period, approximately 7 mL of blood will be 
collected every 12 weeks (and at 2, 4, and 8 weeks after a one-time dose modification that may 
occur as defined in Section 7.11.1) for serum chemistry and haematology testing at the central 
laboratory.  


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Table 6: 
Number and Volume of Blood Samples and Total Blood Volume Collected 
per Subject (Screening through Follow-Up, and Extended Treatment Period) 
Assessment 
Maximum Number  
of Samples 
Volume of Blood  
per Sample (mL) 
Total Volume  
of Blood (mL) 
Haematology  
10 a 
2 
20 
Serum chemistry  
10 a,b 
5 
50 
Serum pregnancy 
2 b 
 
 
Serum IgA 
3 b 
 
 
PK 
4 
4 
16 
Total volume of blood drawn from 
Screening through Follow-Up/ 
Week 26 (mL) 
 
 
86 
Extended treatment period visits 
(Haematology, Serum Chemistry) 
 
7 
7 mL per visit c 
a 
Haematology or serum chemistry are to be performed at Week 26 (Visit 10) only if there are clinically 
significant abnormalities identified at Week 24 (Visit 9).  
b 
Serum pregnancy (Visits 1b and 2) and serum IgA (Visits 1, 7, and 9) will be run from the serum chemistry 
sample.  
c 
Extended treatment period visits occur every 12 weeks, with the exception of visits at 2, 4, and 8 weeks 
following a one-time dose modification for selected subjects as defined in Section 7.11.1. Blood collected for 
standard care assessments during the extended treatment period is not included in this calculation. 
7.9 
Withdrawal from Study 
Subjects will be discontinued from the study in the following situations: 
• Subject decision.  A subject is free to withdraw consent and discontinue participation in 
the study at any time. 
• Adverse event based on Investigator judgment. 
• Subject is uncooperative or noncompliant and will not/cannot adhere to study 
responsibilities. 
• Subject was erroneously enrolled in the study. 
• Pregnancy in a female participant. 
• Subject lost to follow-up despite the diligent efforts of site personnel to trace subject. 
The reason for withdrawal must be noted on the eCRF. 


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Subjects who discontinue study drug will, at discontinuation, have a withdrawal visit equivalent 
to the Week 24 (Visit 9) assessments (post-treatment kidney biopsy will not be required).  The 
reason for withdrawal must be noted on the eCRF.  If an SAE is present at the withdrawal visit or 
at the subject's last participation in the study, the SAE should be followed as described in 
Section 9.2.1. 
7.10 
Study Completion and Early Termination 
The study will end upon completion of all protocol procedures and achievement of study 
objectives.  Rigel may terminate the study at any time.  Conditions that may warrant early 
termination of the study include, but are not limited to, discovery of an unacceptable risk to 
subjects enrolled in the study or the decision by Rigel to suspend or discontinue development of 
the study drug.  If the Investigator becomes aware of any circumstances during the study that 
may reasonably indicate that the study should be terminated, the Investigator will immediately 
notify Rigel and will cooperate with Rigel in the investigation and evaluation of such 
circumstances and any decision of Rigel that may follow. 
Conditions that may warrant termination of the study at a site include, but are not limited to: 
• Failure of the Investigator to comply with pertinent laws or regulations. 
• Submission of false data or material information by the investigational site to Rigel. 
• Failure by the investigational site to adhere to protocol requirements. 
7.11 
Post-Trial Access to Fostamatinib 
Prior to the completion of this study (ie, before the clinical database is locked and unblinded, and 
top line efficacy results are available), subjects who have had at least a 40% decrease in 
proteinuria at Visit 9 from Baseline (or a significant improvement in post-treatment biopsy score, 
in the judgment of the Rigel Medical Monitor) and have tolerated study drug may be permitted to 
continue to receive study drug until the results of this study are known.   
Following discussion of the extended treatment period activities, eligible subjects will sign an 
appendix to the informed consent.  Treatment will continue for those subjects until this study is 
completed with the same double-blinded treatment administered during Visits 2 through 9 
(including any dose reductions).  Study drug will be dispensed every 12 weeks during the 
extended treatment period, provided subjects have no study drug-limiting toxicity and continue 
to receive clinical benefit in the opinion of the Investigator. 
During the extended treatment period, haematology, serum chemistry, urinalysis, and sPCR will 
be analyzed at the central laboratory at every visit. For visits conducted prior to implementation 
of central laboratory testing in the extended treatment period, locally analyzed proteinuria, serum 
creatinine, AST, ALT, bilirubin (total, direct, and indirect) and alkaline phosphatase values 
collected closest to each extended treatment period visit will be recorded in the eCRF, if 
available (See Table 3 for Schedule of Procedures—Extended Treatment).  
Females of childbearing potential will be provided with urine pregnancy test kits to self-
administer monthly between visits as permitted, and will be tested at the site every 12 weeks 


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during extended treatment dispense visits, with results documented in the eCRF and monitored 
by the Sponsor.   
Drug accountability (including any reasons for dose adjustment), concomitant medications, 
blood pressure, and information about any AE or pregnancy that occurs will be recorded in the 
eCRF.  All other information regarding extended treatment with study drug will be recorded in 
each subject’s chart according to local clinical practice.  
If safety or tolerability issues are identified during the extended treatment period, the Investigator 
will follow the dose adjustment procedures as described in Section 7.4.  
7.11.1 
Dose Modification During Extended Treatment Period  
If the sPCR of a subject increases during the extended treatment period to more than 50% greater 
than the Week 24 value across 2 evaluations at least 2 weeks apart (whether analyzed at the local 
or central laboratory), the subject may undergo a dose modification to 150 mg fostamatinib bid 
(whether previously receiving placebo, 100 mg fostamatinib bid, or 150 mg fostamatinib bid) if 
in the Investigator’s judgment the subject has not experienced safety or tolerability issues related 
to study drug. The subject’s original treatment during the 24-week main study and extended 
treatment period will remain double-blind until the end of the study.   
Additional safety visits will occur at 2, 4, and 8 weeks from dose modification to 150 mg 
fostamatinib bid (procedures to be performed are identical to other extended treatment period 
visits before the subject resumes the standard 12-week visit interval at 12 weeks from the point 
of dose modification.  
If a subject does not qualify for or is unwilling to undergo dose modification despite meeting the 
above criteria, the subject will be withdrawn from the study. In addition, if a subject undergoes 
dose modification and, after at least 8 weeks of treatment following dose modification, has 2 or 
more sPCR assessments that are more than 50% greater than the Week 24 value, the subject will 
be withdrawn. No withdrawal visit will be performed, but AE follow-up will occur as specified 
in Section 9.2.1.  


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8.0 
STUDY DRUG 
8.1 
Study Drug Description 
Fostamatinib and matching placebo are supplied as orange film coated tablets in 2 dosage 
strengths:  100 mg and 150 mg. 
Study drug will be labeled in accordance with Good Manufacturing Practice (GMP), local 
regulatory requirements and all other applicable laws and regulations. 
8.1.1 
100 mg Tablets 
Fostamatinib 100 mg tablets are supplied as orange film coated, plain, round, biconvex tablets 
with a diameter of 9 mm.  Each tablet has a total weight of 346 mg and contains 100 mg of 
fostamatinib and the following inert excipients: mannitol, sodium hydrogen carbonate, sodium 
starch glycolate, povidone, magnesium sterate, hypromellose, titanium dioxide, macrogol 400, 
ferric oxide (yellow) and ferric oxide (red). 
Matching placebo tablets containing microcrystalline cellulose and sodium stearyl fumarate are 
supplied. 
8.1.2 
150 mg Tablets 
Fostamatinib 150 mg tablets are supplied as orange film coated, plain, oval, biconvex tablets 
measuring 7.25 mm x 14.5 mm.  Each tablet has a total weight of 520 mg and contains 150 mg 
of fostamatinib and the following inert excipients:  mannitol, sodium hydrogen carbonate, 
sodium starch glycolate, povidone, magnesium sterate, hypromellose, titanium dioxide, macrogol 
400, ferric oxide (yellow) and ferric oxide (red). 
Matching placebo tablets containing microcrystalline cellulose and sodium stearyl fumarate are 
supplied. 
8.2 
Storage 
Supplies of fostamatinib active and placebo tablets will be stored at the study sites in a secure 
location with restricted access and controlled room temperature (below 30°C) with temperature 
monitoring. 
8.3 
How Supplied/Study Drug Dispensation 
Fostamatinib and matching placebo tablets are packaged into blister packs.  Each blister pack 
will contain 34 tablets for 14 days of dosing (1 morning dose and 1 evening dose) plus 3 
additional days.  The appropriate number of blister packs will be assigned by the IWRS for a 
treatment period at each visit.   
Drug will be dispensed as follows:  
• At Baseline (Visit 2), 1 blister pack will be dispensed and subjects will be instructed to 
bring the blister pack containing unused study drug back to the clinic at Week 1 (Visit 3).  


