Clinical trial NCT02077192
Conditions: Immune Thrombocytopenic Purpura
Sponsor: Rigel Pharmaceuticals
Start date: 2014-10-01; Completion date: 2020-06-02
Enrollment: 123 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study was to assess the long term safety of fostamatinib in subjects with persistent/chronic ITP

Detailed description:

Arms: arm 1: Fostamatinib Disodium tablet 100 mg or 150 mg by mouth twice a day
Interventions: intervention 1: Fostamatinib Disodium
Intervention descriptions: intervention 1: Fostamatinib Disodium tablet 100 mg or 150 mg by mouth twice a day

Protocol documents:
Prot_000.pdf: 
 
Certain information within this clinical study report has been redacted (ie, specific content is 
masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 
• Named persons or organizations associated with the study. 
• Patient identifiers within the text, tables, or figures or in by-patient data listings. 
• Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
• Other information as needed to protect confidentiality of Rigel or partners, personal 
information, or to otherwise protect the integrity of the clinical study. 
If needed, certain appendices that contain a large volume of personally identifiable information 
or company confidential information may be removed in their entirety if it is considered that they 
do not add substantially to the interpretation of the data (eg, appendix of investigator’s 
curriculum vitae).  


 
Rigel Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 1 of 80 
V5.0  11 November 2019 
 
CLINICAL PROTOCOL 
A Phase 3 Open Label Extension Study of Fostamatinib Disodium in the Treatment of 
Persistent/Chronic Immune Thrombocytopenic Purpura  
Protocol Number: 
C-935788-049 
EudraCT Number: 
2013-005454-30 
Study Sponsor: 
Rigel Pharmaceuticals, Inc. 
1180 Veterans Boulevard 
South San Francisco, CA 94080 USA 
Tel: +1.650.624.1100 
Sponsor Representative: 
 
 
 
 
 
Version 1.0: 
Version 2.0: 
Version 3.0: 
Version 4.0: 
Version 5.0 
18 December 2013 
08 April 2014 
21 November 2014 
8 November 2016 
11 November 2019 
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. 




Protocol C-935788-049 
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Signature of Agreement for Clinical Protocol C-935788-049 
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 Good Clinical Practice, the 
Declaration of Helsinki, and the regulations of the United States FDA. 
• To maintain adequate and accurate records and to make those records available for inspection 
by Rigel (or its authorized representative), the FDA, or any other Regulatory Agency 
authorized by law. 
• To report to Rigel (or its authorized representative) any adverse events (AEs) or serious AEs 
(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 that 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 
 
 


Protocol C-935788-049 
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TABLE OF CONTENTS 
1.0 
PROTOCOL SYNOPSIS ....................................................................................................9 
2.0 
ABBREVIATIONS AND TERMS ...................................................................................15 
3.0 
INTRODUCTION .............................................................................................................17 
3.1 
Background ........................................................................................................................17 
3.2 
Nonclinical Studies ............................................................................................................17 
3.3 
Clinical Development of Fostamatinib in ITP ...................................................................18 
3.4 
Fostamatinib Safety and Pharmacokinetics .......................................................................19 
3.4.1 
Single Ascending Dose Safety and Pharmacokinetics ......................................19 
3.4.2 
Multiple-dose Pharmacokinetics .......................................................................19 
3.4.3 
Metabolism ........................................................................................................20 
3.4.4 
Drug-Drug Interactions .....................................................................................20 
3.5 
Efficacy in Other Indications .............................................................................................21 
3.6 
Safety .................................................................................................................................21 
3.6.1 
Blood Pressure Elevation ..................................................................................22 
3.6.2 
Liver Function Test Abnormalities ...................................................................22 
3.6.3 
Neutropenia .......................................................................................................23 
3.6.4 
Gastrointestinal (GI) Effects .............................................................................23 
3.6.5 
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 
5.0 
STUDY DESIGN...............................................................................................................26 
5.1 
Summary of Study Description ..........................................................................................26 
5.2 
Rationale for Proposed Dosing ..........................................................................................27 
5.3 
Study Treatment .................................................................................................................27 
5.3.1 
IWRS .................................................................................................................28 
5.4 
Safety Monitoring ..............................................................................................................28 


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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 ..............................................................................................................30 
7.0 
STUDY PROCEDURES ...................................................................................................31 
7.1 
Treatment Period ................................................................................................................31 
7.1.1 
Enrollment (Day 1) ...........................................................................................31 
7.1.2 
Treatment Visits ................................................................................................33 
7.2 
Dose Adjustments ..............................................................................................................33 
7.2.1 
Dose Escalation for Subjects Not Responding at End of Month 1 ...................33 
7.2.2 
Dose Adjustments Due to Adverse Events .......................................................34 
7.2.3 
Non-Diarrhea Gastrointestinal Toxicity ............................................................34 
7.3 
Discontinuation of Nonresponders ....................................................................................34 
7.4 
Rescue Therapy ..................................................................................................................35 
7.5 
Study Follow-Up ................................................................................................................35 
7.6 
Definition of Study Procedures ..........................................................................................35 
7.6.1 
Physical Exam ...................................................................................................35 
7.6.2 
Karnofsky Performance Status Assessment ......................................................36 
7.6.3 
Vital Signs .........................................................................................................36 
7.6.4 
Bleeding Assessment ........................................................................................36 
7.6.5 
Electrocardiogram .............................................................................................36 
7.6.6 
Laboratory Tests................................................................................................36 
7.6.7 
Pregnancy Tests ................................................................................................37 
7.6.8 
Short Form 36 (SF-36) Questionnaire ..............................................................37 
7.7 
Concomitant Therapies ......................................................................................................37 
7.7.1 
Allowed ITP Therapies .....................................................................................37 
7.7.2 
Restricted Medications Unrelated to ITP ..........................................................38 
7.8 
Pharmacokinetic Samples ..................................................................................................38 
7.9 
Withdrawal from Study......................................................................................................39 
7.10 
Study Completion and Early Termination .........................................................................39 
8.0 
STUDY DRUG ..................................................................................................................41 


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8.1 
Study Drug Description .....................................................................................................41 
8.1.1 
100 mg Tablets ..................................................................................................41 
8.1.2 
150 mg Tablets ..................................................................................................41 
8.2 
Storage ...............................................................................................................................41 
8.3 
How Supplied/Study Drug Dispensation ...........................................................................41 
8.4 
Study Drug Administration ................................................................................................42 
8.5 
Study Drug Accountability/Drug Compliance ...................................................................42 
9.0 
ADVERSE EVENTS .........................................................................................................43 
9.1 
Definitions..........................................................................................................................43 
9.2 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators .......................................................................................................................46 
9.2.1 
Adverse Event Reporting Period .......................................................................46 
9.2.2 
Assessment of Adverse Events .........................................................................46 
9.2.3 
Expedited Reporting Requirements for Serious Adverse Events .....................47 
9.3 
Reporting of Serious Adverse Events by Sponsor .............................................................47 
9.4 
Pregnancy ...........................................................................................................................47 
10.0 
STATISTICAL METHODS ..............................................................................................49 
10.1 
General Considerations ......................................................................................................49 
10.2 
Analysis Populations ..........................................................................................................49 
10.3 
Definition of Baseline Measurements ................................................................................49 
10.4 
Analysis of Efficacy Endpoints .........................................................................................50 
10.4.1 
Primary Efficacy Endpoint ................................................................................50 
10.4.2 
Secondary Efficacy Endpoints ..........................................................................51 
10.5 
Safety Endpoints ................................................................................................................51 
10.6 
Analysis of Pharmacokinetic Endpoints ............................................................................52 
10.7 
Determination of Sample Size ...........................................................................................52 
10.8 
Handling of Dropouts and Missing Data ...........................................................................52 
11.0 
ETHICAL AND LEGAL ISSUES ....................................................................................53 
11.1 
Confidentiality of Subject Personal Information ...............................................................53 
11.2 
Institutional Review Board/Independent Ethics Committee..............................................53 
11.3 
Changes to the Study .........................................................................................................54 
11.4 
Protocol Deviations, Violations, Waivers and Exemptions ...............................................54 


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11.5 
Informed Consent...............................................................................................................54 
11.6 
Liability, Insurance, and Financing ...................................................................................55 
12.0 
DATA COLLECTION, RETENTION, AND MONITORING ........................................56 
12.1 
Source Data ........................................................................................................................56 
12.2 
Electronic Case Report Forms ...........................................................................................56 
12.3 
Monitoring .........................................................................................................................56 
12.4 
Data Quality Assurance .....................................................................................................57 
12.5 
Data Collected by Contractors ...........................................................................................57 
12.6 
Availability and Retention of Investigational Records ......................................................57 
13.0 
SUPERVISION OF THE STUDY ....................................................................................59 
14.0 
DISCLOSURE/PUBLICATION OF DATA .....................................................................60 
15.0 
REFERENCES ..................................................................................................................61 
 
LIST OF APPENDICES 
Appendix 1: 
Dose Modification for Possible Drug-Induced Liver Injury..................................62 
Appendix 2: 
Management of Neutropenia..................................................................................64 
Appendix 3: 
Management of Diarrhea .......................................................................................65 
Appendix 4: 
Management of Hypertension ................................................................................68 
Appendix 5: 
SF-36 Questionnaire ..............................................................................................70 
Appendix 6: 
 Karnofsky Performance Status Scale ....................................................................76 
Appendix 7: 
The Immune Thrombocytopenic Purpura Bleeding Score Assessment ................77 
Appendix 8: 
World Health Organization Bleeding Scale ...........................................................78 
Appendix 9: 
Restricted Medications...........................................................................................79 
Appendix 10:  Post Database Lock Extension ...............................................................................80 
 
 
 


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LIST OF TABLES 
Table 1: 
Frequent Adverse Events (Pooled Data - Phase 3 Placebo-Controlled RA 
Studies) ..................................................................................................................22 
Table 2: 
Schedule of Study Procedures ...............................................................................32 
Table 3: 
Dose Adjustment ....................................................................................................34 
Table 4: 
Restricted Medications...........................................................................................38 
 
LIST OF FIGURES 
Figure 1: 
Study Design ..........................................................................................................26 
Figure 2: 
Initial Treatment Allocation ...................................................................................27 
Figure 3: 
Dose Escalation (Subjects starting at 100 mg bid who have not Previously 
had a Dose Reduction) ...........................................................................................33 
 




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Subjects may continue to receive the concomitant medications for ITP that were allowed in 
the prior study (ie, glucocorticoids at dose less than equivalent of 20 mg prednisone daily, 
azathioprine or danazol).  Subjects in whom the platelet count is stable at ≥ 50,000/µL may 
have the dose of concomitant medications for ITP gradually reduced according to standard 
practice. 
At the end of Month 1 (approximately Day 30), subjects receiving fostamatinib 100 mg PO 
bid should have the dose escalated to fostamatinib 150 mg PO bid if platelet count 
< 50,000/µL and the study drug is well tolerated (refer to Section 7.2.1).  Conversely, the 
dose may be reduced at any time to a dose as low as fostamatinib 100 mg PO qd if dose-
limiting AEs are observed as defined by this protocol. 
Certain therapeutic regimens for ITP will be permitted for subjects with platelet counts 
< 50,000/µL who need “rescue” support of the platelet count.  Allowed therapeutic regimens 
include: 
• IVIg: up to 1 g/kg x 1-3 days, or 
• IV anti-D: up to 50-75 µg/kg x 1-2 days, or  
• IV methylprednisolone up to 1 g/day x 1-3 days or oral dexamethasone up to 
40 mg/day x 1-2 days or oral prednisone up to 1 mg/kg/day x 1-3 days. 
At Month 2, blood samples for PK analysis will be collected from a subset of 12 subjects at 
selected sites.  Subjects will remain at the clinic for up to 9 hours during the visit.  When a 
subject arrives at the clinic, the time of the last dose of fostamatinib will be recorded in the 
eCRF. 
Samples (4 mL) of whole blood will be collected at the following time points: predose and 
0.5, 1, 2, 4, 6, and 8 hours post-dose. 
Number of Subjects: Up to 150 subjects will be enrolled at multiple sites. 
Study Population: Patients with persistent/chronic ITP.  For the purpose of this study, the 
term ‘subject’ will refer to patients with persistent/chronic ITP participating in this study. 
Inclusion Criteria: 
1. Subject must be willing and able to give written informed consent by signing an 
IRB-approved Informed Consent Form prior to participating in any study-specific 
procedures.  
2. Subjects must have completed the Week 24 evaluation of Study C-935788-047 or 
C-935788-048 or have discontinued early (starting at Week 12) due to lack of response.  
No more than 7 days may have elapsed between the last day of treatment on Study 
C-935788-047 or C-935788-048 and the initial dosing (Day 1) in Study C-935788-049. 


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3. Male or female at least 18 years of age. 
4. Females must be either post-menopausal for at least 1 year or surgically sterile; or if female 
of child-bearing potential, must not be pregnant or lactating and must agree to use an 
acceptable method of birth control throughout the duration of the trial and for 30 days 
following the last dose.  Acceptable methods of birth control are defined as: hormonal 
contraception (pill, injection or implant) used consistently for at least 30 days prior to 
enrollment, intrauterine device (IUD), double-barrier (ie, condom and spermicide, or 
condom and diaphragm), or complete abstinence. 
5. In the Investigator’s opinion, the subject 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. Any subject who discontinued participation in Study C-935788-047 or C-935788-048 prior 
to Week 12 or for any reason other than lack of response.  Exceptions may be considered 
on a case-by-case basis after consultation between the Investigator and Sponsor with the 
specific reason for the exception noted.  
2. Subjects with poorly controlled hypertension during Study C-935788-047 or  
C-935788-048, defined as persistent or repeated systolic ≥ 140 mmHg, or diastolic 
≥ 90 mmHg whether or not the subject is receiving anti-hypertensive treatment.   
3. Subjects with the following laboratory abnormalities at the time of enrollment (Day 1): a 
leukocyte count < 2,000/µL, a neutrophil count (ANC) of < 1,000/µL, lymphocyte count 
< 750/µL, Hgb < 10 g/dL, or transaminase levels (ALT, AST) > 1.5 x ULN, bilirubin 
> 1.5 x ULN, or estimated glomerular filtration rate (eGFR) < 30 mL/min.  
4. Subjects who have a significant infection, an acute infection such as influenza, or known 
inflammatory process at the time of enrollment into this study.  
5. Subjects who have received any blood or blood products within the 2 weeks prior to 
enrollment (IVIg or anti-D are allowed if used for rescue therapy). 
Investigational Product: Fostamatinib disodium (R935788) 100 mg and 150 mg tablets 
Route of Administration: Oral 
Dose:  The initial dose will be 100 mg fostamatinib PO bid daily.  
At the end of Month 1, subjects who have initiated dosing at fostamatinib 100 mg PO bid in 
this extension study (and who have not previously had a dose reduction) should have their 
dose increased to fostamatinib 150 mg PO bid if the platelet count remains below 50,000/μL 
and the study drug has been well tolerated. 


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Treatment with fostamatinib has been associated with adverse events (AEs) 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. 
Duration of Treatment: A maximum of 5 years or until fostamatinib becomes commercially 
available, whichever comes first. 
Statistical Methods: 
Analysis Populations: 
a. 
Treated Population 
The Treated population will include all enrolled and treated subjects.  All 
efficacy endpoints will be analyzed based on the Treated population, and 
subjects will be analyzed according to their actual treatment.  The efficacy 
analyses based on the Treated population will be considered the primary 
efficacy analyses.  All analyses of safety will also be performed on the Treated 
Population. 
b. 
Per-Protocol Population 
The Per-Protocol (PP) population will include all subjects in the Treated 
population who had no major protocol violations in either study 
All efficacy endpoints will also be analyzed based on the PP population, and 
subjects will be analyzed according to their actual treatment.  The analyses 
based on the PP population will be considered secondary analyses of efficacy. 
Primary Efficacy Endpoint:   
Version 1:  The first version of the primary efficacy endpoint is for the purpose of assessing 
efficacy among all patients while they are on active treatment in one of the prior studies, in the 
current extension study, or in both.  This version of the primary efficacy endpoint is the 
achievement and maintenance of a stable platelet count defined as follows:  
1)  Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
active treatment.  
2)  Achievement of a sustained stable platelet response; defined as no two visits, at 
least 4 weeks apart, with a platelet count < 50,000/ µL, without an intervening visit 
with a platelet count of ≥ 50,000/ µL unrelated to rescue therapy, within a period of 
12 months following initial achievement of the target platelet count (see above). 
The beginning of active treatment may be in the prior study or in the present extension study, 
depending upon when the subject first received active treatment.  Subjects who discontinue 
treatment due to lack of efficacy or to an AE prior to 12 months following achievement of a 
platelet count of at least 50,000/μL will be considered failures.  This endpoint will be 
summarized using counts and percentages, together with a 95% exact (Clopper-Pearson) 
confidence interval (CI) for the true percentage. 


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Version 2:  The second version of the primary efficacy endpoint is for the purpose of a within-
subject, between-study comparison of fostamatinib and placebo among subjects randomized to 
placebo in either of the prior studies.  This version of the primary efficacy endpoint is the 
achievement and maintenance of a stable platelet count defined as follows:  
1)  Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
treatment (placebo treatment in the prior study and fostamatinib treatment in the 
present study) and  
2)  Achievement of a sustained stable platelet response; defined as no two visits, at 
least 4 weeks apart, with a platelet count < 50,000/µL, without an intervening visit 
with a platelet count of ≥ 50,000/µL unrelated to rescue therapy, within a period of 
12 weeks following initial achievement of the target platelet count (see above).  
Subjects who discontinue treatment due to lack of efficacy or to an AE prior to 12 weeks 
following achievement of a platelet count of at least 50,000/μL, will be considered failures.  
The null and alternative hypotheses for the comparison of fostamatinib vs. placebo are as 
follows:  
H0: pF = pP     vs.   H1: pF ≠ pP 
where pF and pP denote the true proportions achieving and maintaining a stable platelet count 
for fostamatinib and placebo, respectively.  The null hypothesis will be tested using a 2-sided 
McNemar’s test conducted with a significance level of 0.05.   
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints are as follows:  
• Duration of stable platelet response. 
• Proportion of subjects in whom a reduction in the dose of concomitant ITP therapy 
can be achieved while maintaining an adequate platelet count. 
The duration of stable platelet response will be analyzed using the Kaplan-Meier method, and 
the Kaplan-Meier estimate of the median duration of stable platelet response will be presented 
together with the 95% CI for the true median.  
Achieving a reduction in the dose of concomitant ITP therapy while maintaining an adequate 
platelet count will be summarized using counts and percentages and a 95% exact (Clopper-
Pearson) CI for the true percentage.  A two-sided, McNemar’s test will be performed to 
compare the proportions of successes between the fostamatinib and placebo treatments. 
Safety Endpoints: 
The safety outcomes of this study include the frequency and severity of bleeding according to 
the IBLS, the change from baseline in blood pressure, liver function, and ANC; the incidence 
of GI complaints; infection; and overall AEs. 
Pharmacokinetic Endpoints: 
Pharmacokinetic parameters to be estimated for the major metabolite R406 include maximum 
plasma concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration-
time curve through 8 hours (AUC(0-8)).  Cmax and Tmax will be taken directly from the data; 


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AUC(0-8) will be calculated using the linear trapezoidal method.  These PK parameters will be 
summarized using descriptive statistics. 
Determination of Sample Size: 
The sample size will be based upon the number of subjects in the C-935788-047 and 
C-935788-048 studies who are eligible to participate in this study and who choose to 
participate. 


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2.0 
ABBREVIATIONS AND TERMS 
ADP 
Adenosine Diphosphate 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibodies 
ANC 
Absolute Neutrophil Counts 
Anti-D IgG 
Anti-Rho (D) immunoglobulin 
APLA 
Antiphospholipid antibodies 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BCR 
B-cell receptor 
BCRP 
Breast cancer resistant protein 
bid  
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 
CRO 
Contract Research Organization 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FcR 
Fc receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
h 
hour 
HIPAA 
Health Insurance Portability and Accountability Act 
IBLS 
Immune Thrombocytopenic Purpura Bleeding Score 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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Ig 
Immunoglobulin 
IgG 
Immunoglobulin G 
INR/aPTT 
International Normalized Ratio/Activated Partial Thromboplastin Time 
IRB 
Institutional Review Board 
ISI 
International sensitivity index 
ITP 
Immune Thrombocytopenic Purpura 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVIg 
Intravenous IgG 
IWRS 
Interactive web response system 
KPS 
Karnofsky Performance Status 
LFT 
Liver function tests 
OATP 
Organic anion transporter 
PD  
Pharmacodynamic 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PO 
by mouth 
PP 
Per protocol 
qd 
once daily 
R406 
Rigel compound R940406 (the major metabolite of R788) 
R788 
Rigel compound R935788 (fostamatinib) 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SF-36 
Short form-36 
SOP 
Standard operating procedure 
SRC 
Safety Review Committee 
Syk 
Spleen tyrosine kinase 
Tmax 
Time of maximum plasma concentration 
ULN 
Upper limit of normal 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 
WHO 
World Health Organization 


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3.0 
INTRODUCTION 
3.1 
Background 
ITP is a disorder manifested by immune mediated platelet destruction.  It is estimated that there 
are 50–100 new cases per million persons each year in the U.S. and Europe, with the cases 
roughly divided among adults and children.  The natural history of the disease in children is 
different and generally more benign than ITP in adults.  ITP may be primary or secondary to a 
variety of conditions, including autoimmune disease (ie, systemic lupus erythematosis), 
lymphoid malignancies, or chronic viral diseases such as hepatitis and HIV. 
ITP in adults is typically a chronic disease, with a low spontaneous remission rate.  Although 
responses to glucocorticoids, intravenous IgG (IVIg), splenectomy, and thrombopoietic agents 
may be encouraging, a significant number of patients remain severely thrombocytopenic for long 
durations and are subject to risk of spontaneous or trauma-induced hemorrhage.  Even in 
asymptomatic patients, platelet counts below 20,000/μL - 30,000/μL often prompt treatment. 
Fcγ receptor (FcγR) signaling in monocytes and macrophages plays an important role in the 
initiation and propagation of autoimmune responses.  The activating FcγR are associated with a 
signaling subunit, referred to as the FcRγ chain, whose phosphorylation subsequent to receptor 
activation results in the recruitment and activation of spleen tyrosine kinase (Syk).  Syk kinase is 
an important component of the signaling system of activated Fc receptors, as well as the B-cell 
receptor (BCR). 
Aggregation of the Fc receptors, induced by antibody-antigen complexes, can induce a multitude 
of cellular functions (including degranulation, arachidonic acid metabolism, antibody dependent 
cellular cytotoxicity, phagocytosis and cytokine secretion) depending on the cell type, and leads 
to tissue damage and the propagation of inflammatory responses.  FcγR have been implicated in 
immune destruction of platelets.  Accelerated clearance of circulating IgG-coated platelets via 
Fc receptor (FcR)-bearing macrophages in the spleen and liver is a key mechanism in ITP.  
Fostamatinib (R788), the prodrug of R406, is a potent and relatively selective inhibitor of Syk 
and consequently of the FcR and BCR signaling pathways.  Fostamatinib inhibits Syk and FcR 
signaling at concentrations generally achieved with doses of 100 mg twice daily (bid) and above, 
and both preclinical and early clinical data have affirmed its activity in ITP. 
3.2 
Nonclinical Studies 
Bussel et al reported on a preclinical study with a R788/R406 in a murine model of ITP. (1)  Mice 
injected with an antibody directed to a platelet βII integrin (anti-CD41) were thrombocytopenic 
(70% reduction) when platelets were enumerated 24 hours post injection.  Mice treated with 
25 or 40 mg/kg R788 were partially protected from the antibody-induced thrombocytopenia.  
Mice treated with vehicle alone displayed no protection.  To confirm this work, Rigel embarked 
on a similar study of antibody-induced thrombocytopenia.  Genetically identical inbred C57BL/6 
mice and genetically heterogeneous CD-1 outbred mice were pretreated with vehicle or 20, 40, 
or 80 mg/kg R788 and dosed at 4-8 hour intervals for the duration of the study.  Drug 
administration was initiated at various times prior to and following injection of platelet-depleting 
antibody (anti-CD41) or isotype control antibody.  Whole blood was collected, and platelet 


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counts determined at 2 time points, (8 or 24 hours), following administration of depleting 
antibody.  
Vehicle-treated C57BL/6 mice injected with CD41 antibody demonstrated uniform and 
significant platelet depletion at 8 hours post administration (350 x 103 platelets/μL whole blood 
in vehicle-treated mice, compared with 1,200 x103 platelets/μL in the isotype control mice, 
representing a 71% reduction in platelet count).  Vehicle-treated CD-1 mice injected with 
anti-CD41 antibody also demonstrated uniform and significant platelet depletion at 8 hours 
post-antibody administration, showing a mean reduction of platelets to 33 x 103 platelets/μL 
whole blood, which is 2.4% of the isotype control-treated animal platelet count (1,376 x 103 
platelets/μL).  Significant prevention of platelet depletion was seen in both C57BL/6 (p < 0.05) 
and CD-1 (p < 0.001) strains of mice treated with the 80 mg/kg dose of fostamatinib (mean 
platelet counts of 651 x 103 platelets/μL whole blood and 280 x 103 platelets/μL, respectively).  
The platelet counts from both C57BL/6 and CD-1 mice treated with 20 or 40 mg/kg fostamatinib 
were not significantly different from those in vehicle-treated mice (p > 0.05). 
In the absence of disease, fostamatinib/R406 had no effect on the time required for cessation of 
bleeding following an acute injury (tail nick).  Wild-type (normal mice) treated with R406 at 
concentrations in excess of 15 μM, had no significant difference in bleeding time compared with 
untreated mice or mice treated with vehicle alone, while the active controls, treated with aspirin, 
had a significant prolongation of bleeding time. 
3.3 
Clinical Development of Fostamatinib in ITP 
A Phase 2 pilot trial (Study C-935788-007) in adults with persistent/chronic ITP (defined as 
platelet count < 30,000/μL for ≥ 3 months) is ongoing (now as an investigator sponsored 
study). (1) All patients had failed at least 2 standard therapeutic regimens.  Patients were treated 
with escalating doses of fostamatinib in cohorts of 3.  After a cohort completed 4 weeks of 
treatment, a subsequent cohort could be initiated.  Patients were required to complete 2 weeks at 
a given dose before the dose could be increased (by 25 mg bid).  Dosing was initiated at 75 mg 
bid to 150 mg bid.  Patients who responded, and then had their platelet counts decline, could 
have their dose further increased to a maximum of 175 mg bid.  Eighteen patients entered the 
study and 2 patients remain on study. 
In the twelve patients that responded to fostamatinib, the median platelet count increased from 
16 x 109/L at baseline to a median peak of 105 x 109/L.  Twelve patients achieved at least 
1 substantial platelet increase, which was sustained in 8 patients.  Patients with a sustained 
response had increased platelet counts on at least 67% of occasions, and experienced a reduced 
need for IVIg treatment or a tapering of steroids while on the study drug.  The median dose of 
fostamatinib for the 8 patients with sustained response was 125 mg bid.  Four patients had a 
transient response to fostamatinib however these patients continued to take study drug due to an 
improvement in clinical parameters such as bleeding, need for rescue medications, and ability to 
taper steroids.  There appeared to be no clinical differences between responders and 
non-responders. (1) 
Eighteen patients were included in the safety analysis during the initial treatment period.  The 
3 most commonly reported AEs were blood pressure increased (11 patients), petechiae 


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(10 patients), and aspartate aminotransferase increased (9 patients (61.1%, 55.6%, and 50.0%, 
respectively).  Diarrhea was reported by 6 (33.3%) patients during the initial treatment period.  
Thirteen patients were included in the safety analysis during the responder extension period 
(treatment up to 24 months).  The 5 most commonly reported AEs during this treatment period 
(experienced by all 8 patients) were blood glucose increased (10 patients), ecchymosis 
(9 patients), blood glucose decreased, blood pressure increased, and diarrhea (76.9%, 69.2%, 
61.5%, respectively).  An increase in aspartate transaminase (AST) was reported by 7 (53.8%) 
patients during the responder extension period.  The transaminase increases were reported for 
any value greater than the upper limit of normal (ULN).  Only 1 patient had a value 3 x ULN, 
and that patient had pre-existing autoimmune hepatitis.  
3.4 
Fostamatinib Safety and Pharmacokinetics 
3.4.1 
Single Ascending Dose Safety and Pharmacokinetics 
R406, the major metabolite generated through the dephosphorylation of the prodrug R788 by 
intestinal phosphatases, appears rapidly in the systemic circulation after fostamatinib dosing, 
with median tmax ranging between 1 and 3 hours.  Negligible levels of R788 are found in plasma.  
The terminal half-life of R406 ranges from 12 to 19 hours.  Increasing the dose of fostamatinib 
tablets from 100 to 300 mg results 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 150 mg fostamatinib and a 100 mcg intravenous (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 area under the curve (AUC) and maximum plasma 
concentration (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 subjects generally tended to be comparable 
to other studies in which white subjects were enrolled. 
3.4.2 
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.   
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.  