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• At Week 1 (Visit 3), following accountability, the blister pack of study drug dispensed at 
Baseline (Visit 2) will be re-dispensed to cover dosing until Week 2 (Visit 4). 
• At Week 2 (Visit 4), following accountability, 1 new blister pack will be dispensed to 
cover dosing until Week 4 (Visit 5). 
• At Weeks 4 and 8 (Visits 5 and 6), following accountability, 2 blister packs will be 
dispensed.  
• At Weeks 12 and 18 (Visits 7 and 8), following accountability, 3 blister packs will be 
dispensed. 
• During the extended treatment period (for visits at 12 week intervals), following 
accountability, 6 packs will be dispensed. At Dose Modification Visits (see Section 7.11 
and Table 3) blister packs will be re-dispensed following accountability.  
Subjects will be instructed to return their blister pack(s) at each visit for drug accountability 
purposes. 
8.4 
Study Drug Administration 
For bid dosing, subjects will self-administer 1 tablet twice daily by mouth: once in the morning 
and once in the evening.  Morning and evening doses should be at least 8 hours apart and should 
be taken at approximately the same time each day.   
For qd dosing, subjects will self-administer 1 tablet daily by mouth in the morning. 
Tablets may be taken with or without food.  Tablets should not be taken with grapefruit juice or 
other known CYP3A4 inhibitors (refer to Appendix 5).  In the event of gastric upset, it may be 
useful to take tablets with food. 
8.5 
Unblinding 
In the event of a medical emergency, when management of a subject’s condition requires 
knowledge of the study drug, the subject’s treatment may be unblinded to disclose the identity of 
the study drug dispensed.  Investigators seeking to unblind the subject’s treatment assignment 
will contact the Rigel Medical Monitor, who will utilize the IWRS if unblinding is considered 
warranted by the Investigator.  The IWRS will record the reason for unblinding, the name of the 
user account that performed the unblinding, and the date and time of the unblinding on the 
unblinding confirmation.  The Investigator must thoroughly document the circumstances 
surrounding the unblinding in the subject’s medical record and in the eCRF.   
Where direct Investigator-initiated unblinding access to the IWRS is required by the Competent 
Authority, the Rigel Medical Monitor must be notified of any unblinding, ideally prior to 
initiating the unblinding process but no later than 24 hours after the decision to unblind. 
8.6 
Study Drug Accountability/Drug Compliance 
The Investigator will be responsible for monitoring the receipt, storage, dispensation, and 
accountability of all study drug according to accepted medical and pharmaceutical practice.  All 


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documentation of study drug shipments must be retained by the site.  Accurate, original site 
records must be maintained of study drug inventory and dispensation.  All records must be made 
available to the Sponsor (or designee) and appropriate regulatory agencies upon request.  


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9.0 
ADVERSE EVENTS 
9.1 
Definitions 
Adverse Event (AE): An AE is any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug. 
For the purposes of this clinical study, AEs include only treatment emergent events which are 
either new or represent detectable exacerbations of pre-existing conditions. (8, 9) 
AEs may include, but are not limited to: 
• Subjective or objective symptoms spontaneously offered by the subject and/or identified 
by the Investigator or study staff including laboratory abnormalities of clinical 
significance. 
• Any AEs experienced by the subject through the completion of final study procedures. 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the target disease that were 
not present before the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as venipuncture). 
The following are NOT considered an AE: 
• Pre-Existing Condition: A pre-existing condition (documented on the medical history 
eCRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
• Pre-Planned Hospitalization: A hospitalization planned prior to signing the ICF is not 
considered an SAE but rather a therapeutic intervention.  However, if during the pre-
planned hospitalization an event occurs which prolongs the hospitalization or meets any 
other SAE criteria, the event will be considered an SAE.  Surgeries or interventions that 
were under consideration but not performed prior to enrollment in the study will not be 
considered serious if they are performed after enrollment in the study for a condition that 
has not changed from its baseline level.  Hospitalizations for social reasons or due to long 
travel distances are also not considered SAEs. 
• Diagnostic Testing and Procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
Serious Adverse Event (SAE): 
Note: The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the 
grade of an AE (see below).  “Serious” is a regulatory definition. 


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A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose: 
• Results in death. 
• Is life-threatening.  (With regards to determining if an AE is serious, “life-threatening” is 
defined as an AE in which the subject was at risk of death at the time of the event.  It 
does not refer to an event which hypothetically might have caused death if it were more 
severe.  If either the Investigator or the Sponsor believes that an AE meets the definition 
of life threatening, it will be considered life-threatening). 
• Requires in-patient hospitalization or prolongation of an existing hospitalization. 
• Results in persistent or significant disability/incapacity (eg, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in deciding whether other situations, such 
as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, should also be considered serious (examples of 
such events are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias, or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse).  Given that the Investigator’s perspective may be informed by 
having actually observed the event and Rigel is likely to have broader knowledge of the study 
drug and its effects to inform its evaluation of the significance of the event, if either Rigel or the 
Investigator believes that the event is serious, the event will be considered serious. 
Suspected Adverse Reaction: 
Any AE for which there is a “reasonable possibility” that the study drug caused the AE will be 
regarded as a Suspected Adverse Reaction by Rigel. 
“Reasonable Possibility,” for the purposes of safety reporting, means there is evidence to suggest 
a causal relationship between the study drug and the AE.  Examples of types of evidence that 
would suggest a causal relationship between the study drug and the AE are: 
• A single occurrence of an event that is uncommon and known to be strongly associated 
with study drug exposure (eg, angioedema, blood dyscrasias, rhabdomyolysis, hepatic 
injury, anaphylaxis, and Stevens-Johnson syndrome). 
• One or more occurrences of an event that is not commonly associated with study drug 
exposure but is otherwise uncommon in the population exposed to the study drug (eg, 
include tendon rupture or heart valve lesions in young adults or intussusception in healthy 
infants).  If the event occurs in association with other factors strongly suggesting 
causation (eg, strong temporal association, event recurs on rechallenge), a single case 
may be sufficiently persuasive; but often, more than 1 occurrence (from 1 or multiple 
studies) would be needed before the Sponsor could make a determination of whether the 
study drug caused the event. 