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It is worthwhile to note in the context of the single and multiple dose pharmacokinetic (PK) 
studies that platelet aggregation studies were performed and there was no effect on collagen or 
adenosine diphosphate (ADP) induced platelet aggregation at the highest doses tested. 
3.4.3 
Metabolism 
The prodrug R788 is dephosphorylated in the intestinal mucosa to R406, the major metabolite, 
which in turn undergoes 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 low. 
3.4.4 
Drug-Drug Interactions 
3.4.4.1 
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 when fostamatinib is administered alone. 
• Ranitidine, which increases gastric pH, did not have a clinically relevant effect on the PK 
of R406.  
• Single doses of rosuvastatin and simvastatin did not have a clinically relevant effect on 
the PK of R406.   
3.4.4.2 
Effect of Fostamatinib on Exposure of Other Drugs 
• R406 and R788 are substrates for and/or inhibitors of transporters (P-glycoprotein (P-gp) 
and breast cancer resistant protein (BCRP)), cytochrome P450 (CYP3A4) and other 
enzymes (UGT1A1).  R406 is a weak inhibitor of OATP1B1 in vitro, but this 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 AEs (SAEs) in the clinical safety database 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 3048 patients in the long-term extension studies in rheumatoid arthritis (RA), 
as well as from the Phase 2 oncology program (studies in B- or T-cell lymphoma, diffuse 
large B-cell lymphoma, solid tumors and immune thrombocytopenia) up to 19th April 
2012.  In total, 389 patients were on a statin, (41 on rosuvastatin) while participating in a 
study.  An analysis of SAEs did not reveal a new or emerging signal, nor did liver 
function differ from that observed in the general patient population.  The body of 


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evidence from the safety profile in the clinic provides little evidence 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. 
• 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 pharmacodynamic (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. 
3.4.4.3 
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. 
3.5 
Efficacy in Other Indications 
To date, evidence of efficacy has been seen in open label Phase 2 studies in patients with B-cell 
lymphoma, in particular CLL.  In 7 of the 8 completed randomized, blinded, and placebo-
controlled Phase 2 and 3 RA trials, comprising over 3,000 patients, fostamatinib was effective in 
reducing joint tenderness and swelling and in improving functional outcome.  The effective dose 
range was 100 to 150 mg bid.  A lower dose (50 mg bid) was ineffective; the higher dose 
(150 mg bid) had more adverse effects without additional efficacy.  In the 2 largest trials, no 
evident benefit on decreasing bone erosion or joint space narrowing was observed.  For 
additional details, see Investigator Brochure. 
3.6 
Safety 
A number of 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 


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with RA, severely ill patients with lymphoma and advanced solid tumors, chronically ill patients 
with ITP, and in healthy subjects), has been consistent, and includes dose-dependent effects on 
blood pressure (BP), ANC, dizziness, gastrointestinal (GI) complaints and liver function test 
abnormalities, all of which are reversible and manageable with appropriate safety monitoring 
(Table 1).  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 tumors, the overall pattern of 
reported AEs was consistent with a population of heavily pretreated, relapsed patients with solid 
tumors of varying histologies. 
Table 1: 
Frequent Adverse Events 
(Pooled Data - Phase 3 Placebo-Controlled RA Studies) 
Sign/Symptom 
Fostamatinib 
Placebo  
N = 715 
254 PY 
100 mg bid 
N = 723 
288 PY 
100 mg bid (1 month) 
followed by 150 mg qd  
N = 710 
277 PY 
BP > 140/90 
333 
(46%) 
315 
(44%) 
170 (24%) 
BP > 160/100 
66 
(9%) 
63 
(9%) 
24 
(3%) 
Diarrhea 
94 
(33%) 
112 
(40%) 
32 
(13%) 
Nausea 
36 
(13%) 
41 
(15%) 
17 
(7%) 
Dizziness 
18 
(6%) 
12 
(4%) 
5 
(1%) 
Abdominal Pain* 
39 
(14%) 
38 
(14%) 
27 
(11%) 
ALT/AST ≥ 3 x ULN 
38 
(5%) 
37 
(5%) 
17 
(2%) 
PMN < 1500/µL 
66 
(9%) 
41 
(6%) 
8 
(1%) 
ALT= Alanine aminotransferase, AST = Aspartate aminotransferase, BP = Blood pressure, PY = Patient years, PMN = 
Polymorphonuclear leukocytes, ULN = Upper limit of normal 
* 
Represents various verbatim terms 
3.6.1 
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 
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. 
3.6.2 
Liver Function Test Abnormalities 
Mild to moderate increases in liver enzymes (ALT and AST) have been observed in 


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fostamatinib-treated patients.  A very small number of patients have experienced elevations > 10 
x ULN.  Liver function test (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, three in Phase 2 and two in Phase 3 have met the Hy’s law criteria for 
potential drug-induced liver injury.  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. 
3.6.3 
Neutropenia 
Dose-dependent decreases in ANC 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 ITP 
trial (although the experience was admittedly limited).  Dose reduction has generally resulted in 
resolution of the neutropenia and permitted patients to remain on study drug for prolonged 
periods.  To date, in the RA studies, 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. 
3.6.4 
Gastrointestinal (GI) Effects 
GI adverse effects have been reported in patients receiving fostamatinib.  Diarrhea is the most 
commonly reported event and can generally be managed with loperamide and/or study drug 
interruption or dose reduction.  Abdominal pain and nausea have also been among the commonly 
reported AEs. 
There have been twelve 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 like antihypertensives and NSAIDs. 
All but 1 episode resolved; this episode, in a patient with dyslipidemia who was using NSAIDs, 
had a fatal outcome.  The relationship between fostamatinib and pancreatitis, if any, remains 
unclear. 
3.6.5 
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 diarrhea, nausea, vomiting and abdominal pain.  For more information on 
the safety and activity of fostamatinib, see Investigators’ Brochure.   


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4.0 
 STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
The primary objective of this study is to assess the long term safety of fostamatinib in subjects 
with persistent/chronic ITP. 
The secondary objectives of this study are to establish the long-term efficacy of fostamatinib in 
achieving and maintaining a stable platelet count in subjects who complete the treatment phase 
of Study C-935788-047 or C-935788-048, and to assess the PK profile of fostamatinib in 
subjects with persistent/chronic ITP.  
4.2 
Primary Efficacy Endpoint 
Version 1:  The first version of the primary efficacy endpoint is for the purpose of assessing 
efficacy among all patients while they are on active treatment in one of the prior studies, in the 
current extension study, or in both.  This version of the primary efficacy endpoint is the 
achievement and maintenance of a stable platelet count defined as follows:  
1) Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
active treatment  
2) Achievement of a sustained stable platelet response; defined as no 2 visits, at least 
4 weeks apart, with a platelet count < 50,000/µL, without an intervening visit with a 
platelet count of ≥ 50,000/µL unrelated to rescue therapy, within a period of 12 months 
following initial achievement of the target platelet count (see above)  
Version 2:  The second version of the primary efficacy endpoint is for the purpose of a within-
subject, between-study comparison of fostamatinib and placebo among subjects randomized to 
placebo in either of the prior studies, This version of the primary efficacy endpoint is the 
achievement and maintenance of a stable platelet count defined as follows:  
1) Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
treatment (placebo treatment in the prior study and fostamatinib treatment in the present 
study) and  
2) Achievement of a sustained stable platelet response; defined as no 2 visits, at least 
4 weeks apart, with a platelet count < 50,000/µL, without an intervening visit with a 
platelet count of ≥ 50,000/µL unrelated to rescue therapy, within a period of 12 weeks 
following initial achievement of the target platelet count (see above)  
4.3 
Secondary Efficacy Endpoints 
• The duration of any stable platelet response 
• Proportion of subjects in whom a reduction in the dose of concomitant ITP therapy can 
be achieved while maintaining an adequate platelet count 


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4.4 
Safety Endpoints 
Safety endpoints include the frequency and severity of bleeding according to the IBLS; change 
from baseline (baseline value is the value at the initiation of active therapy) in blood pressure, 
liver function, and ANC; the incidence and severity of gastrointestinal (GI) effects (nausea, 
vomiting, diarrhea, abdominal pain); infection; and overall AEs.   
4.5 
Pharmacokinetic Endpoints 
Characterization of the PK profile of R406 (the active metabolite of fostamatinib) including 
Cmax, AUC, and Tmax in a subset of subjects with ITP. 


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5.0 
STUDY DESIGN 
5.1 
Summary of Study Description 
This is a Phase 3 multicenter, open-label extension study to evaluate the long-term safety and the 
efficacy of fostamatinib in achieving and maintaining a stable platelet response in subjects with 
persistent/chronic ITP.  For the purpose of this study, the term ‘subject’ will refer to patients with 
persistent/chronic ITP participating in this study.  Up to 150 subjects will be enrolled at multiple 
sites.  The study will consist of monthly visits for 18 months followed by every-other-month 
visits for a maximum of 5 years of treatment or until commercial availability of drug, whichever 
comes first (Figure 1).   
Figure 1: 
Study Design 
 
*At the end of Month 1 subjects receiving fostamatinib 100 mg bid should have the dose 
escalated to fostamatinib 150 mg bid if the platelet count is < 50,000/µL. 
Eligible subjects include subjects from Study C-935788-047 or C-935788-048 who have 
completed the Week 24 evaluation or who discontinue early (starting at Week 12) due to lack of 
response.  Subjects must meet the Inclusion/Exclusion criteria listed in Section 6.1 and 
Section 6.2 to be eligible to participate in the study.  All subjects will receive open-label 
fostamatinib.  Subjects designated as responders (defined as platelet count ≥ 50,000/µL) at the 
time of rollover will continue in the extension study at their current Study C-935788-047 or 
C-935788-048 dose and regimen.  Subjects who enter the extension study as nonresponders 
(defined as platelet count < 50,000/µL) will be allocated to fostamatinib 100 mg PO bid 
regardless of their dose and regimen in the prior study.  Subjects will remain blinded to their 
treatment assignment from Study C-935788-047 or C-935788-048 (active or placebo). 
Subjects may continue to receive the concomitant medications for ITP that were allowed in the 
prior study (ie, glucocorticoids at a dose less than the equivalent of 20 mg prednisone daily, 
azathioprine or danazol).  Subjects in whom the platelet count is stable at ≥ 50,000/µL may have 
the dose of concomitant medications for ITP gradually reduced according to standard practice. 
At the end of Month 1 (approximately Day 30), subjects receiving fostamatinib 100 mg PO bid 
should have the dose escalated to fostamatinib 150 mg PO bid if platelet count < 50,000/μL and 
the study drug is well tolerated (refer to Section 7.2.1).  Conversely, the dose may be reduced at 
any time to a dose as low as fostamatinib 100 mg PO qd if dose-limiting AEs are observed as 




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Subjects will self-administer the study drug throughout the 60-month treatment period.  Subjects 
on a bid dosing regimen will self-administer 1 tablet once in the morning and once in the evening 
at least 8 hours apart.  Subjects on a qd dosing regimen will self-administer 1 tablet per day by 
mouth in the morning. 
At the end of Month 1 (approximately Day 30), subjects receiving fostamatinib 100 mg PO bid 
should have the dose escalated to fostamatinib 150 mg PO bid if platelet count < 50,000/μL and 
the study drug is well tolerated (refer to Section 7.2.1).  
Subjects whose platelet count is consistently < 50,000/µL following 3 months (12 weeks) of 
treatment, and at least 4 weeks at a dose of 150 mg PO bid (provided this higher dose was 
tolerated), should be discontinued from the study, unless tangible clinical benefit for the use of 
fostamatinib is evident and the Sponsor agrees (all instances must be reviewed with the 
Sponsor’s Medical Monitor).  Examples of tangible clinical benefit may include, but are not 
limited to: 
• Credible increase in platelet count (eg, increase in platelet count of at least 20,000/µL 
over initial baseline to a count ≥ 30,000/µL)  
• Reduction in bleeding 
• Reduction in the need for rescue therapy 
5.3.1 
IWRS  
An Interactive Web Response System (IWRS) will be used to dispense the appropriate dose of 
fostamatinib to subjects in the study.  The IWRS will assign a bottle number to each subject who 
is eligible for the open-label extension study.   
5.4 
Safety Monitoring  
The Rigel Medical Monitor and representatives will closely monitor the safety of study drug on 
an ongoing basis by assessing reported AEs, vital signs, clinical laboratory values (hematology, 
serum chemistry, and urinalysis), and physical exams. 
5.5 
Safety Review Committee 
An independent safety review committee (SRC) will also monitor safety throughout the study. 
5.6 
Administrative Structure 
This trial is sponsored by Rigel.  Up to 150 subjects will be enrolled at multiple sites.   


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A contract research organization (CRO) will be responsible for project management and team 
training, site identification and activation, site monitoring and management, data management, 
randomization code assignment, and writing and preparation of the final clinical study report.  A 
second vendor will be responsible for biometrics.  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 directly in an electronic case report form (eCRF) via an electronic data 
capture (EDC) system.  An IWRS will be used for study drug inventory management.  Counting 
of platelets will be performed at the investigational institution or by local laboratories affiliated 
with the clinical sites enrolling subjects in the study.  A central laboratory will be used for testing 
other routine laboratory parameters as well as biospecimen storage (see Section 7.6.6 for 
additional instruction).   