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• An aggregate analysis of specific events that can be anticipated to occur in the study 
population independent of study drug exposure.  Such events include known 
consequences of the underlying disease or condition under investigation (eg, symptoms, 
disease progression) or events unlikely to be related to the underlying disease or 
condition under investigation but commonly occur in the study population independent of 
drug therapy (eg, cardiovascular events in an elderly population).  An aggregate analysis 
(across studies) will identify those events that occur more frequently in the study drug 
treatment group than in a concurrent or historical control group. 
This definition of suspected adverse reaction and the application of the reasonable possibility 
causality standard is considered to be consistent with the concepts and discussion about causality 
in the ICH E2A guidance. 
Unexpected: An AE that is not listed in the Investigator’s Brochure or is not listed at the 
specificity or severity that has been observed.  For example, hepatic necrosis would be 
“unexpected” (by virtue of greater severity) if the Investigator’s Brochure referred only to 
elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator’s Brochure 
listed only cerebral vascular accidents.  “Unexpected” also refers to AEs that are mentioned in 
the Investigator’s Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the study drug but are not specifically mentioned as occurring 
with the study drug under investigation. 
Causality: The Investigator is to assess the causal relation (eg, whether there is a reasonable 
possibility that the study drug caused the event) using the following definitions: 
• Probable: A reaction: that follows a reasonable temporal sequence from administration 
of the investigational study drug or its class of drugs; that follows a known or expected 
response pattern to the suspected investigational study drug; and that could not be 
reasonably explained by the known characteristics of that subject’s clinical state or the 
background rate for the event in the population being studied. 
• Possible: A reaction that follows a reasonable temporal sequence from administration 
and/or that follows a known or expected response pattern to the suspected investigational 
study drug, but that could readily have been produced by a number of other factors. 
• Unlikely: A reaction that does not follow a reasonable temporal sequence from 
administration or there is a reasonably compelling alternative explanation, however, 
causation by the investigational study drug cannot be ruled out. 
Assessment of Severity 
The following grading system should be used to assess severity: 
• Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities. 
• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject and which may interfere with daily activities but are usually 
ameliorated by simple therapeutic measures. 


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• Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment. 
9.2 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
The Investigator is responsible for ensuring that all AEs (including SAEs) that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the eCRF.  All SAEs 
also must be reported on the SAE Report Form (see Section 9.2.3 for further information). 
9.2.1 
Adverse Event Reporting Period 
The AE reporting period begins with the first dose of study drug and ends with the final study 
(follow-up) visit.  AEs that occur between the time of consent and first dose of study drug will be 
reported as Medical History. 
If an SAE is present at the follow-up visit (Week 26, Visit 10) or final visit for subjects receiving 
extended treatment as described in Section 7.11.1, it should be followed to resolution or 
stabilization unless the subject is lost to follow-up.  Resolution means the subject has returned to 
baseline state of health or the Investigator does not expect any further improvement or worsening 
of the event. 
In case of ongoing SAEs at the moment of database closure, the data obtained at the moment of 
database closure will be used in the statistical analysis.  The follow-up of the SAE will be 
documented in the source documents and will be described in the final report or as an addendum, 
as appropriate. 
9.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points 
during the study.  All AEs and SAEs, whether volunteered by the subject, discovered by study 
staff during questioning, or detected through PE, clinically significant laboratory test, or other 
means, will be recorded in the subject’s medical record and on the AE eCRF and, when 
applicable, on an SAE form. 
Each recorded AE or SAE will be described by its duration (eg, start and end dates), severity, 
regulatory seriousness criteria, if applicable, suspected relationship to the investigational product 
(see guidance above), and any actions taken. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  The primary cause of death on the 
autopsy report should be the term reported.  Autopsy and postmortem reports must be forwarded 
to Rigel, or designee, as described below. 
If study drug is discontinued because of an SAE, this information must be included in the SAE 
report. 


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9.2.3 
Expedited Reporting Requirements for Serious Adverse Events 
An Investigator should report a SAE within 1 day (ie, immediately but no later than the end of 
the next business day) of his/her awareness of the event by completing and sending the provided 
SAE form to Rigel’s authorized safety representative.  [NOTE: In UK, SAEs must be reported 
within 24 hours.] 
Additionally, all fatal or life-threatening SAEs should be telephoned to Rigel as soon as the 
Investigator learns of the event. 
The SAE form should be sent to the following fax or email: 
Email: clinsafety@rigel.com 
Fax: see Study Reference Manual 
The site may contact the Medical Monitor (listed below) with questions regarding the reporting 
of SAEs. 
Daniel Magilavy, MD 
Medical Monitor 
Rigel Pharmaceuticals, Inc. 
Tel.: +1.650.624.1372 
Mobile: +1.603.770.7216 
Fax: +1.650.624.1282 
E-Mail: dmagilavy@rigel.com 
9.2.4 
Reporting of Serious Adverse Events by Sponsor 
Regulatory Authorities, IECs/IRBs, and Principal Investigators will be notified of SAEs in 
accordance with applicable requirements (eg, GCPs, ICH guidelines, national regulations, and 
local requirements).  The country-specific requirements, timelines, and processes for complying 
with these requirements are described in detail in the Study Operations Manual and/or Safety 
Plan. 
Rigel’s Safety Surveillance Committee will review and evaluate accumulating safety data from 
the entire clinical trial database for the study drug at appropriate intervals (eg, quarterly) to 
identify new safety signals or increased frequency of events.  This will include an aggregate 
review and comparison to the control group of SAEs that were deemed as “not suspected” as 
being associated with use of the study drug. 
9.3 
Pregnancy 
Although pregnancy itself is not regarded as an AE, the outcome of any pregnancy that occurs 
during the study must be documented. 
Prior to study enrollment, females of childbearing potential must agree in the ICF to take 
appropriate measures to avoid pregnancy at all times during the study, commencing from the 


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time of consent to 30 days after the last dose of study drug, and, if pregnancy occurs, they must 
agree to report the pregnancy and cooperate with the Investigator as set forth below. 
Should a pregnancy occur, the female study participant must immediately inform the Investigator 
and must immediately discontinue study drug.  The Investigator should counsel the study 
participant on any risks of continuing the pregnancy and any possible effects on the fetus in view 
of the subject’s participation in the study.  The study participant must agree to follow-up by the 
Investigator regarding the outcome of any pregnancy that occurs during the study.  Outcome is 
defined as elective termination of the pregnancy, miscarriage, or delivery of the fetus.  For 
pregnancies with an outcome of live birth, the newborn infant will be followed by the 
Investigator until it is 30 days old.  Any congenital anomaly/birth defect noted in the infant must 
be reported as an SAE. 
The Investigator will notify Rigel or its authorized representative of a pregnancy occurring in a 
female study participant within 14 days of first becoming aware of such pregnancy using the 
pregnancy notification form.  All follow-up information gathered by the Investigator shall be 
reported to the Sponsor within 14 days of Investigator’s first knowledge of such information 
using the pregnancy exposure form. 
 


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10.0 STATISTICAL METHODS 
10.1 
General Considerations 
The statistical analysis of the data obtained from this study will be performed using SAS® 
version 9.2 or higher.  All inferential tests will be 2-sided and will be performed using a type I 
error rate of 5%, unless otherwise indicated.  
A detailed statistical analysis plan will be developed as a separate document and will be finalized 
prior to database lock. 
10.2 
Analysis Populations 
The Intent-to-Treat (ITT) population will include all randomised subjects.  All efficacy endpoints 
will be analyzed based on the ITT population, and subjects will be analyzed according to their 
randomised treatment assignment.  The efficacy analyses based on the ITT population will be 
considered the primary efficacy analyses. 
The Per-Protocol (PP) population will include all subjects in the ITT population who had no 
major protocol violations.  Major protocol violations will include: 
• Not receiving any study treatment 
• Not receiving the correct study treatment 
• Not receiving sufficient treatment 
• Failing to meet eligibility criteria 
• Other major protocol violations, as determined by a blinded review of the data prior to 
database lock 
For analysis of the primary efficacy endpoint, the main analysis will be performed with baseline 
defined as the average between Visit 2 and the most recent screening value prior to Visit 2 (a 
secondary analysis, with the Visit 2 value alone as baseline, will be performed). For all other 
analyses, baseline measurements will be the last measurement for the corresponding variable 
prior to the first randomised dose at Visit 2.  
Safety and efficacy data from the extended treatment period will not be subjected to statistical 
analysis.  
10.3 
Analysis of Efficacy Endpoints 
The number of subjects who were screened, enrolled into the study and completed the study 
through Visit 9 will be summarized by treatment group using all enrolled subjects.  The reasons 
that treated subjects withdrew from the study will also be summarized.  Efficacy data from the 
extended treatment period will not be included in the statistical analysis. 
Subject demographic data (age, gender, race, ethnicity) will be summarized by treatment group 
using the Safety population, as will baseline characteristics of height and weight. 


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10.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change from Baseline (Visit 2) of proteinuria as 
measured by sPCR at 24 weeks (Visit 9).  This will be analyzed using an ANCOVA model in the 
ITT population.  The ANCOVA model will include both the treatment group and the 
presence/absence of endothelial hypercellularity at baseline as factors and will adjust for the 
proteinuria at baseline (as a covariate).  The urine protein-creatinine ratio will be log-transformed 
prior to analysis.  Missing Week 24 (Visit 9) data will be imputed using a multiple imputation 
procedure to be described in the SAP. 
10.3.2 
Secondary Efficacy Endpoints 
The safety population will include all randomised subjects who received at least 1 dose of the 
allocated study drug.  The safety population will be analyzed for all safety assessments.  The 
subjects will be analyzed as treated.   
Secondary efficacy endpoints related to proteinuria will measured by sPCR (as is the case for the 
primary efficacy endpoint). 
All secondary efficacy endpoints will be analyzed using both the ITT and PP populations.  
Additionally, the primary efficacy endpoint will be analyzed using the PP population as a 
sensitivity analysis.  No adjustments will be made for multiplicity. 
The following secondary endpoints will be analyzed using an ANCOVA model which includes 
the treatment group and presence/absence of endothelial hypercellularity at baseline as factors, 
with mean estimates of the variable adjusted for the baseline value: 
• Mean change from pre-treatment to post-treatment in mesangial hypercellularity on renal 
biopsies.  
• Mean change from pre-treatment to post-treatment in endocapillary hypercellularity on 
renal biopsies. 
• Mean change from pre-treatment to post-treatment in segmental sclerosis/adhesion on 
renal biopsies. 
• Mean change from pre-treatment to post-treatment in global glomerulosclerosis score on 
renal biopsies 
• Mean change from pre-treatment to post-treatment in tubulointerstitial scarring on renal 
biopsies. 
• Mean change from Baseline (Visit 2) of eGFR at 12 weeks (Visit 7). 
• Mean change from Baseline (Visit 2) of eGFR at 24 weeks (Visit 9). 
• Mean change from Baseline (Visit 2) of proteinuria at 12 weeks (Visit 7). 
• Shift in haematuria (dipstick test) from Baseline (Visit 2) at 12 weeks (Visit 7). 


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• Shift in haematuria (dipstick test) from Baseline (Visit 2) at 24 weeks (Visit 9). 
Estimates will be provided for the following contrasts: 1) combined fostamatinib group vs. 
placebo; 2); 150 mg fostamatinib group vs. placebo; and 3) 100 mg fostamatinib group vs. 
placebo. 
Fisher’s exact test will be used to assess whether the percentage of subjects who meet the 
following criteria differ between the pooled fostamatinib and placebo groups: 
• Have a ≥ 30% reduction in sPCR from Baseline (Visit 2) to Week 24 (Visit 9) 
• Have sPCR < 50mg/mmoL at Week 12 
The 95% CIs for the percentages will also be provided. 
Shift tables will display the change in category from Baseline (Visit 2) to Week 24 (Visit 9) for 
the following categorical parameters: 
• Presence/absence of segmental sclerosis/adhesion 
• Presence/absence of global glomerulosclerosis 
• Presence/absence of tubulointerstitial scarring 
Fisher’s exact test will assess whether there is an association between the change in these 
categories from Baseline (Visit 2) to Week 24 (Visit 9) and treatment group (ie, combined 
fostamatinib group vs. placebo). 
10.4 
Analysis of Safety 
All safety variables will be analyzed using the Safety population.  The safety population will 
include all randomised subjects who received at least 1 dose of the allocated study drug.  The 
safety population will be used for analysis of all safety assessments through Visit 10.  Safety data 
from the extended treatment period will not be included in the statistical analysis. 
The safety endpoints will assess the safety and tolerability of fostamatinib as assessed by the 
incidence of adverse events, clinical laboratory results (haematology, serum chemistry, and 
urinalysis), vital signs, and physical examinations.  Safety parameters of particular interest will 
include increases in blood pressure, adverse effects on liver function tests including transaminase 
elevations, diarrhoea, other GI symptoms and neutropenia. 
The safety outcomes of this study include the change from baseline in blood pressure, liver 
function, and absolute neutrophil count (ANC) and the incidence of GI complaints and 
infections, as well as the incidence of any adverse events. 
For each treatment group, descriptive statistics will be presented by visit for the actual values and 
the changes from baseline for systolic and diastolic blood pressure, each liver function test (ALT, 
AST, alkaline phosphatase, and bilirubin [total, direct, and indirect]), and ANC.  


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The difference between fostamatinib and placebo in the mean change from baseline will also be 
presented for each endpoint.  The numbers and percentages of subjects with GI complaints and 
infections at any time during the double-blind treatment period will be presented by treatment 
group for the Safety Population.  Fisher’s Exact Test will be used to test for a difference between 
fostamatinib and placebo in the proportions of subjects experiencing GI complaints and 
infections.  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with at least 1 adverse event, at least 1 serious adverse event 
(SAE), and at least 1 treatment related adverse event will be presented by treatment group.  AEs 
that are possibly or probably related to study treatment, or for which the relationship to study 
treatment is missing, will be considered treatment related.  AEs will be summarized at the 
subject level by MedDRA system organ class (SOC) and preferred term using frequencies and 
percentages.  AEs will also be tabulated at the event level by severity and by relationship to 
study treatment for each treatment group. 
10.5 
Analysis of Pharmacokinetic Endpoints 
Plasma concentrations of R406 will be summarized by visit using descriptive statistics including 
the number of subjects, arithmetic mean, standard deviation, geometric mean, median, minimum, 
maximum, and coefficient of variation for each treatment group. 
10.6 
Analysis of Exploratory Endpoints 
No inferential statistical analysis will be performed on the exploratory endpoints regarding 
change in histologic staining from pre-treatment to post-treatment renal biopsies (macrophage 
subsets, Syk, Phospho-Syk, Smad 6, Smad 7).  Only descriptive statistics will be used. 
10.7 
Determination of Sample Size 
A sample size of 25 evaluable subjects in each of the 3 treatment groups will have an 80% power 
to detect a 43% reduction in proteinuria from Baseline (Visit 2) to 24 weeks (Visit 9) between 
the pooled fostamatinib and placebo groups, using a 2-sided t-test with α = 0.05 and log-
transformed data.  This calculation assumes that the 3 treatment groups have the same mean and 
standard deviations of urinary protein/ creatinine ratio (130 mg/mmol ± 120 mg/mmol) at 
Baseline (Visit 2) and that the values for the placebo group remain constant over 24 weeks.  
Treatment allocation ratio will be 1:2 for the placebo: combined fostamatinib groups. 
10.8 
Handling of Dropouts and Missing Data 
For the primary endpoint analysis, missing Week 24 (Visit 9) values of sPCR will be imputed 
using a multiple imputation method to be specified in the SAP. 
Missing data for the secondary endpoints will not be imputed. 


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10.9 
Interim Analysis of Results from 100 mg bid Cohort 
An interim analysis of safety data was conducted for a portion of the subjects in the 100 mg bid 
cohort prior to proceeding to the 150 mg bid cohort.  
An interim analysis of safety and efficacy data was conducted for all data collected through 
Week 26/Follow-Up from the 100 mg bid cohort. Statistical methods for the interim safety and 
efficacy analysis were specified in the Statistical Analysis Plan. 
 