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6.0 
SUBJECT SELECTION 
6.1 
Inclusion Criteria 
1. Subject must be willing and able to give written informed consent by signing an 
IRB-approved Informed Consent Form prior to participating in any study-specific 
procedures.  
2. Subjects must have completed the Week 24 evaluation of Study C-935788-047 or 
C-935788-048 or have discontinued early (starting at Week 12) due to lack of response.  No 
more than 7 days may have elapsed between the last day of treatment on the Study 
C-935788-047 or C-935788-048 and initial dosing (Day 1) in Study C-935788-049. 
3. Male or female at least 18 years of age. 
4. Females must be either postmenopausal for at least 1 year or surgically sterile; or if female of 
child-bearing potential, must not be pregnant or lactating and must agree to use an acceptable 
method of birth control throughout the duration of the trial and for 30 days following the last 
dose.  Acceptable methods of birth control are defined as: hormonal contraception (pill, 
injection or implant) used consistently for at least 30 days prior to enrollment, intrauterine 
device (IUD), double-barrier (ie, condom and spermicide, or condom and diaphragm), or 
complete abstinence. 
5. In the Investigator’s opinion, the subject 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. Any subject who discontinued participation in Study C-935788-047 or C-935788-048 prior 
to Week 12 or for any reason other than lack of response.  Exceptions may be considered on 
a case-by-case basis after consultation between the Investigator and Sponsor with the specific 
reason for the exception noted.  
2. Subjects with poorly controlled hypertension during Study C-935788-047 or C-935788-048, 
defined as persistent or repeated systolic ≥ 140 mmHg, or diastolic ≥ 90 mmHg whether or 
not the subject is receiving antihypertensive treatment.   
3. Subjects with the following laboratory abnormalities at the time of enrollment (Day 1): a 
leukocyte count < 2,000/µL, an ANC of < 1,000/µL, lymphocyte count < 750/µL, Hgb 
< 10 g/dL, or transaminase levels (ALT, AST) > 1.5 x ULN, bilirubin > 1.5 x ULN, or 
estimated glomerular filtration rate (eGFR) < 30 mL/min.  
4. Subjects who have a significant infection, an acute infection such as influenza, or known 
inflammatory process at the time of enrollment into this study.  
5. Subjects who have received any blood or blood products within the 2 weeks prior to 
enrollment (IVIg or anti-D are allowed if used for rescue therapy). 


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7.0 
STUDY PROCEDURES 
The study procedures to be performed at each visit are shown in Table 2. 
7.1 
Treatment Period  
7.1.1 
Enrollment (Day 1) 
Subjects must be willing to sign and date an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) approved informed consent form (ICF) prior to participating in any 
study-specific procedure activities.  Subjects will retain their same Subject ID number as per 
Study C-935788-047 or C-935788-048, as applicable. 
Subjects who have completed the Week 24 assessments in the previous ITP study within 7 days 
of enrollment in the extension study do not need to repeat these same assessments.  The 
assessments performed during the Week 24 visit in the prior ITP study will be used to qualify 
subject for enrollment in the extension study.  The subject must sign the ICF prior to enrollment 
in the extension study. The following assessments must be performed in order for a subject to be 
eligible for the extension study.  
All local and central laboratory results must be reviewed for eligibility prior to enrollment. 
• Inclusion/Exclusion Criteria 
• SF-36, (must be administered prior to any other study specific procedures (refer to 
Appendix 5) 
• Physical examination, vital signs, and KPS (refer to Error! Reference source not found.) 
• Concomitant medications 
• Bleeding Assessments by ITP Bleeding Scale (IBLS)  (refer to Appendix 7) 
• 12-lead electrocardiogram (ECG) 
• Complete blood count (CBC) with differential and reticulocyte count 
• Platelet count (performed at institutional or local lab) 
• Serum chemistry 
• Immunoglobulin levels 
• Urinalysis 
• Pregnancy test (for females of childbearing potential) 
• AEs 


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Table 2: 
Schedule of Study Procedures  
 
Day 1 Screen/ 
Enrollmenta 
End of Month 1  
(± 3 days) 
Months 2–18  
(± 3 days) 
Months 19–60  
(± 1 week) 
Follow-up  
(± 7 days)i 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Physical exam/KPS 
X 
X 
monthly 
every other month 
X 
Concomitant medications 
X 
X 
monthly 
every other month 
X 
Vital signsb 
X 
X 
monthly 
every other month 
X 
Bleeding assessmentc 
X 
X 
monthly 
every other month 
X 
ECG 
X 
 
 
 
 
Hematologyd 
X 
 
monthly 
every other month 
X 
Platelets 
X 
X 
monthly 
every other month 
X 
Serum chemistries (including LFTs)e 
X 
 
Months 4, 8, 12, 16 
every other month 
X 
LFTs onlyf 
 
 
monthly (in months full serum 
chemistries not done) 
 
X 
Immunoglobulin levels 
X 
 
 
 
X 
Urinalysis 
X 
 
Months 4, 8, 12, 16 
every 4 months 
X 
Urine pregnancy testg 
X 
 
every other month 
every other month 
 
SF-36h 
X 
 
Month 12 
 
 
AEs 
X 
X 
monthly 
every other month 
X 
PK 
 
 
Month 2 
 
 
Study drug dispensed/Accountability 
X 
X 
monthly 
every other month 
 
Dose adjustment (prn) 
X 
X 
monthly 
every other month 
 
a 
Screen/Enrollment (Day 1): These procedures are equivalent to Week 24 visit of Study C-935788-047 or C-935788-048; assessments performed as part of Week 24 may be 
used to assess subject’s eligibility to roll over and do not need to be repeated specific to Study C-935788-049. 
b 
Vital Signs: blood pressure, pulse and temperature 
c   
Bleeding assessment: IBLS scale only; prior to Version 4, protocol used both IBLS (Appendix 7) and WHO (Appendix 8) bleeding scales 
d 
Hematology: CBC with differential, RBC, hemoglobin, hematocrit, MCHC, MCH, MCV, MPV, RDW, reticulocytes 
e 
Serum chemistries: Na, K, Cl, bicarbonate (CO2), Ca, PO4, BUN, creatinine, globulin, glucose, LDH, AST, ALT, alkaline phosphatase, total bilirubin, total protein, albumin 
f 
LFTs: ALT, AST, ALP, LDH, and bilirubin (total and direct)  
g 
Pregnancy Test: For women of childbearing potential, regardless of birth control methodology   
h 
SF-36:  At visits where the SF-36 is evaluated the SF-36 must be the first assessment performed. 
i 
Follow-up visit: to be completed approximately 2 weeks (+/- 7 days)  after subject’s last treatment or at the time of early treatment termination  




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7.2.2 
Dose Adjustments Due to Adverse Events 
Treatment with fostamatinib has been associated with AEs 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 diarrhea (refer to Appendix 3 for guidance regarding diarrhea-related dose 
adjustments) (2)  
• Increase in BP to > 140/90 mmHg (refer to Appendix 4 for guidance regarding 
BP-related dose adjustments) 
• Other severe or life-threatening AEs considered related to study drug administration 
Subjects who have their dose reduced may be considered for a re-escalation of the study drug 
dose, following resolution of the AE resulting in dose reduction, and only after consultation with 
the Medical Monitor.  If a subject experiences additional dose-limiting AEs, the dose of study 
drug may be further reduced to a dose as low as 100 mg qd.  When dose reduction results in a 
once-daily dose of fostamatinib, subjects will take the daily study drug dose in the morning. 
Table 3 details the strategy for dose adjustment in subjects who experience AEs requiring dose 
reduction. 
Table 3: 
Dose Adjustment 
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. 
7.2.3 
Non-Diarrhea 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. 
7.3 
Discontinuation of Nonresponders 
After 3 months (12 weeks) of treatment, (and a minimum of 4 weeks treatment at 150 mg PO 
bid, unless this higher dose was not tolerated), any subject whose platelet count consistently 


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remains < 50,000/µL should be discontinued from the study, unless tangible clinical benefit from 
the use of fostamatinib is evident and the Sponsor agrees (discuss any exceptions with the 
Sponsor’s Medical Monitor).  Examples of tangible clinical benefit may include, but are not 
limited to: 
• Credible increase in platelet count (eg, increase in platelet count of at least 20,000/µL 
over the initial baseline to a count ≥ 30,000/µL)   
• Reduction in bleeding 
• Reduction in the need for rescue therapy 
7.4 
Rescue Therapy  
Certain therapeutic regimens for ITP will be permitted for subjects with platelet counts 
< 50,000/µL who need “rescue” support of the platelet count. 
Circumstances in which “rescue” therapy can be administered include: 
• Platelet count < 50,000/µL and at immediate risk of bleeding or with clinically significant 
bleeding or wet purpura 
• Platelet count < 50,000/µL and requires urgent or emergent surgery 
Allowed therapeutic regimens include: 
• IVIg: up to 1 g/kg x 1-3 days, or 
• IV anti-D: up to 50-75 µg/kg x 1-2 days, or  
• IV methylprednisolone up to 1 g/day x 1-3 days or oral dexamethasone up to 40 mg/day x 
1-2 days or oral prednisone up to 1 mg/kg/day x 1-3 days 
The Investigator must discuss all instances of “rescue therapy” with the Sponsor’s Medical 
Monitor, in advance of initiating the therapy whenever possible.   
7.5 
Study Follow-Up  
Subjects will be instructed to return to the clinic 2 weeks following the last dose of study drug 
for follow-up study assessments.  If a SAE is present at the last visit, follow-up should occur as 
indicated in Section 9.3. 
7.6 
Definition of Study Procedures 
7.6.1 
Physical Exam 
The initial physical exam should include evaluation of the head, eye, ear, nose, and throat, 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological 
systems as well as an assessment of the Karnofsky Performance Status (Appendix 6).  Physical 
examinations will include weight at the enrollment visit only.  Subsequent examinations may be 
symptom-directed at the discretion of the Investigator.  Physical examinations will be performed 


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as per the study schedule in Table 2.  Any new or worsened abnormalities should be recorded as 
AEs after enrollment.  No rectal or pelvic examination is required. 
7.6.2 
Karnofsky Performance Status Assessment  
The KPS (3) is a widely used method used to assess the functional status of patients.  KPS will be 
collected as part of the eligibility criteria.  The KPS describes the patient's functional status using 
percentage value ranges from 100%, no evidence of disease to 0%, death.  The assessor must 
also be the same person who is performing the physical exam for the study visit.   
7.6.3 
Vital Signs 
Vital signs (including blood pressure, pulse, and temperature) will be assessed at each study 
visit.  All blood pressure determinations should be made with the subject seated and taken after 
the subject rests for 3 minutes.  If the initial blood pressure at any visit is > 130 mmHg systolic 
or > 80 mmHg diastolic, the blood pressure should be taken at least 2 additional times at least 
5-10 minutes apart, and all 3 measurements will be recorded in the eCRF. 
7.6.4 
Bleeding Assessment  
Bleeding symptoms will be assessed using the IBLS at each study visit. (4) The IBLS will include 
assessment of bleeding at 9 anatomical sites over the past week graded from 0 (none) to 
2 (marked bleeding).  Assessment of bleeding at 2 sites, skin and oral, should be assessed by 
physical examination (see Appendix 7).   
The World Health Organization bleeding scale (Appendix 8) was collected during the first 
2 years of treatment, but has been discontinued in Version 4 of the protocol. 
The assessor must be a physician, doctor of osteopathic medicine, physician’s assistant, or nurse 
practitioner.  The assessor must also be the same person who is performing the physical exam for 
the study visit.  The IBLS is to be performed by the same assessor for each subject at each study 
visit, whenever possible. 
7.6.5 
Electrocardiogram 
A 12-lead ECG will be obtained after 5 minutes of rest in the supine position using equipment at 
the site according to the schedule in Table 2.  The investigator or designee will evaluate the ECG 
for abnormalities. 
7.6.6 
Laboratory Tests  
Laboratory samples will be obtained according to the schedule in Table 2.  The following tests 
are to be collected and analyzed for the study 
• Platelet Counts (performed at institutional/local lab) 
• Hematology: red blood cell count (RBC); white blood cell count (WBC), hemoglobin, 
hematocrit, WBC differential (ANC (segmented, bands, total), lymphocytes, eosinophils 


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and basophils), MCHC, MCH, MCV, MPV, RDW, and reticulocyte count (performed at 
central lab) 
• Serum chemistry: Na, K, Cl, bicarbonate (CO2), Ca, PO4, BUN, creatinine, globulin, 
glucose, LDH, AST, ALT, alkaline phosphatase, total bilirubin, total protein, albumin 
(performed at central lab) 
• Liver function tests: ALT, AST, alkaline phosphatase (ALP), lactate dehydrogenase 
(LDH) as well as total, direct, and indirect bilirubin (performed at central lab; if LFTs are 
being followed more frequently due to elevations, they may be performed at the 
institutional/local lab) 
• Quantitative serum immunoglobulin levels: IgM, IgG, and IgA (performed at central lab) 
• Urinalysis: appearance, glucose, ketones, blood, protein, nitrate, bilirubin, specific 
gravity, pH, urobilinogen, and leukocytes.  If positive for blood or protein trace, then 
include microscopy (performed at central lab)   
All subjects’ laboratory results with clinically significant abnormal values should be followed 
regularly until the values return to the normal range or until a more plausible alternative cause, 
other than drug-related AE, is identified. 
7.6.7 
Pregnancy Tests 
Urine pregnancy tests (performed at the site) will be obtained at intervals throughout the study.  
Subjects who have a confirmed positive pregnancy test at any time during the study will be 
discontinued from further study drug administration and will be followed for safety (see 
Section 9.4). 
7.6.8 
Short Form 36 (SF-36) Questionnaire 
Subjects will complete the SF-36 v2, standard version, a generic health survey consisting of 
36 questions, (Appendix 5), yielding 8 health-related quality of life (HRQoL) domains (physical 
functioning, role-physical, bodily pain, general health, vitality, social function, role-emotional, 
mental health) as well as a psychometrically based physical component score (PCS) and mental 
component score (MCS).  The SF-36 will be administered according to the schedule in Table 2.  
At visits where the SF-36 is administered the SF-36 should be the first assessment performed.  
Subjects must complete the questionnaire on their own without input of study personnel. 
7.7 
Concomitant Therapies 
Concomitant therapies will be recorded in the eCRF at all visits.  
7.7.1 
Allowed ITP Therapies 
Subjects may continue concurrent therapies for ITP that were allowed at entry (ie, 
glucocorticoids at a dose less than the equivalent of 20 mg prednisone daily, or azathioprine, or 
danazol).  Consideration can be given to tapering the dose of any concomitant ITP medication, in 


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subjects whose platelet count is stable at ≥ 50,000/μL.  New treatments for ITP may not be 
added. 
7.7.2 
Restricted Medications Unrelated to ITP 
Due to the potential for drug-drug interactions with fostamatinib, the following specific 
treatments are either not allowed or restricted during the course of this study, (see Table 4 and 
the additional information included in Appendix 9). 
Table 4: 
Restricted Medications 
Drug 
Restriction 
CYP3A4 inhibitors and inducers  
The active metabolite of fostamatinib is metabolized by CYP3A4.  
Restrictions on the co-administration of CYP3A4 inhibitors and 
inducers are described in Appendix 9. 
P-gp substrate 
Fostamatinib is an in vitro inhibitor of P-gp.  Restrictions on the co-
administration of P-gp substrates (eg, digoxin) are described in 
Appendix 9. 
HMG-CoA reductase inhibitors  
Fostamatinib may increase plasma concentrations of HMG-CoA 
reductase inhibitors.  Information on the co-administration of HMG-
CoA reductase inhibitors is found in Appendix 9.   
7.8 
Pharmacokinetic Samples 
At Month 2, blood samples for PK analysis will be collected from a subset of 12 subjects at 
selected sites.  Subjects participating in the PK portion of the study will be instructed not to take 
the morning dose of fostamatinib on the day of Month 2 visit.  Subjects will remain at the clinic 
for up to 9 hours during the visit.  When a subject arrives at the clinic, the time of the last dose of 
fostamatinib will be recorded in the eCRF. 
Samples (4 mL) of whole blood to provide a minimum of 2 mL plasma for PK analysis, will be 
collected into the appropriately labeled tubes containing K2EDTA anticoagulant at the following 
time points: 
• pre-dose and 0.5, 1, 2, 4, 6, and 8 hours postdose 
The time each PK sample is drawn as well as the time the morning dose is taken (at the clinic) 
will be recorded in the eCRF. 
Samples will be shipped to and stored at the central laboratory at -70°C 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. 