 
 


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11.0 ETHICAL AND LEGAL ISSUES 
This protocol was designed and will be conducted, recorded, and reported in compliance with 
applicable laws, rules, and regulations, including GCP.  The Investigator and study staff are 
responsible for conducting this study in accordance with ICH/GCP, and the Declaration of 
Helsinki, as well as all applicable national and international laws and regulations. 
11.1 
Confidentiality of Subject Personal Information 
Information on the confidential treatment of subject personal information collected in the study 
must be provided to each subject in the Informed Consent (see Section 11.5).  In addition, an 
authorisation for the collection, use, disclosure, and transfer of subject personal information (an 
“Authorisation”), in compliance with the applicable laws, rules, and regulations of the 
jurisdiction where the study is to be conducted, must be provided to each subject, either as part 
of the ICF or as a separate signed document. 
The Investigator will assign a unique identifier or code to each subject to be used in lieu of the 
subject’s name in study documentation and in reporting of AEs, for the purpose of ensuring the 
confidential treatment of the study participant’s personal and health information.  The 
Investigator will maintain in a secure location a master key to the subject identifier list consisting 
of the unique subject identifiers, subject names, and dates of birth, to allow unambiguous 
identification of each subject included in the study. 
Researchers, monitors, and auditors shall be required to strictly adhere to professional standards 
and applicable law concerning the confidential treatment of the subject information. 
11.2 
Independent Ethics Committee/Institutional Review Board 
The protocol, ICF, any advertisements to recruit subjects, and materials to be given to the 
subjects during the study, must be approved by an appropriate IEC/IRB.  IEC/IRB approval must 
also be obtained for any protocol amendments and ICF revisions before implementing the 
changes. 
The Investigator is responsible for providing the IEC/IRB with any required information before 
or during the study, such as SAE expedited reports or study progress reports. 
The IEC/IRB must comply with national and international regulations. 
Rigel will not initiate the first study drug shipment to the study site until the study site provides 
Rigel or its authorized representative with: 
1. A copy of the IEC/IRB (and Regulatory Authority, where applicable) letter that grants 
formal approval; and 
2. A copy of the IEC/IRB-approved ICF (and Regulatory Authority-approved ICF, where 
applicable). 


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11.3 
Changes to the Study 
Before any significant changes to the design of the study are made, a protocol amendment will 
be issued by Rigel that must be submitted to and approved by the IEC/IRB and signed by the 
Investigator.  No other change in the study procedures, except to protect the health, safety, or 
welfare of subjects in the study, is permitted or shall be effected without the mutual agreement of 
the Investigator and Rigel. 
11.4 
Protocol Deviations, Violations, Waivers and Exemptions 
A protocol deviation is defined as “a variation from processes or procedures defined in a 
protocol.” Deviations usually do not preclude the overall evaluability of subject data. 
However, if a protocol violation (defined as “a significant departure from the processes and 
procedures that were required by the protocol”) occurs, it may result in data that are not deemed 
evaluable for a protocol analysis and/or may require subject(s) to be discontinued. 
If a protocol violation has occurred, a protocol waiver must be approved by the Medical Monitor 
in order to allow the subject to continue in the study. 
A protocol exemption is defined as: 
• An allowance to enroll a specific subject into the study who has a conflict with a specific 
inclusion or exclusion criterion; or 
• An allowance to continue subject participation in a study when a departure from the study 
protocol is planned or expected.   
A protocol exemption must be approved by the Medical Monitor in advance of the protocol 
departure taking place. 
11.5 
Informed Consent 
The ICF and process for obtaining informed consent must comply with the applicable national 
and international laws, rules, and regulations.  The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate in the study and to comply with the instructions of the Investigator and 
study staff.  The Investigator/designee will fully explain, in terms understandable to the subject, 
the nature of the study, along with the aims, methods, anticipated benefits, potential risks, and 
any discomfort that participation in the study may entail.  The ICF must be signed and dated by 
the subject before the subject participates in any study-related activities.  The original and any 
amended signed and dated ICFs must be retained in the subject’s file at the study site, and a copy 
must be given to the subject at the time that it is signed by the subject.  The Investigator must 
also maintain a log of all informed consents obtained. 
The Investigator/study staff must provide Rigel or its authorized representative with the proposed 
ICF for Rigel’s review and comment prior to submitting the ICF to the IEC/IRB.  The study 
center and the Investigator will include Rigel’s proposed changes to the ICF prior to submitting 
the ICF to the IEC/IRB for review and approval. 


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11.6 
Liability, Insurance, and Financing 
If, during the study, a subject experiences an illness or potential study drug or study procedure 
side effect or other possible study-related injury, appropriate medical care will be provided by 
the Investigator/designee. 
Rigel Pharmaceuticals, Inc., the sponsor of the study, will provide reimbursement to the site for 
the cost of any medical treatment of any injury or illness caused by the study drug or the protocol 
procedures, except to the extent that any such injury or illness was caused by the negligence of 
the Investigator or study personnel, for example, their failure to follow the protocol, or the 
subject’s failure to follow the Investigator’s instructions. 
The ICF will include a description of this reimbursement policy, in addition to any provisions 
required by applicable national or international regulations.  Financial compensation for lost 
wages, disability, or discomfort due to the study drug or protocol procedures is not offered by the 
Sponsor. 
The Sponsor is insured against potential liabilities caused by the study drug and/or protocol 
procedures.  A confirmation or certificate of such insurance and essential information about 
insurance coverage will be provided by the Sponsor upon request. 
A separate written contract covering the obligations of the Sponsor and of the Institution and 
Investigator with regards to the study is required before the study drug may be delivered to the 
study site. 
For all Rigel clinical studies, each Investigator and Subinvestigator will provide a signed 
Financial Disclosure Form.  Each Investigator will notify Rigel or its authorized representative of 
any relevant changes to the information included on such Financial Disclosure Form during the 
conduct of the study and for 1 year after the study has been completed. 


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12.0 DATA COLLECTION, RETENTION, AND MONITORING 
12.1 
Source Data 
12.1.1 
Source Documentation Requirements 
The Investigator/study staff must maintain adequate and accurate paper and/or electronic source 
documentation to enable the subsequent verification of study data.  Source documentation for 
this study may include, but not be limited to, original documents such as ICFs, subject 
questionnaires, laboratory reports, hospital and/or clinic or office records documenting subject 
visits, and treatments or procedures pertaining to SAEs.  Entry of data into the eCRFs will 
comply with all applicable regulatory requirements to ensure the reliability, quality, integrity, 
and traceability of the electronic source data.   
12.2 
Electronic Case Report Forms 
Electronic Case Report Forms (eCRFs) will be used to collect the clinical study data.  The 
eCRFs will be entered by study staff and must be completed for each screened subject with all 
required study data accurately recorded. 
The eCRF exists within an EDC system with controlled access managed by Rigel or its 
authorized representatives for this study.  Study staff will be appropriately trained in the use of 
eCRFs and application of electronic signatures before the start of the study and prior to being 
given access to the EDC system.  Original data and any changes of data will be recorded using 
the EDC system, with all changes tracked by the system and recorded in an electronic audit trail.  
The Investigator will attest that the information contained in the eCRFs is true by providing 
electronic signature within the EDC system prior to database lock.  After database lock, the 
Investigator will receive a copy of the subject data (eg, CD-ROM, or other appropriate media) 
for archiving at the study site. 
At all times, the Investigator has final responsibility for the accuracy and authenticity of all 
clinical data. 
12.3 
Monitoring 
This study will be monitored by Rigel or its authorized representative in accordance with current 
GCP.  The study monitor(s) is responsible for monitoring whether the study is conducted 
according to applicable Rigel or its authorized representative standard operating procedures 
(SOPs), the protocol, and other written instructions and regulatory guidelines.  Training will be 
provided for key investigative personnel in all aspects of study conduct. 
In order to ensure the data are accurate, complete, and verifiable, and that the conduct of the 
study is in compliance with the currently approved protocol, ICH, GCP, and with the applicable 
regulatory requirements, it is mandatory that Rigel or its authorized representative, and other 
regulatory authorities, have access to all original electronic and paper source documents (as 
described in Section 12.1 and Section 12.2) at reasonable times and upon reasonable notice.  
During the review of source documents, the confidentiality of the subject will be respected with 
strict adherence to professional standards and regulations (refer to Section 11.1). 