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The following PK parameters will be estimated for R406: 
• Cmax 
• Tmax 
• AUC0-8 
Cmax and Tmax will be taken directly from the data; AUC0-8 will be calculated using the linear 
trapezoidal method.  Descriptive measures of plasma levels will be provided for each time point 
and will include the geometric mean and associated 95% CI.   
Actual blood sampling times will be used for all PK analyses.  Nominal blood sampling times 
will be used for summary statistics of plasma concentrations and graphs of mean plasma 
concentrations versus time. 
7.9 
Withdrawal from Study 
Subjects will be discontinued from study treatment in the following situations: 
• Subject decision.  A subject is free to withdraw consent and discontinue participation in 
the study at any time. 
• AE based on Investigator judgment  
• Subject is uncooperative or noncompliant and will not/cannot adhere to study 
responsibilities, including failure to complete patient diary or appear for study visits 
• 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 
Subjects may be withdrawn from study treatment and from the study in the event of lack of 
platelet response (defined as platelet count < 50,000/µL) following 3 months (12 weeks) of 
treatment unless Sponsor approval is obtained. 
Subjects who are withdrawn from the study during the treatment period will have a withdrawal 
visit equivalent to the Follow-up Visit assessments.  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. 
7.10 
Study Completion and Early Termination 
The study will end upon completion of all protocol procedures.  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 for this indication.  If the Investigator 


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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 


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8.0 
STUDY DRUG 
8.1 
Study Drug Description 
Fostamatinib is supplied as orange film coated tablets in two dosage strengths:  100 mg and 
150 mg. 
Study drug will be labeled in accordance with Good Manufacturing Practices (GMP), local 
regulatory requirements, and all other applicable laws. 
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 stearate, hypromellose, titanium dioxide, macrogol 400, 
ferric oxide (yellow) and ferric oxide (red). 
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 stearate, hypromellose, titanium dioxide, 
macrogol 400, ferric oxide (yellow) and ferric oxide (red). 
8.2 
Storage 
Supplies of fostamatinib tablets will be stored at the study site in a secure location with restricted 
access and room temperature (below 30° C) with temperature monitoring. 
8.3 
How Supplied/Study Drug Dispensation 
Fostamatinib tablets are packaged in bottles.  Each bottle will contain 70 tablets to provide a 
30-day supply of study drug plus overage for an additional 5 days of dosing, if needed.  At 
Enrollment (Day 1) a single bottle of fostamatinib will be dispensed.  
Subjects should be instructed to bring the bottle containing unused study drug back to the clinic 
at the next visit.  At each monthly visit, following accountability, 1 new bottle of study drug will 
be dispensed to cover dosing until the next visit. 
The procedure outlined above for accountability and dispensing of fostamatinib should be 
followed for all subsequent visits. 


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8.4 
Study Drug Administration 
Fostamatinib will be self-administered, bid by mouth, once in the morning and once in the 
evening for 24 months.  In the event that the dose of fostamatinib is reduced to once daily due to 
AEs, study drug will be taken in the morning.   
If a subject misses a scheduled dose, they should be instructed to continue to take their next dose 
as normal and should not take 2 doses at the same time.   
Fostamatinib may be taken with or without food.  Subjects should be instructed not to take 
fostamatinib with grapefruit juice or any other food or drink known to inhibit CYP3A4.  Subjects 
who experience gastric upset following dosing, may be advised to take fostamatinib with food.  
8.5 
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 
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. (5, 6) 
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 is not considered an AE unless the 
severity, frequency, or character of the event worsens during the study period.  For the 
purpose of this study, pre-existing conditions are those documented in the Study C-935788-
047 or C-935788-048 as medical history.  
• 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: 
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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An SAE 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 one occurrence (from one 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 International Conference on Harmonisation (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; 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 of AEs 
other than diarrhea (See Appendix 3 for grading system to be used for diarrhea): 
• 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 page of the eCRF. 
9.2.1 
Adverse Event Reporting Period 
The AE reporting period begins from the last dose of study drug in Study C-935788-047 or 
C-935788-048 and ends with the final study (Follow-Up) visit in the Study C-935788-049. All 
ongoing AEs from Study C-935788-047 or C-935788-048 will be followed as AEs in Study 
C-935788-049. 
If an SAE is present at the Follow-Up Visit, 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 24 hours of his/her awareness of the event by 
completing and sending the provided SAE form to Rigel’s authorized safety representative.  
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 email or fax: 
Email: clinsafety@rigel.com 
Fax: Refer to the Study Reference Manual 
The site may contact the Medical Monitor (listed below) with questions regarding the reporting 
of SAEs. 
Sites should contact: 
 
 
 
 
 
 
 
9.3 
Reporting of Serious Adverse Events by Sponsor 
Regulatory Authorities, IRBs/IECs, 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. 
9.4 
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 
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. 


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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 
Continuous variables will be summarized using descriptive statistics, specifically the mean, median, 
standard deviation, minimum, and maximum.  Categorical variables will be summarized using 
frequencies and percentages. 
The statistical analysis of the data obtained from this study will be performed using SAS® version 9.1 
or higher.  All 1-sided tests will be performed at the 0.025 significance level, and all 2-sided tests 
will be performed at the 0.05 significance level, unless otherwise indicated.  
A full statistical analysis plan will be finalized before database lock. 
10.2 
Analysis Populations 
The Treated population will include all enrolled and treated subjects.  All efficacy endpoints will 
be analyzed based on the Treated population, and subjects will be analyzed according to their 
actual treatment.  The efficacy analyses based on the Treated population will be considered the 
primary efficacy analyses.  All analyses of safety will also be performed on the Treated 
Population. 
The Per-Protocol (PP) population will include all subjects in the Treated population who had no 
major protocol violations in either study.  Major protocol violations will include: 
• Not receiving any study treatment 
• Not receiving the correct study treatment 
• Failing to meet eligibility criteria 
• Other major protocol violations, as determined by a review of the data prior to database lock 
All efficacy endpoints will also be analyzed based on the PP population, and subjects will be 
analyzed according to their actual treatment.  The analyses based on the PP population will be 
considered secondary analyses of efficacy. 
10.3 
Definition of Baseline Measurements 
Baseline measurements will be the last measurement for the corresponding variable prior to the 
first randomized dose at Visit 3 in the Study C-935788-047 or C-935788-048. 


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10.4 
Analysis of Efficacy Endpoints 
10.4.1 
Primary Efficacy Endpoint 
10.4.1.1 
Version 1 
The first version of the primary efficacy endpoint is for the purpose of assessing efficacy among 
all patients while they are on active treatment in one of the prior studies, in the current extension 
study, or in both.  This version of the primary efficacy endpoint is the achievement and 
maintenance of a stable platelet count defined as follows:  
1)  Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
active treatment 
2)  Achievement of a sustained stable platelet response; defined as no two visits, at least 
4 weeks apart, with a platelet count < 50,000/ µL, without an intervening visit with a 
platelet count of ≥ 50,000/ µL unrelated to rescue therapy, within a period of 
12 months following initial achievement of the target platelet count (see above)  
The beginning of active treatment may be in the prior study or in the present extension study, 
depending upon when the subject first received active treatment.  Subjects who discontinue 
treatment due to lack of efficacy or to an AE prior to 12 months following achievement of a 
platelet count of at least 50,000/μL will be considered failures.  This endpoint will be 
summarized using counts and percentages, together with a 95% exact (Clopper-Pearson) CI for 
the true percentage.  
10.4.1.2 
Version 2 
The second version of the primary efficacy endpoint is for the purpose of a within-subject, 
between-study comparison of fostamatinib and placebo among subjects randomized to placebo in 
either of the prior studies.  This version of the primary efficacy endpoint is the achievement and 
maintenance of a stable platelet count, defined as follows:  
1)  Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
treatment (placebo treatment in the prior study and fostamatinib treatment in the 
present study) and  
2)  Achievement of a sustained stable platelet response; defined as no two visits, at least 
4 weeks apart, with a platelet count < 50,000/ µL, without an intervening visit with a 
platelet count of ≥ 50,000/ µL unrelated to rescue therapy, within a period of 
12 weeks following initial achievement of the target platelet count (see above).  
Subjects who discontinue treatment due to lack of efficacy or to an AE prior to 12 weeks 
following achievement of a platelet count of at least 50,000/μL, will be considered failures.  The 
null and alternative hypotheses for the comparison of fostamatinib vs. placebo are as follows:  
H0: pF = pP     vs.   H1: pF ≠ pP 
where pF and pP denote the true proportions achieving and maintaining a stable platelet count for 
fostamatinib and placebo, respectively.  The null hypothesis will be tested using a 2-sided 


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McNemar’s test conducted with a significance level of 0.05.  This analysis will be performed for 
the Treated and Per Protocol populations. 
10.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows:  
• Duration of stable platelet response 
• Proportion of subjects in whom a reduction in the dose of concomitant ITP therapy can 
be achieved while maintaining an adequate platelet count 
Duration of stable platelet response is defined as the time, following active treatment, from when 
the subject first achieves a platelet count of at least 50,000/μL until the first of two visits with 
platelet counts < 50,000/µL that are at least 4 weeks apart without an intervening visit with a 
platelet count ≥ 50,000/µL unrelated to rescue therapy.  Subjects who drop out of the study 
before achieving a stable platelet response will be assigned a value of 0 for this endpoint.  
Subjects who drop out of or complete the study while still maintaining a stable platelet response 
will be censored as of the time of the last platelet measurement prior to dropping out or 
completing the study.  For subjects who have achieved and are maintaining a stable platelet 
response but who discontinue treatment due to lack of efficacy or to an AE, duration of stable 
platelet response will be defined as the time from first achieving a platelet count of at least 
50,000/μL until discontinuation of treatment.  The duration of stable platelet response will be 
analyzed using the Kaplan-Meier method, and the Kaplan-Meier estimate of the median duration 
of stable platelet response will be presented together with the 95% CI for the true median.  
Achieving a reduction in the dose of concomitant ITP therapy while maintaining an adequate 
platelet count will be summarized using counts and percentages and a 95% exact (Clopper-
Pearson) CI for the true percentage.  A two-sided, McNemar’s test will be performed to compare 
the proportions of successes between the fostamatinib and placebo treatments. 
10.5 
Safety Endpoints 
The safety outcomes of this study include the frequency and severity of bleeding according to the 
IBLS, the change from baseline in blood pressure, liver function, and ANC, the incidence of GI 
complaints, and the incidence of AEs. 
The mean of the IBLS scores across visits during the treatment period will be summarized using 
descriptive statistics.  
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.  The one-sample t-test will be 
used to test whether the mean change from baseline equals 0 for each post-baseline time point.  
The numbers and percentages of patients with GI complaints at any time during the treatment 
period will be presented for the Safety Population.  


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AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with at least one AE, at least one SAE, and at least one 
treatment-related AE will be presented.  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. 
10.6 
Analysis of Pharmacokinetic Endpoints 
Plasma concentrations of R406 will be collected for a subset of patients at Month 2 Plasma 
concentrations will be summarized by time point using descriptive statistics including: the 
number of patients, arithmetic mean, standard deviation, geometric mean and associated 95% CI, 
median, minimum, maximum, and coefficient of variation for each treatment group.  Nominal 
blood sampling times will be used for these analyses.  A graph of mean plasma concentration of 
R406 versus nominal blood sampling time will be produced for each treatment group. 
The following PK parameters will be estimated for R406:  maximum plasma concentration 
(Cmax), time to Cmax (Tmax), and area under the plasma concentration-time curve through 8 hours 
(AUC(0-8)).  Cmax and Tmax will be taken directly from the data; AUC(0-8) will be calculated using 
the linear trapezoidal method.  These PK parameters will be summarized by treatment group 
using descriptive statistics.  Actual blood sampling times will be used for these analyses. 
10.7 
Determination of Sample Size 
No sample size calculations were performed for this study.  The sample size will be based upon 
the number of subjects in the C-935788-047 and C-935788-048 studies who are eligible to 
participate in this study and who choose to participate.   
10.8 
Handling of Dropouts and Missing Data 
No imputation will be performed for missing data.  
 


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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 United States Code of Federal 
Regulations (CFR), 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 
authorization for the collection, use, disclosure, and transfer of subject personal information (an 
“Authorization”), 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 (for example, in the US, a Health Insurance 
Portability and Accountability Act [HIPAA] Authorization will be used). 
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 
Institutional Review Board/Independent Ethics Committee 
The protocol, ICF, any advertisements to recruit subjects, or materials to be given to the subjects 
during the study must be approved by an appropriate IRB/IEC.  IRB/IEC approval must also be 
obtained for any protocol amendments and ICF revisions before implementing the changes. 
The Investigator is responsible for providing the IRB/IEC with any required information before 
or during the study, such as SAE expedited reports or study progress reports. 
The IRB/IEC must comply with current US regulations (§ 21 CFR 56), as well as 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: 
• 
A copy of the IRB/IEC (and Regulatory Authority, where applicable) letter that grants 
formal approval; and 
• 
A copy of the IRB/IEC-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 IRB/IEC 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 US regulations 
(§ 21 CFR Part 50), as well as other 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 IRB/IEC.  The study 


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center and the Investigator will include Rigel’s proposed changes to the ICF prior to submitting 
the ICF to the IRB/IEC for review and approval. 
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 (as designated on the Form 
FDA 1572) will provide a signed Financial Disclosure Form in accordance with § 21 CFR 54.  
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 
The Investigator/study staff must maintain adequate and accurate source documentation to 
document the treatment and study course of a subject and to substantiate the integrity of the trial 
data submitted for review to the regulatory authorities.  These documents include investigators’ 
study files and original subject clinical source documents generated at the study site.  The term 
“original” means the first recording of the data. 
The Investigator will ensure the study files are maintained, including the eCRFs and query 
forms, protocol/amendments, IRB/EC and regulatory approvals with associated correspondence, 
informed consents, study drug records, staff curriculum vitae, all correspondence, and other 
appropriate documents. 
Subject source documents may include, but are not limited to, subject hospital/clinic records, 
hospital and/or clinic or office records documenting subject visits, ICFs, subject questionnaires, 
laboratory reports, ECGs, and treatments or procedures pertaining to SAEs.  The investigator 
must assure that all original source documents are available to support monitoring activities. 
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) are 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. 


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In order to assure 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 the Rigel or its authorized representative, the FDA, 
and other regulatory 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). 
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 the 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 IRB/EC with a final 
report and provide Rigel or 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. 


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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.  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. 
Essential documentation includes, but is not limited to, the Investigator’s Brochure; signed 
protocol and amendments; signed Form FDA 1572 (or equivalent), signed Informed Consent and 
HIPAA Authorization (US only); 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 IRB/IEC 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, ECG tracing) 
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 the FDA or other 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 concurrence 
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. Podolanczuk A, Lazarus AH, Crow AR, et al. Of mice and men: an open-label pilot study 
for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 2009; 
113(14): 3154–60. Epub 2008/12/20.   
2. Yang JC, Reguart N, Barinoff J, et al. Diarrhea associated with afatinib: an oral ErbB 
family blocker. Expert review of anticancer therapy 2013; 13(6): 729–36. Epub 
2013/03/20.   
3. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in 
cancer. In: MacLeod CM, editor. Evaluation of Chemotherapeutic Agents. New York: 
Columbia University Press; 1949; 191–205.   
4. Page LK, Psaila B, Provan D, et al. The immune thrombocytopenic purpura (ITP) 
bleeding score: assessment of bleeding in patients with ITP. Bri J Haem 2007; 138(2): 
245–248. Epub 2007/06/05.   
5. FDA. Guidance for Industry and Investigators: Safety reporting requirements for INDs 
and BA/BE studies. Food and Drug Administration (FDA); 2012.   
6. ICH. Guideline for industry: clinical safety data management: definitions and standards 
for expedited reporting (ICH-E2A). International Conference on Harmonisation (ICH) 
1995.   
7. USDHHS. Common terminology criteria for adverse events (CTCAE). In: NIH, NCI, 
editors. 2009.   
8. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and 
management of blood pressure in patients receiving vascular endothelial growth factor 
signaling pathway inhibitors. J Nat Canc Instit 2010; 102(9): 596–604.   
9. FDA. Guidance for Industry: Drug-induced liver injury: premarketing clinical evaluation. 
In: FDA,CDER,CBER.http://www.fda.gov/downloads/drugs/guidancecompliance 
regulatory information/guidances/ucm174090.pdf: issued July 2009.   
10. Miller AB, Hoogstraten B, Staquet M, Winkler A.  Reporting results of cancer treatment.  
Cancer 1981; 47(1): 207–214.   
   
 


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Appendix 1: Dose Modification for Possible Drug-Induced Liver Injury 
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 interrupted 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.  
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 bilirubin > 2x ULN, with ALP < 2x ULN (Hy’s law criteria 
met), please follow the instructions below: 
• Stop study drug treatment and contact the Sponsor's medical monitor immediately to 
discuss the data and consider withdrawal of the subject from the study for possible 
drug-induced liver injury.   
• The Investigator will follow the subject until liver biochemistry parameters and any 
appropriate clinical symptoms and signs return to normal or baseline levels, or as long as 
medically indicated. 
• The Investigator will investigate the etiology of the event and perform diagnostic 
investigations as discussed with the Sponsor’s Medical Monitor. 


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If AST or ALT ≥ 3x ULN or TBL > 2x ULN, and the subject is exhibiting the following 
symptoms:  nausea, vomiting, abdominal pain: 
• Study drug administration should immediately be interrupted. 
• LFTs, including bilirubin and alkaline phosphatase should be repeated every 
3 days/72 hours until ALT/AST or TBL returns to < 1.5x ULN. 
• When the ALT/AST or TBL returns to < 1.5x ULN study drug may be restarted at dose 
level -1. 
If AST or ALT ≥ 3x ULN or TBL > 2x ULN and subject is asymptomatic: 
• Repeat LFTs, including bilirubin and ALP, within 72 hours. 
• If repeat testing shows an increase in ALT/AST or TBL and the ALT/AST value exceeds 
5x ULN, interrupt study drug administration. 
• LFTs, including bilirubin and alkaline phosphatase should be repeated every 
3 days/72 hours until ALT/AST is decreasing, and should be followed until transaminase 
returns to < 1.5x ULN. 
• Upon return of ALT/AST or TBL to < 1.5x ULN, study drug may be restarted at dose 
level -1. 
 
Source: FDA 2009 (9) 


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Appendix 2: Management of Neutropenia 
Based on data from previous clinical studies, treatment with fostamatinib may be associated with 
lowering of ANC. 
A decrease in ANC may require adjustment of the dose of study drug.  Follow the dose 
adjustment guidelines as outlined below when adjusting the dose of study medication. 
Dose Adjustment 
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 ANC to < 1,000/μL: 
• Repeat ANC within 72 hours. 
• If repeat testing confirms that ANC is < 1,000/μL, immediately interrupt study drug 
administration. 
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, immediately interrupt study drug until ANC > 1,500/μL. 
• Restart study drug at dose level -2. 


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Appendix 3: Management of Diarrhea 
Diarrhea  
• Based on data from previous clinical studies, treatment with fostamatinib may be 
associated with diarrhea. 
• Subjects should be made aware that they may experience diarrhea and instructed  to 
contact the clinical site if they experience diarrhea. 
• Careful monitoring, and early, aggressive treatment of diarrhea will ensure that severe 
complications such as dehydration are avoided. 
• In some circumstances it may be necessary to adjust the dose of study drug.  Follow the 
dose adjustment guidelines outlined below when adjusting the dose of study medication. 
Dose Adjustment 
 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 Diarrhea:  The US National Cancer Institute has introduced the 
following criteria for the grading of severity of diarrhea: (7)  
• 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 Diarrhea 
• 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. 


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• Consider stool sample for microbiologic evaluation and antibiotics if subject is 
neutropenic. 
• Grade 1, consider initiating treatment with loperamide according to the regimen below.  
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. 
o Not to exceed a maximum of 20 mg (10 tablets) in 24 hours. 
• Subjects with persistent diarrhea (> 48 hours) should be monitored carefully for 
dehydration and electrolyte imbalance. 
Grade 3 or 4 Diarrhea 
• The subject should be instructed to immediately interrupt 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 diarrhea 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 diarrhea improves to ≤ Grade 1, restart study drug at dose level -1. 
Management of Second Event of Grade 3 and 4 Diarrhea 
• Immediately interrupt study drug administration. 
• 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 diarrhea has been 
resolved: 
o 4 mg loperamide initial dose. 


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o 2 mg loperamide after each subsequent loose stool.  
o Not to exceed a maximum of 20 mg (10 tablets) in 24 hours. 
• When diarrhea improves to ≤ Grade 1, restart study drug at dose level -2. 
 
Source:  Yang 2013 (2) 
 
 


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Appendix 4: 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, diabetes or renal insufficiency consideration should be given to maintaining 
the blood pressure below 130/80 mmHg. 
In previous clinical studies evaluating fostamatinib, the following antihypertensive agents have 
proven effective in managing BP: 
• Calcium channel blockers 
• Angiotensin converting enzyme inhibitors 
• Angiotensin receptor blockers 
• Beta-blockers 
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 below when adjusting the dose of study medication. 
Dose Adjustment 
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 subject becomes symptomatic due to blood pressure elevation. 
• 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 randomization: 
• Immediately interrupt study drug administration. 
• Initiate or increase anti-hypertensive medication. 
• Reassess BP twice weekly. 
• If repeat BP ≥ 180/110 mmHg despite anti-hypertensive treatment, discontinue study 
drug.  
• Increase anti-hypertensive medications until control is established. 
• Restart study drug 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 
randomization: 
• Continue study drug at assigned dose level. 
• Initiate or increase anti-hypertensive therapy immediately.  
• 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 when blood pressure < 140/90 mmHg. 
If BP is ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic but below 160 systolic or 100 
diastolic at any visit after randomization: 
• 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 initiate or increase antihypertensive therapy immediately.  
• 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 to dose level -1. 
 
Source:  Maitland 2010 (8) 
 


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Appendix 5: SF-36 Questionnaire 
 


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Appendix 6:  
Karnofsky Performance Status Scale 
 
Scale (%) 
Description 
100 
Normal; no complaints 
(ECOG 0) 
90 
Able to carry on normal activities; minor signs or symptoms of disease  
(ECOG 0) 
80 
Normal activity with effort  
(ECOG 1) 
70 
Cares for self; unable to carry on normal activity or do active work 
(ECOG 1) 
60 
Requires occasional assistance but able to care for most of his/her needs  
(ECOG 2) 
50 
Requires considerable assistance and frequent medical care  
(ECOG 2) 
40 
Disabled: requires special care and assistance 
(ECOG 3) 
30 
Severely disabled; hospitalization indicated, though death not imminent  
(ECOG 3)  
20 
Very sick; hospitalization necessary; active supportive treatment necessary 
(ECOG 4) 
10 
Moribund 
(ECOG 4) 
0 
Dead 
Source:  Karnofsky 1949 (3) 


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Appendix 7: The Immune Thrombocytopenic Purpura Bleeding Score Assessment 
 
 
Bleeding Score 
Site  
0 
1 
2 
Skin (Physical Examination 
(PE))   
None 
1–5 bruises and/or 
scattered petechiae 
>5 bruises with 
size >2 cm and/or 
diffuse petechiae 
Oral (PE) 
None 
1 blood blister or >5 
petechiae or gum 
bleeding that clears 
easily with rinsing 
Multiple blood 
blisters and/or gum 
bleeding 
Skin (Hx) 
None 
1–5 bruises and/or 
scattered petechiae 
>5 bruises with 
size >2 cm and/or 
diffuse petechiae 
Oral (Hx) 
None 
1 blood blister or >5 
petechiae and/or 
gum bleeding <5 
min 
Multiple blood 
blisters and/or gum 
bleeding >5 min 
Epistasis 
None 
Blood when blowing 
nose and/or 
epistaxis <5 min 
(per episode) 
Bleeding >5 min 
(per episode) 
Gastrointestinal (GI) 
None 
Occult blood 
Gross blood 
Urinary (U) 
None 
Microscopic  
(+ve dipstick) 
Macroscopic 
Gynecological (GYN) 
None  
(normal 
period) 
Spotting not at time 
of normal period 
Bleeding >spotting 
not at time of 
period 
or very heavy 
period 
Pulmonary 
None 
N/A 
Yes 
Intracranial hemorrhage 
None 
N/A 
N/A 
Subconjunctival hemorrhage 
None 
Yes 
N/A 
Source:  Page 2007 (4)  


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Appendix 8: World Health Organization Bleeding Scale 
 
0 – No bleeding 
1 – Petechiae 
2 – Mild blood loss 
3 – Gross blood loss 
4 – Debilitating blood loss 
 
 
Source:  Miller 1981 (10) 
 


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Appendix 9: 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 subtherapeutic concentrations; 
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%.  Subjects should have their dose of HMG-
CoA reductase lowered and lipid response (CPK, clinical signs) followed closely to monitor for 
any adverse effects associated with higher concentrations, including myositis. 
Subjects’ concomitant medications should be examined for additional possible drug-drug 
interactions.  The list below is not an exhaustive list (the Sponsor’s Medical Monitor should be 
consulted in the event of questions). 
List of Inhibitors and Inducers of CYP3A4 
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 
 
 
CYP3A Inducers 
Barbiturates 
Efavirenz 
Nevaripine 
Pioglitazone 
Rifampin 
Rifabutin 
Carbamazepine 
Phenytoin 
Modafinil 
St. John’s Wort 
 
 
 


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Appendix 10:  
Post Database Lock Extension 
After the final database lock, patients who continue to receive study drug will be cared for 
according to local clinical practice.  All visits  required in the original protocol must be 
completed and the data reported in the EDC.  Protocol changes made after database lock must be 
approved by the Sponsor. The information in this section will not be provided to all 
Investigators; but rather to Investigators who continue to treat patients with study drug. 
Patients will receive the same dose of study drug that the investigator has determined provided 
clinical benefit before database lock.  The dose may be adjusted down during this period but 
cannot be adjusted to a dose higher than 150 mg PO BID, and only if this dose level was 
previously well tolerated.  No more than 6 months of study drug will be dispensed at any one 
time.  Treatment on this extension may continue for up to 12 months if the patient is tolerating 
study drug, has not withdrawn from the study, and is considered by the investigator to continue 
to receive clinical benefit.   
After the final database lock, for patients who continue to receive study drug, the following 
information will be recorded in the patient chart (unless otherwise directed) according to local 
practice: 
• Concomitant medication use 
• Study drug dispensing/accountability on the Drug Accountability Log 
• AEs and SAEs.   
o SAEs must be reported to the Sponsor on the Rigel SAE form as described in 
Section 9.2.3 including information relevant to SAE interpretation (eg, concomitant 
medications or laboratory values [local testing]).  The sponsor will advise the Investigator 
or study site personnel on how to proceed in the event of an SAE. The IB is the reference 
document used for the definition of expectedness/listedness. 
• The date and reason for patient withdrawal from the study 
Final study visit procedures will not be conducted for patients who continue to receive study 
drug.  On-site monitoring will be limited, and only SAEs will be collected after the final database 
lock. Completion of eCRFs will no longer be required as no further analysis or data validation 
will be performed.  Also, the SAEs will not be integrated in any integrated analysis that may be 
performed.   