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Monitoring visits will occur as required during the conduct of the study.  The study monitor will 
physically visit the study site(s) at least 2 times during the study duration (interim and close out 
visits) or more, if deemed necessary, and will be allowed, on request, to inspect the various 
records of the study.  The study monitor will contact the study site via telephone and written 
communication regularly throughout the conduct of the study to maintain current and personal 
knowledge of the study.  It will be the study monitor’s responsibility to remotely inspect the 
eCRFs at regular intervals throughout the study to verify adherence to the protocol and the 
completeness, correctness, and accuracy of all eCRF entries.  The study monitor should have 
access to laboratory test results and any other source records and data needed to verify the entries 
on the eCRFs.  The Investigator agrees to cooperate with the study monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
Upon completion or termination of the study, the Investigator will notify the IEC/IRB with a 
final report and provide Rigel or its authorized representatives with a copy of the final report. 
12.4 
Data Quality Assurance 
The handling of data, including data quality assurance, will comply with this protocol, the 
informed consent, the contract between the site and Rigel, and all applicable regulatory 
requirements and guidelines (eg, ICH and GCP), and Rigel’s authorized representative’s SOPs 
and working instructions.  Data management and control processes and quality assurance 
specific to this study will be described in a data management/validation plan.  All steps and 
actions taken regarding data management and quality assurance will be documented in a data 
handling report. 
12.5 
Data Collected by Contractors 
Rigel will be responsible for ensuring that the collection, evaluation, and archiving of study data 
by Rigel’s representatives and vendors adheres to the protocol specifications and GCP 
requirements. 
12.6 
Availability and Retention of Investigational Records 
A file for each subject must be maintained that includes the signed ICF (including confidential 
treatment of subject information) and copies of source documentation related to that subject.  
The Investigator must ensure the reliability and availability of source documents from which the 
information on the eCRF was derived and will comply immediately with any reasonable request 
of Rigel or its authorized representative to confirm information recorded on eCRFs. 
Subject identity information will be maintained by the Investigator for 15 years.  All other 
essential documentation will be retained by the Investigator for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug, and according to any local 
regulations.  Should the Investigator/ Institution be unable to continue maintenance of subject 
files for the full 15 years, Rigel will assist in this regard.  Rigel will inform the 
Investigator/Institutions as to when these documents no longer need to be retained. 


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Essential documentation includes, but is not limited to: the Investigator’s Brochure; signed 
protocol and amendments; signed Informed Consent; signed (electronically), dated, and 
completed eCRFs, and documentation of eCRF corrections; source documents; notification of 
SAEs and related reports; any study drug dispensing and accountability logs; shipping records of 
investigational product and study-related materials; dated and documented IEC/IRB approval; 
normal laboratory values; decoding procedures for blinded studies; curricula vitae for study staff; 
and pertinent study-related correspondence.  No study document or image (eg, scan, radiograph) 
should be destroyed without prior written agreement between Rigel and the Investigator.  Should 
an Investigator wish to move the study records to another location, advance written notice will be 
given to Rigel.  Study records will not be transferred to another party without Rigel’s advance 
written consent. 
Rigel or its authorized representative may perform an audit at any time during or after 
completion of this study.  All study-related documentation must be made available to the 
designated auditor.  In addition, a representative of applicable national Regulatory Agencies may 
choose to inspect a study site at any time prior to, during, or after completion of the clinical 
study.  In the event of such an inspection, Rigel will be available to assist in the preparation.  All 
pertinent study data should be made available, as requested, to the Regulatory Authority for 
verification, audit, or inspection purposes. 
The Investigator agrees that all data and information that is generated as a result of conducting 
the study or that is received from Rigel or its authorized representative, including this protocol, 
eCRFs, and any other study information, is and shall remain the sole and exclusive property of 
Rigel.  The Investigator and study staff will not disclose any Rigel information to any third party 
(except employees or agents of the study site directly involved in the conduct of the study who 
need to know the information for the purpose of carrying out the study and who are contractually 
bound to maintain its confidentiality) without prior written consent of Rigel.  The Investigator 
further agrees to take all reasonable precautions to prevent the disclosure of Rigel confidential 
information by any employee or agent of the study site to any third party or otherwise into the 
public domain. 


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13.0 SUPERVISION OF THE STUDY 
The Investigator is responsible for the supervision of study conduct in accordance with the 
protocol, including collection of and maintenance of adequate and appropriate study 
documentation.  The Investigator may delegate some of the work involved in the conduct of the 
study.  The Investigator shall ensure that all study staff are qualified by education, experience, 
and training to perform their specific responsibilities in relation to the study.  All individuals 
involved in the conduct of the study and working with the study documentation must complete 
the Delegation of Authority Log. 


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14.0 DISCLOSURE/PUBLICATION OF DATA 
All results derived from the study are the exclusive property of Rigel Pharmaceuticals, Inc. and 
are considered confidential to Rigel.  Written permission from Rigel is required prior to 
disclosing any information relative to this study or the study drug. 
After conclusion of the study, Investigators in this study may communicate, orally present, or 
publish in scientific journals or other scholarly media, the results of the study from their study 
site only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of Rigel in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 2 years; or  
• As otherwise permitted in writing and in advance by Rigel. 
The Investigator will submit to Rigel any proposed publication or presentation along with the 
name of the respective scientific journal or presentation forum at least 30 days prior to 
submission of the publication or presentation.  The Investigator will comply with Rigel’s request 
to delete references to its confidential information in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent protection 
on the contents of any publication if deemed necessary by Rigel.  This requirement should not be 
construed as a means of restricting publication but is intended solely to assure consonance 
regarding data, evaluations, and conclusions and to provide an opportunity to share with the 
Investigator any new and/or unpublished information of which he/she may be unaware. 


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15.0 REFERENCES 
1. 
Smith J, McDaid JP, Bhangal G, Chawanasuntorapoj R, Masuda ES, Cook HT, Pusey 
CD, Tam FW. A spleen tyrosine kinase inhibitor reduces the severity of established 
glomerulonephritis. Journal of the American Society of Nephrology : JASN. 
2010;21(2):231-6. 
2. 
McAdoo SP, Reynolds J, Bhangal G, Smith J, McDaid JP, Tanna A, Jackson WD, 
Masuda ES, Cook HT, Pusey CD, Tam FW. Spleen tyrosine kinase inhibition attenuates 
autoantibody production and reverses experimental autoimmune GN. Journal of the 
American Society of Nephrology : JASN. 2014;25(10): 2291–2302. 
3. 
Bahjat FR, Pine PR, Reitsma A, Cassafer G, Baluom M, Grillo S, Chang B, Zhao FF, 
Payan DG, Grossbard EB, Daikh DI. An orally bioavailable spleen tyrosine kinase 
inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis and 
rheumatism. 2008;58(5):1433-44. 
4. 
Deng GM, Liu L, Bahjat FR, Pine PR, Tsokos GC. Suppression of skin and kidney 
disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis and 
rheumatism. 2010;62(7):2086-92. 
5. 
Kim MJ, McDaid JP, McAdoo SP, Barratt J, Molyneux K, Masuda ES, Pusey CD, Tam 
FW. Spleen tyrosine kinase is important in the production of proinflammatory cytokines 
and cell proliferation in human mesangial cells following stimulation with IgA1 isolated 
from IgA nephropathy patients. Journal of immunology. 2012;189(7):3751-8. 
6. 
Yang JC, Reguart N, Barinoff J, Kohler J, Uttenreuther-Fischer M, Stammberger U, 
O'Brien D, Wolf J, Cohen EE. Diarrhea associated with afatinib: an oral ErbB family 
blocker. Expert review of anticancer therapy. 2013;13(6):729-36. 
7. 
Working Group of the International Ig ANN, the Renal Pathology S, Cattran DC, Coppo 
R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, et al. 
The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, 
and classification. Kidney international. 2009;76(5):534-45. 
8. 
FDA. Guidance for Industry and Investigators: Safety reporting requirements for INDs 
and BA/BE studies. Food and Drug Administration (FDA); 2012. 
9. 
ICH. Guideline for industry: clinical safety data management: definitions and standards 
for expedited reporting (ICH-E2A). International Conference on Harmonisation (ICH) 
1995. 
10. 
USDHHS. Common terminology criteria for adverse events (CTCAE). In: NIH, NCI, 
editors. 2009. 
 


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Appendix 1: 
Guideline for Dose Modification for Possible Drug-Induced Liver 
Injury (DILI):  AST or ALT 3x ULN or TBL > 2xULN 
The Investigator is responsible for determining whether the subject meets Hy’s law criteria for 
severe liver injury:  aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3x 
upper limit of normal (ULN) plus total bilirubin (TBL) > 2x ULN and alkaline phosphatase 
(ALP) < 2x ULN.  
• Note:  Fostamatinib is an inhibitor of UGT1A1, the enzyme responsible for the 
glucuronidation of bilirubin; occasionally an isolated increase in total and unconjugated 
(indirect) bilirubin may be observed.  Study drug should not be held for an isolated 
increase in total and unconjugated (indirect) bilirubin.  
• The study Medical Monitor should be notified immediately of any potential case meeting 
Hy’s law criteria. 
Table 1: 
Dose Adjustment 
Starting Dose 
Dose Level 
-1 
Dose Level 
-2 
Dose Level 
-3a  
Dose Level 
-4a 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd 
Discontinue 
------- 
150 mg PO bid 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd Discontinue 
a 
The Sponsor’s Medical Monitor should be consulted prior to consideration of dose modification to 
levels -3 or -4. 
Identification 
If AST or ALT ≥ 3x ULN and total (and/or conjugated) bilirubin > 2x ULN, with ALP < 
2x ULN (Hy’s law criteria met), the Investigator should follow the instructions below: 
• Stop study drug treatment immediately and withdraw the subject from the study 
for possible drug-induced liver injury.   
• Complete the appropriate LFT module of the case report form (CRF) with the 
original laboratory test results. 
• Follow the subject until liver biochemistry parameters and any clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated. 
• Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Sponsor’s Medical Monitor. 
If AST or ALT ≥ 3x ULN or total (and/or conjugated) bilirubin > 2x ULN, and the 
subjects are exhibiting the following symptoms:  nausea, vomiting, abdominal pain: 
• Withhold/ interrupt dosing with study drug immediately. 
• Repeat LFTs, including bilirubin and alkaline phosphatase every 3 days/72 hours 
until ALT/AST or total (and/or conjugated) bilirubin returns to < 1.5x ULN. 


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• Complete the appropriate LFT module of the CRF with the original laboratory test 
result. 
• When the ALT/AST or total (and/or conjugated) bilirubin returns to < 1.5x ULN, 
study drug may be restarted at dose level -1. 
If AST or ALT ≥ 3x ULN or total (and/or conjugated) bilirubin > 2x ULN and subject is 
asymptomatic: 
• Complete the appropriate LFT module of the CRF with the original laboratory test 
result. 
• Repeat LFTs, including bilirubin and ALP, within 72 hours. 
• If repeat testing shows an increase in ALT/AST or total (and/or conjugated) 
bilirubin and the ALT/AST value exceeds 5x ULN, hold dosing with the study 
drug. 
• Repeat LFTs, including bilirubin and alkaline phosphatase every 3 days/72 hours 
until ALT/AST is decreasing, and should be followed until transaminase returns 
to < 1.5x ULN. 
• In subjects for whom study drug is interrupted, upon return of ALT/AST or total 
(and/or conjugated) bilirubin to < 1.5x ULN, study drug may be restarted at dose 
level -1. 
REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm0
06499.htm 
 
 


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Appendix 2: 
Guideline for Management of Neutropenia 
Based on data from previous clinical studies, treatment with fostamatinib may be associated with 
lowering of absolute neutrophil count (ANC). 
A decrease in ANC may require adjustment of the dose of study drug.  Follow the dose 
adjustment guidelines in Table 1 and outlined below when adjusting the dose of study 
medication. 
Table 1: 
Dose Adjustment 
Starting Dose 
Dose Level 
-1 
Dose Level 
-2 
Dose Level 
-3a  
Dose Level 
-4a 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd 
Discontinue 
------- 
150 mg PO bid 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd Discontinue 
a 
The Sponsor’s Medical Monitor should be consulted prior to consideration of dose modification to 
levels -3 or -4. 
Decrease in absolute neutrophil count (ANC) to < 1,000/μL: 
• Repeat ANC within 72 hours in the local laboratory. 
• If repeat testing confirms that ANC is < 1,000/μL, hold study drug dosing. 
o Repeat ANC at 72 hour intervals. 
• When ANC recovers to > 1,500/μL, restart study drug at dose level -1. 
Second event of ANC < 1,000/μL: 
• Confirm ANC as above. 
• If confirmed, hold study drug until ANC > 1,500/μL. 
• Restart study drug at dose level -2. 
 
 


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Appendix 3: 
Guideline for Management of Diarrhoea 
Diarrhoea  
• Based on data from previous clinical studies, treatment with fostamatinib may be 
associated with diarrhoea. 
• Subjects should be made aware that they may experience diarrhoea and instructed to 
contact the clinical site if they experience diarrhoea. 
• In some circumstances it may be necessary to adjust the dose of study drug.  Follow the 
dose adjustment guidelines in Table 1 and outlined below when adjusting the dose of 
study medication. 
Table 1: 
Dose Adjustment 
Starting Dose 
Dose Level 
-1 
Dose Level 
-2 
Dose Level 
-3a  
Dose Level 
-4a 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd 
Discontinue 
------- 
150 mg PO bid 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd Discontinue 
a 
The Sponsor’s Medical Monitor should be consulted prior to consideration of dose modification to 
levels -3 or -4. 
Grading of Severity of Diarrhoea:  The US National Cancer Institute has introduced the 
following criteria for the grading of severity of diarrhoea: (10)  
• Grade 1:  Increase of less than 4 stools per day over baseline 
• Grade 2:  Increase of 4 to 6 stools per day over baseline, not interfering with 
activities of daily living (ADL) 
• Grade 3:  Increase of ≥ 7 stools per day over baseline; incontinence; 
hospitalization indicated; interference with self-care ADL 
• Grade 4:  Life-threatening consequences; urgent intervention indicated  
• Grade 5:  Death 
Grade 1 or 2 Diarrhoea 
• Study drug may be continued. 
• Discontinue all laxatives. 
• Subjects should be instructed to drink 8-10 glasses of water or clear fluids per 
day. 
• Subjects should be encouraged to make dietary changes including elimination of 
dairy products and eating smaller but more frequent meals. 
• Consider stool sample for microbiologic evaluation and antibiotics if subject is 
neutropenic. 