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan  
 
 
SAP Version: 
Version 5.0 
Date of SAP Version 
May 27, 2020 
 
 
 
Sponsor: 
Rigel Pharmaceuticals, Inc. 
1180 Veterans Boulevard 
South San Francisco, CA  94080, USA  
 
Study Title: 
A Phase 3 Open Label Extension Study of Fostamatinib 
Disodium in the Treatment of Persistent/Chronic Immune 
Thrombocytopenic Purpura  
 
Drug Name:  
Tavalisse® (Fostamatinib Disodium) 
Protocol Number: 
C-935788-049 
 
EudraCT Number: 
2013-005454-30 
 
Protocol Version/Date: 
Final Protocol Version 5.0, dated November 19, 2019 
 
 
 
Author: 
 
 
 
  
Director of Biostatistics 
Rigel Pharmaceuticals, Inc. 
  
 
 
 


 
Rigel Pharmaceutical 
SAP Version 5.0 
Page 2 of 33 
 
CONFIDENTIAL  
 
 
APPROVAL SHEET 
Product: 
Fostamatinib Disodium 
 
Protocol Number: 
C-935788-049 
 
EudraCT Number: 
2013-005454-30 
 
Version: 
Version 5.0 
 
Version Date: 
May 27, 2020 
 
 
The undersigned have reviewed this statistical analysis plan and find it to be consistent with the 
protocol as it applies to their respective areas. 
 
Approver 
Signature 
Date 
 
Executive Director of Biometrics 
Rigel Pharmaceuticals, Inc. 
 
 
 
 
Vice President Clinical Science and Safety 
Rigel Pharmaceuticals, Inc 
 
 
 
 
 
 


 
Rigel Pharmaceutical 
SAP Version 5.0 
Page 3 of 33 
 
CONFIDENTIAL  
 
 
TABLE OF CONTENTS 
APPROVAL SHEET ....................................................................................................................... 2 
LIST OF ABBREVIATIONS AND TERMS ................................................................................. 5 
1.0 
INTRODUCTION ............................................................................................................... 7 
2.0 
STUDY OBJECTIVES ....................................................................................................... 8 
3.0 
INVESTIGATIONAL PLAN ............................................................................................. 8 
3.1. 
OVERALL STUDY DESIGN SUMMARY ......................................................................................................... 8 
3.2. 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT ................................................................................ 11 
3.3. 
BLINDING ................................................................................................................................................. 12 
3.4. 
DETERMINATION OF SAMPLE SIZE ............................................................................................................ 12 
3.5. 
CHANGES TO THE PROTOCOL-SPECIFIED ANALYSES ................................................................................ 12 
4.0 
EFFICACY, SAFETY AND PHARMACOKINETIC ENDPOINTS AND 
DEFINITIONS .............................................................................................................................. 13 
4.1. 
DEMOGRAPHIC CHARACTERISTICS ........................................................................................................... 13 
4.2. 
ITP HISTORY AND PREVIOUS ITP PROCEDURES ....................................................................................... 13 
4.3. 
PRIMARY EFFICACY ENDPOINT ................................................................................................................ 14 
4.4. 
SECONDARY EFFICACY ENDPOINTS .......................................................................................................... 15 
4.5. 
SAFETY ENDPOINTS .................................................................................................................................. 15 
4.6. 
OTHER ENDPOINTS ................................................................................................................................... 16 
4.7. 
PHARMACOKINETIC ENDPOINTS ............................................................................................................... 16 
5.0 
STATISTICAL METHODS ............................................................................................. 17 
5.1. 
GENERAL CONSIDERATIONS ..................................................................................................................... 17 
5.2. 
ADJUSTMENTS FOR COVARIATES ............................................................................................................. 17 
5.3. 
HANDLING OF DROPOUTS AND MISSING DATA ........................................................................................ 17 
5.4. 
INTERIM ANALYSES AND DATA MONITORING .......................................................................................... 17 
5.5. 
MULTICENTER STUDY .............................................................................................................................. 17 
5.6. 
MULTIPLE COMPARISONS / MULTIPLICITY ............................................................................................... 17 
5.7. 
EXAMINATION OF SUBGROUPS ................................................................................................................. 18 
5.8. 
DEFINITION OF BASELINE MEASUREMENTS .............................................................................................. 18 
6.0 
ANALYSIS POPULATIONS ........................................................................................... 18 
6.1. 
TREATED POPULATION ............................................................................................................................. 18 
7.0 
PATIENT DISPOSITION ................................................................................................. 18 
8.0 
DEMOGRAPHIC, BASELINE CHARACTERISTICS, ITP HISTORY AND 
PREVIOUS PROCEDURES ......................................................................................................... 19 
9.0 
STUDY DRUG DISPENSING, COMPLIANCE, AND EXPOSURE ............................. 19 
10.0 
EFFICACY ANALYSES .................................................................................................. 20 
10.1 
PRIMARY EFFICACY ENDPOINT ................................................................................................................ 20 
10.1.1 
VERSION 1 ........................................................................................................................................... 20 
10.1.2 
VERSION 2 ........................................................................................................................................... 20 
10.2 
SECONDARY EFFICACY ENDPOINT ........................................................................................................... 21 
10.2.1 
Duration of Platelet Response ........................................................................................................ 21 
10.2.2 
Total Duration of Platelet Response .............................................................................................. 21 


 
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10.2.3 
Reduction in the Dose of Concomitant ITP Therapy ...................................................................... 21 
10.3      ADDITIONAL EFFICACY ANALYSES ............................................................................................................. 21 
11.0 
SAFETY ANALYSES ...................................................................................................... 22 
11.1 
ADVERSE EVENTS .................................................................................................................................... 22 
11.2 
CLINICAL LABORATORY TESTS ................................................................................................................ 23 
11.3 
VITAL SIGNS............................................................................................................................................. 24 
11.4 
IBLS AND WHO BLEEDING SCALE SCORES .......................................................................................... 25 
11.5 
PHYSICAL EXAMINATION ......................................................................................................................... 25 
11.6 
KARNOFSKY PERFORMANCE STATUS (KPS) ............................................................................................ 25 
11.7 
CONCOMITANT MEDICATIONS .................................................................................................................. 25 
12.0 
OTHER ANALYSES ........................................................................................................ 25 
12.1 
PHARMACOKINETICS ................................................................................................................................ 25 
12.2 
SF-36 ....................................................................................................................................................... 26 
12.4 
PROTOCOL DEVIATIONS ........................................................................................................................... 26 
12.5 
RESCUE THERAPY ................................................................................................................................... 26 
13.0 
REFERENCES .................................................................................................................. 28 
14.0 
APPENDICES ................................................................................................................... 29 
 
 


 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
AIHA 
Autoimmune Hemolytic Anemia 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Counts 
ANOVA 
Analysis of variance 
AST 
Aspartate Aminotransferase 
bid  
bis in die (twice daily) 
BP 
Blood Pressure 
CI 
Confidence interval 
CTCAE  
Common Terminology Criteria for Adverse Events 
DHHS 
Department of Health and Human Services 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FACIT-F 
Functional Assessment of Chronic Illness Therapy - Fatigue Scale  
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgG 
Immunoglobulin G 
IRB 
Institutional Review Board 
ITP 
Immune Thrombocytopenic Purpura 
IV 
Intravenous 
IVIg 
Intravenous IgG 
kg 
Kilogram 
KPS 
Karnofsky Performance Status 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Tests 
LS 
Least Square  
mg 
Milligram 


 
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Abbreviation 
Definition 
PK 
Pharmacokinetic 
PP 
Per Protocol 
qd 
quaque die (once daily) 
RTX 
Rituximab  
R406 
Rigel compound R940406 
R788 
Rigel compound R935788 (fostamatinib) 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
Syk 
Spleen Tyrosine Kinase 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale  
wAIHA 
Warm Autoimmune Hemolytic Anemia 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


 
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1.0 
INTRODUCTION 
This document details the analysis plan for the study entitled “A Phase 3 Open Label Extension 
Study of Fostamatinib Disodium in the Treatment of Persistent/Chronic Immune 
Thrombocytopenic Purpura”. It describes the proposed efficacy and safety analyses, including 
planned summary tables and by-subject data listings.  
Immune Thrombocytopenic Purpura (ITP) is a disorder manifested by immune mediated platelet 
destruction. It is estimated that there are 50–100 new cases per million persons each year in the 
U.S. and Europe, with the cases roughly divided between adults and children. The natural history 
of the disease in children is different and generally more benign than ITP in adults. ITP may be 
primary or secondary to a variety of conditions, including autoimmune disease (e.g., Systemic 
Lupus Erythematosus), lymphoid malignancies, or chronic viral diseases such as hepatitis and 
HIV.  
ITP in adults is typically a chronic disease, with a low spontaneous remission rate. Although 
responses to glucocorticoids, intravenous IgG (IVIg), splenectomy, and thrombopoietic agents 
may be encouraging, a significant number of patients remain severely thrombocytopenic for long 
durations and are subject to risk of spontaneous or trauma-induced hemorrhage. Even in 
asymptomatic patients, platelet counts below 20,000/μL - 30,000/μL often prompt treatment.  
Fcγ receptor (FcγR) signaling in monocytes and macrophages plays an important role in the 
initiation and propagation of autoimmune responses. The activating FcγR are associated with a 
signaling subunit, referred to as the FcRγ chain, whose phosphorylation subsequent to receptor 
activation results in the recruitment and activation of spleen tyrosine kinase (Syk). Syk is an 
important component of the signaling system of activated Fc receptors, as well as the B-cell 
receptor (BCR).  
Aggregation of the Fc receptors, induced by antibody-antigen complexes, can induce a multitude 
of cellular functions (including degranulation, arachidonic acid metabolism, antibody dependent 
cellular cytotoxicity, phagocytosis and cytokine secretion) depending on the cell type, and leads 
to tissue damage and the propagation of inflammatory responses. FcγR have been implicated in 
immune destruction of platelets. Accelerated clearance of circulating IgG-coated platelets via 
Fcγ receptor (FcγR)-bearing macrophages in the spleen and liver is a key mechanism in ITP. 
Fostamatinib (R788), the prodrug of R406, is a potent and relatively selective inhibitor of Syk 
and consequently of the FcR and BCR signaling pathways. Fostamatinib inhibits Syk and FcR 
signaling at concentrations generally achieved with doses of 100 mg twice daily (bid) and above, 
and both preclinical and early clinical data have affirmed its activity in ITP. 
Additional details of the program are described in the Protocol. 


 
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2.0 
STUDY OBJECTIVES 
The primary objective of this study is to assess the long-term safety of fostamatinib in subjects 
with persistent/chronic ITP. 
The secondary objectives of this study are: 
• To establish the long-term efficacy of fostamatinib in achieving and maintaining a stable 
platelet count in subjects who complete the treatment phase of Study C-935788-047 or 
Study C-935788-048 
• To assess the pharmacokinetic (PK) profile of fostamatinib in subjects with 
persistent/chronic ITP.  
3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design Summary 
This is a Phase 3 multi-center, open label extension study to evaluate the long-term safety and 
efficacy of fostamatinib in achieving and maintaining a stable platelet response in subjects with 
persistent/chronic Immune Thrombocytopenic Purpura (ITP).  For the purpose of this study, the 
term ‘subject’ will refer to patients with persistent/chronic ITP participating in this study.  Up to 
150 subjects will be enrolled at multiple sites.  The study will consist of monthly visits for 18 
months followed by every-other-month visits for a  maximum of 5 years of treatment or until 
commercial availability of drug, whichever comes first. 
Figure 1: Study Design 
 
*At Month 1  subjects receiving fostamatinib 100 mg bid should have the dose 
escalated to fostamatinib 150 mg bid if the platelet count is <50,000/µL. 
Eligible subjects include subjects from Study C-935788-047 or C-935788-048 who have 
completed the Week 24 evaluation or who discontinue early (starting at Week 12) due to lack of 
response.  Subjects must meet the Inclusion/Exclusion criteria listed in Section 6.1 and Section 
6.2 of the protocol to be eligible to participate in the study.    Subjects designated as responders 
(defined as platelet count ≥ 50,000/µL) at the time of rollover will continue in the extension 
study at their current Study C-935788-047 or C-935788-048 dose and regimen.  Subjects who 


 
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enter the extension study as non-responders (defined as platelet count < 50,000/µL) will be 
allocated to fostamatinib 100 mg PO bid regardless of their dose and regimen in the prior study.  
All subjects will receive open-label fostamatinib. Subjects will remain blinded to their treatment 
assignment (active or placebo) from Study C-935788-047 or C-935788-048. 
At Month 1, subjects receiving fostamatinib 100 mg PO bid should have the dose escalated to 
fostamatinib 150 mg PO bid if platelet count < 50,000/μL and the study drug is well tolerated 
(refer to Section 7.2.1 of the protocol).  Conversely, the dose may be reduced at any time to a 
dose as low as fostamatinib 100 mg PO qd if dose limiting AEs are observed as defined by the 
extension study protocol (see Section 7.2.2 and Appendix 1, Appendix 2, Appendix 3, and 
Appendix 4 of the protocol). 
A schedule of study procedures for this study is presented in Table 1.   