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• Grade 1, consider initiating treatment with loperamide according to the regimen 
below (not to exceed a maximum of 20mg in 24 hours).  Grade 2, initiate 
treatment with loperamide according to the regimen below: 
o 4 mg loperamide initial dose. 
o 2 mg loperamide after each subsequent loose stool. 
• Subjects with persistent diarrhoea (> 48 hours) should be monitored carefully for 
dehydration and electrolyte imbalance. 
Grade 3 or 4 Diarrhoea 
• The subject should be instructed to withhold immediately study drug. 
• Initiate aggressive fluid replacement to treat potential dehydration. 
• Consider stool sample for microbiologic evaluation and antibiotics if subject is 
neutropenic. 
• Begin treatment with loperamide and continue treatment until the diarrhoea has 
resolved: 
o 4 mg loperamide initial dose. 
o 2 mg loperamide after each subsequent loose stool.  
o Not to exceed a maximum of 20 mg (10 tablets) in 24 hours. 
• When diarrhoea improves to ≤ Grade 1, restart study drug at dose level -1. 
Management of Second Event of Grade 3 and 4 Diarrhoea 
• Temporarily withhold study drug dosing. 
• Initiate aggressive fluid replacement to treat potential dehydration. 
• Consider stool sample for microbiologic evaluation and antibiotics if subject is 
neutropenic. 
• Begin treatment with loperamide and to continue treatment until the diarrhoea has 
been resolved: 
o 4 mg loperamide initial dose. 
o 2 mg loperamide after each subsequent loose stool.  
o Not to exceed a maximum of 20 mg (10 tablets) in 24 hours. 
• When diarrhoea improves to ≤ Grade 1, restart study drug at dose level -2. 
 
REFERENCES 
Yang JC, Reguart N, Barinoff J, Kohler J, Uttenreuther-Fischer M, Stammberger U, et al. 
Diarrhea associated with afatinib: an oral ErbB family blocker. Expert review of 
anticancer therapy. 2013;13(6):729-36. 


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Appendix 4: 
Guideline for Management of Hypertension 
Treatment with fostamatinib may cause blood pressure elevation in certain subjects.  It is 
believed that this effect is a result of off-target activity against the VEGFR2 receptor.  Increases 
in BP have proven to be amenable to treatment, generally without a requirement for study drug 
interruption.  Subjects with elevated blood pressure should receive prompt treatment. 
Blood pressure for all subjects should be kept below 140/90 mmHg; for subjects with increased 
cardiovascular risk or renal insufficiency, consideration should be given to maintaining the blood 
pressure below 130/80 mmHg.  Subjects should remain on the same dose of ACEi or ARB 
during the dosing period (Visits 2-9).  If additional anti-hypertensive therapy is required, other 
agents (beta-blockers, calcium channel blockers, or diuretics) should be added.  In previous 
clinical studies evaluating fostamatinib, the following anti-hypertensive agents (alone or in 
combination) have proven effective in managing BP: 
• Angiotensin converting enzyme inhibitors 
• Angiotensin receptor blockers 
• Calcium channel blockers 
• Beta-blockers 
• Diuretics 
If aggressive and appropriate anti-hypertensive therapy does not control BP (< 140/90), it may be 
necessary to reduce the dose of study medication. 
Management Algorithm for Elevated Blood Pressure  
Follow the dose adjustment guidelines in Table 1 when adjusting the dose of study medication. 
Table 1: 
Dose Adjustment 
Starting Dose 
Dose Level 
-1 
Dose Level 
-2 
Dose Level 
-3a  
Dose Level 
-4a 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd 
Discontinue 
------- 
150 mg PO bid 
100 mg PO bid 
150 mg PO qd 
100 mg PO qd Discontinue 
a 
The Sponsor’s Medical Monitor should be consulted prior to consideration of dose modification to 
levels -3 or -4. 
The following should result in prompt discontinuation of study medication: 
• The blood pressure cannot be brought under control despite best efforts at blood pressure 
management. 
 


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If BP ≥ 180/110 mmHg at any time after randomisation: 
• Temporarily withhold dosing with study drug. 
• Adjust anti-hypertensive medications. 
• Reassess BP twice weekly.  
• If a repeat BP ≥ 180/110 mmHg despite adjusted anti-hypertensive treatment, 
permanently discontinue study drug.  
• Increase anti-hypertensive medications until control is established. 
• Restart study drug (at a reduced dose, see Table 1) when blood pressure < 140/90 mm 
Hg. 
If the BP is found to be 160-179 systolic or 100-109 diastolic at any visit after 
randomisation: 
• Continue study drug at assigned dose level. 
• Adjust anti-hypertensive therapy.  
• Reassess BP twice weekly. 
• If, after 1 week, the BP remains ≥ 160-179 systolic or ≥ 100-109 diastolic despite 
aggressive antihypertensive therapy, interrupt study drug administration. 
• Increase anti-hypertensive medications until control is established. 
• Restart study drug (at a reduced dose, see Table 1) when blood pressure < 140/90 mm 
Hg. 
If BP is ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic but below 160 systolic or 100 
diastolic at any visit after randomisation: 
• Continue study drug at assigned dose level. 
• Repeat blood pressure assessment within 1 week. 
• 
If blood pressure remains above ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic after 
1 week adjust antihypertensive therapy.  
• Continue to monitor BP weekly until control is established. 
• If BP remains ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic for more than 8 weeks, 
despite aggressive antihypertensive therapy, reduce dose of study drug (see Table 1). 
REFERENCES 
Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott WJ, et al. Initial assessment, 
surveillance, and management of blood pressure in patients receiving vascular endothelial 
growth factor signaling pathway inhibitors. Journal of the National Cancer Institute. 
2010;102(9):596-604. 
 


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Appendix 5: 
Restricted Medications 
Subjects taking fostamatinib may be affected by drug-drug interactions.  
Fostamatinib is metabolized by CYP3A4.  In the presence of a strong inhibitor of CYP3A4, 
the systemic exposure of the active metabolite of fostamatinib may be increased significantly.  
Strong inhibitors of CYP3A should not be co-administered with fostamatinib.  Inducers of 
CYP3A4 may lower concentrations of active drug, possibly to sub-therapeutic concentrations, 
and their use in subjects taking fostamatinib should be limited.   
Fostamatinib is an in vitro inhibitor of P-glycoprotein and affects digoxin bioavailability by 
inhibiting P-gp.  If a subject requires digoxin or is taking digoxin concurrently with fostamatinib, 
digoxin levels should be monitored carefully according to local practice, as the digoxin dose may 
need to be lowered. 
Fostamatinib is known to increase the plasma concentration of the HMG-CoA reductase 
inhibitors simvastatin and rosuvastatin by 50-100%.  If a subject develops muscle pain or 
weakness, the dose of HMG-CoA reductase may need to be lowered and the subject monitored 
closely for any adverse effects associated with myositis. 
Subjects’ concomitant medications should be examined for additional possible drug-drug 
interactions. 
List of Inhibitors and Inducers of CYP3A4 
The list below is not an exhaustive list (the Sponsor’s Medical Monitor should be consulted in 
the event of questions). 
 
Strong Inhibitors of CYP3A4 
Clarithromycin 
Telithromycin 
Ketoconazole 
Itraconazole 
Fluvoxamine 
Nefazodone 
Ritonavir 
Indinavir 
Nelfinavir 
Sequinavir 
Atazanavir 
 
 
 
 
Moderate Inhibitors of CYP3A 
Amiodarone 
Aprepitant 
Erythromycin 
Troleandomycin 
Fluconazole 
Imatinib 
Verapimil 
Diltiazem 
Amprenavir 
Fosamprenavir 
Grapefruit juice 
Seville oranges 
Star fruit 
 
 


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CYP3A Inducers 
Barbiturates 
Efavirenz 
Nevaripine 
Pioglitazone 
Rifampin 
Rifabutin 
Carbamazepine 
Phenytoin 
Modafinil 
St. John’s Wort 
 
 
 

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