 
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Table 1: 
Schedule of Study Procedures 
 
Day 1 
Screen/ 
Enrollmenta 
End of 
Month 1  
(± 3 days) 
Months 2–18  
(± 3 days) 
Months 19–
60  
(± 1 week) 
Follow-up  
(± 7 days)i 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Physical exam/KPS 
X 
X 
monthly 
every other 
month 
X 
Concomitant 
medications 
X 
X 
monthly 
every other 
month 
X 
Vital signsb 
X 
X 
monthly 
every other 
month 
X 
Bleeding assessmentc 
X 
X 
monthly 
every other 
month 
X 
ECG 
X 
 
 
 
 
Hematologyd 
X 
 
monthly 
every other 
month 
X 
Platelets 
X 
X 
monthly 
every other 
month 
X 
Serum chemistries 
(including LFTs)e 
X 
 
Months 4, 8, 
12, 16 
every other 
month 
X 
LFTs onlyf 
 
 
monthly (in 
months full 
serum 
chemistries 
not done) 
 
X 
Immunoglobulin levels 
X 
 
 
 
X 
Urinalysis 
X 
 
Months 4, 8, 
12, 16 
every 4 
months 
X 
Urine pregnancy testg 
X 
 
every other 
month 
every other 
month 
 
SF-36h 
X 
 
Month 12 
 
 
AEs 
X 
X 
monthly 
every other 
month 
X 
PK 
 
 
Month 2 
 
 
Study drug 
dispensed/Accountabilit
y 
X 
X 
monthly 
every other 
month 
 
Dose adjustment (prn) 
X 
X 
monthly 
every other 
month 
 




 
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3.3. 
Blinding 
This is an open label study, so no blinding will be done. However, subjects will remain blinded 
to their treatment assignment (active or placebo) from the previous study. 
3.4. 
Determination of Sample Size 
No sample size calculations were performed for this study.  The sample size will be based upon 
the number of patients in the C-935788-047 and C-935788-048 studies who are eligible to 
participate in this study and choose to participate.   
3.5. 
Changes to the Protocol-Specified Analyses 
For the method of assigning subject to treatment (as mentioned in Section 3.2), protocol states 
that the responders will initiate open-label fostamatinib treatment with the dose and regimen that 
was efficacious in achieving a stable platelet response in Study C-935788-047 or C-935788-048. 
In reality, the patients were not required to be stable responders but rather to have at least one 
platelet count of at least 50,000/μL. 
The protocol defines the baseline value as the last measurement for the corresponding variable 
prior to the first randomized dose at Visit 3 in Study C-935788-047 or C-935788-048. For the 
analyses described by this SAP, the baseline value will be defined as the last measurement for 
the corresponding variable prior to the first dose of fostamatinib in Study C-935788-047 or C-
935788-048 (for fostamatinib patients in the previous study) or the present study (for placebo 
patients in the previous study), unless specified otherwise in the SAP.  
For secondary efficacy endpoint, duration of stable platelet response, has been changed to 
duration of platelet response, the  protocol specified that subjects who drop out of the study 
before achieving a platelet response will be assigned duration of platelet response of 0 and will 
be censored. In addition to the duration of platelet response, total duration of platelet response is 
also defined in Section 4.4 in this SAP and will be analyzed. 
For secondary efficacy endpoint, subjects with reduction in the dose of concomitant ITP therapy 
while maintaining an adequate platelet count (yes/no), the protocol states that a two-sided, 
McNemar’s test was to be performed to compare the proportions of subjects achieving a 
reduction in the dose of concomitant ITP therapy while maintaining an adequate platelet count 
between the fostamatinib and placebo treatments. In this SAP, no McNemar’s test will be 
performed, instead the patient level of listing for the  concomitant ITP therapy using during the 
present study will be provided in data listing. 
Also, per protocol version 5, one-sample t-test was to be used to evaluate the mean change from 
baseline for each post-baseline time point for the safety endpoints of systolic and diastolic blood 


 
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pressure, liver function test [i.e., ALT, AST, alkaline phosphatase, and bilirubin (total, direct, 
and indirect)] and ANC. This one-sample t-test will not be performed.  
Interventions required to manage hypertension will also be summarized by baseline use of anti-
hypertensives. 
The additional exploratory efficacy endpoints and other endpoints are defined in Appendix 14.1. 
The additional other endpoints for SF-36 are presented as follows: 
• Patients with change from baseline ≥ 8 at Month 12 for each of 8 SF-36 domains 
(physical functioning, role physical, bodily pain, general health, vitality, social 
functioning, role emotional, and mental health), respectively(yes/no)   
• Patients with change from baseline ≥ 8 for physical health summary score and mental 
health summary score, respectively(yes/no)   
 
 
4.0 
EFFICACY, SAFETY AND PHARMACOKINETIC ENDPOINTS AND 
DEFINITIONS 
4.1. 
 Demographic Characteristics 
 Demographic characteristics include the following:  
• Age (years)  
• Age Category (years):  < 50, 50 – <65, and ≥ 65 
• Age Category (years):  65 - <75, and ≥ 75 (this age category is only for patients with 
age ≥ 65 years old) 
• Gender 
• Ethnicity 
• Race 
• Weight (kg) 
• Weight Category (kg): <65, 65 -< 80, 80 - <90 and ≥ 90 
• Height (cm) 
• Body Mass Index (BMI) (kg/m^2)  
• Body Mass Index BMI Category (kg/m^2): <18.5, 18.5 -<30 and ≥ 30 
Demographic characteristics  above are defined the same way as those in Study C-935788-047 or 
C-935788-048 baseline. 
4.2. 
ITP History and Previous ITP Procedures 
ITP history, previous ITP procedures, and baseline characteristics include the followings:  
• Baseline Platelet count(/uL) 
• Baseline IBLS scores and baseline WHO Bleeding Scale scores 
• Previous Splenectomy (Yes/No) 
• Duration of ITP (years)  
• Type of prior ITP (Persistent ITP or Chronic ITP) 


 
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• Prior ITP therapies 
• Number of unique prior ITP therapies 
 
Baseline Platelet count(/uL) is defined as last measurement prior to the first dose of fostamatinib, 
either the first dose of fostamatinib in Study C-935788-047 or C-935788-048 (for fostamatinib 
patients in the previous study) or the present study (for placebo patients in the previous study). 
 
Baseline IBLS scores and baseline WHO Bleeding Scale scores, previous splenectomy (Yes/No), 
duration of ITP (years), type of prior ITP (Persistent ITP or Chronic ITP), prior ITP therapies 
and the number of unique prior ITP therapies are defined in the same way as presented for Study 
C-935788-047 or C-935788-048.  
 
4.3. 
Primary Efficacy Endpoint 
Version 1:  The first version of the primary efficacy endpoint is for the purpose of assessing 
efficacy among all patients while they are on active treatment in one of the prior studies, in the 
current extension study, or in both.  This version of the primary efficacy endpoint is the 
achievement and maintenance of a stable platelet response defined as follows:  
1) Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
active treatment and  
2) Achievement of a sustained stable platelet response; defined as no two visits, at least 4 
weeks apart, with a platelet count < 50,000/ µL, without an intervening visit with a 
platelet count of ≥ 50,000/ µL unrelated to rescue therapy, within a period of 12 months 
following initial achievement of the target platelet count (see above).  
 
The beginning of active treatment may be in the prior study or in the present extension study, 
depending upon when the patient first received active treatment.  Patients who discontinue 
treatment due to lack of efficacy or to an AE prior to 12 months following achievement of a 
platelet count of at least 50,000/μL will be considered failures.  
 
Version 2:  The second version of the primary efficacy endpoint is for the purpose of a within-
patient, between-study comparison of fostamatinib and placebo among patients randomized to 
placebo in either of the prior studies, This version of the primary efficacy endpoint is the 
achievement and maintenance of a stable platelet response defined as follows:  
1) Achievement of a platelet count of at least 50,000/µL within 12 weeks of beginning 
treatment (placebo treatment in the prior study and fostamatinib treatment in the present 
study) and  
2) Achievement of a sustained stable platelet response; defined as no two visits, at least 4 
weeks apart, with a platelet count < 50,000/ µL, without an intervening visit with a 
platelet count of ≥ 50,000/ µL unrelated to rescue therapy, within a period of 12 weeks 
following initial achievement of the target platelet count (see above).   
 


 
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Platelet counts taken within 28 days of rescue therapy will be excluded when determining the 
value of this endpoint. Patients who discontinue treatment or patients who are rescued prior to 12 
weeks following achievement of a platelet count of at least 50,000/μL, will be considered 
failures. 
4.4. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• The duration of platelet response (months) and total duration of platelet response 
(months) 
• Patients with reduction in the dose of concomitant ITP therapy while maintaining an 
adequate platelet count (yes/no) 
 
Duration of platelet response will be defined as the length of time from when the patient first 
achieves a platelet count of at least 50,000/μL until the first of two visits with platelet counts 
< 50,000/µL that are at least 4 weeks apart without an intervening visit with a platelet count 
≥ 50,000/µL unrelated to rescue therapy.   
 
Four additional definitions of duration of platelet responses are stated in Appendix 14.2 
 
Patients who drop out of the study before achieving a platelet response (i.e., achieving a platelet 
count of ≥ 50,000/μL will be assigned a value of 0 for this endpoint. Patients who drop out of the 
study by the time of database lock while still maintaining a platelet response will be censored as 
of the time of the last platelet measurement prior to dropping out of the study. Similarly, patients 
who remain in the study by the time of database lock while still maintaining a platelet response 
will be censored as of the time of the last platelet measurement prior to the time of database lock. 
For patients who have achieved and are maintaining a platelet response but who have 
discontinued treatment due to lack of efficacy or to an AE by the time of database lock,  duration 
of platelet response will be defined as the time from first achieving a platelet count of ≥ 
50,000/μL  until discontinuation of treatment. 
The total duration of platelet response is defined as the sum of all durations of platelet responses.    
Regarding the secondary efficacy endpoint of patients with reduction in the dose of concomitant 
ITP therapy while maintaining an adequate platelet (yes/no), a patient is said to have reduction 
while maintaining an adequate platelet count if the date of reduction of dose of concomitant ITP 
therapy occurs within the span of the duration of a platelet response during the C-935788-049 
study and the reduction was not prompted by AE. 
 
4.5. 
Safety Endpoints 
The following safety endpoints will be evaluated: 
• Adverse events 
• Adverse events of interest, including:  


 
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 Gastrointestinal (GI) events 
o Nausea 
o Vomiting,  
o Diarrhea as reported by SMQ (v19.1) of non-infectious diarrhea 
o Abdominal pain 
 Infection 
 Hypertension as reported by SMQ (v19.1)  
 Increases in transaminases and/or total bilirubin as defined by SMQ (v19.1) of 
Hepatic Disorder 
 Neutropenia  
• Percent change from baseline in lab assessments (hematology, serum chemistry and liver 
function tests) over time  
• Presence of abnormal changes from baseline in laboratory values per Common 
Terminology Criteria for Adverse Events (CTCAE) criteria V 5.0 (e.g., hematology, 
chemistry) 
• Severity of bleeding according to the IBLS and the WHO bleeding scale 
• Change from baseline in vital signs (i.e., systolic /diastolic blood pressures, pulse, 
temperature) over time  
• Post baseline blood pressure categorized based on post baseline systolic and diastolic 
blood pressure values.   
4.6. 
Other Endpoints 
• Change and percent change from baseline in Karnofsky Performance Status (KPS) over 
time 
• Change from baseline in Short form-36 (SF-36) over time 
 
4.7. 
 Pharmacokinetic Endpoints 
Characterization of the PK profile of R406 (the active metabolite of fostamatinib) including 
Cmax, AUC, and Tmax in a subset of subjects with ITP. 
 


 
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5.0 
STATISTICAL METHODS 
5.1. 
General Considerations 
The statistical analysis for this study will be performed using SAS® version 9.4 or higher.  All 
one-sided statistical tests will be performed at the 0.025 significance level, and all two-sided tests 
will be performed at the 0.05 significance level, unless otherwise indicated.  
Prior study treatment group will refer to the patient's randomized treatment group (fostamatinib 
or placebo) from the previous study in which the patient participated. Unless otherwise specified.  
Analyses will be based on only the data from the present study (C935788-049), except for the 
baseline value and a few other exceptions (e.g., duration of platelet response, primary efficacy 
endpoint, and the platelet count by-visit summary.   
Data collected in this study will be documented using summary tables and patient data listings. 
Continuous variables will be summarized using descriptive statistics, specifically the mean, 
median, 25th percentile (Q1), 75th percentile (Q3), standard deviation, minimum and maximum. 
Categorical variables will be summarized using frequencies and percentages.   
Data listings will be sorted by prior study treatment group and patient ID number. All date fields 
will be presented in a format of ddmmmyyyy (i.e., 01Jan2014) in the listings. All data will be 
included in the data listings.  
As a global note, platelet counts taken within 28 days of rescue therapy will be excluded from 
any platelet count related analyses. 
5.2. 
Adjustments for Covariates   
No adjustments for covariates will be made.  
5.3. 
Handling of Dropouts and Missing Data 
No imputation will be performed for missing data 
5.4. 
Interim Analyses and Data Monitoring 
An interim analysis was performed for purposes of inclusion in the New Drug Application for 
fostamatinib.   
5.5. 
Multicenter Study 
This is a multicenter study. Up to 150 patients will be enrolled at multiple sites. No adjustments 
for site will be made in the statistical analyses.   
5.6. 
Multiple Comparisons / Multiplicity  
No adjustments for multiple comparisons/multiplicity will be made.  
 


 
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5.7. 
Examination of Subgroups 
Platelet count will be summarized by 047/048 primary efficacy endpoint responder status and 
049 primary efficacy endpoint version 2 responder status for 047/048 placebo patients, and for 
049 primary efficacy endpoint Version 1 responders (defined in Section 4.3).  
Maximum systolic and diastolic blood pressure on active treatment (post-baseline of the present 
study) will be summarized by baseline use of anti-hypertensives.  
Interventions required to manage hypertension will also be summarized by baseline use of anti-
hypertensives and by prior study treatment group (fostamatinib and placebo) and overall. 
 
5.8. 
Definition of Baseline Measurements  
For the summary of baseline characteristics of present study, the baseline characteristics used for 
summary are defined in Section 4.1 and 4.2.   
For the calculation of change from baseline, the baseline value is defined as the last measurement 
for the corresponding variable prior to the first dose of fostamatinib in Study C-935788-047 or 
C-935788-048 (for fostamatinib patients in the previous study) or the present study (for placebo 
patients in the previous study).  
6.0 
ANALYSIS POPULATIONS 
6.1. 
Treated Population 
The Treated Population will include all enrolled and treated patients in the present study.  All 
efficacy and safety analyses will be performed on the Treated Population.  
7.0 
PATIENT DISPOSITION 
The number of patients signing the informed consent, screen failures, and patients in the Treated 
Population will be presented.   The numbers and percentages of patients who discontinued from 
the study at the time of database lock, along with the reason for discontinuation, will be also be 
presented. 


 
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8.0 
DEMOGRAPHIC, BASELINE CHARACTERISTICS, ITP HISTORY AND 
PREVIOUS PROCEDURES 
The demographic/baseline characteristics and ITP history/previous procedures are defined in 
Section 4.1 and 4.2, respectively. Descriptive statistics will be presented for the continuous 
variables. Frequencies and percentages will be presented for the categorical variables.   
9.0 
STUDY DRUG DISPENSING, COMPLIANCE, AND EXPOSURE 
The dose level of fostamatinib dispensed and changes in the dose level dispensed will be 
summarized by visit using counts and percentages. Changes in the dose level dispensed include 
increase in dose level dispensed and decrease in dose level dispensed, respectively as follows: 
• Increase in dose level dispensed, including change from 100 mg bid to 150 mg bid, change 
from 150 mg qd to 100 mg bid and change from 100 mg qd to150 mg qd, respectively 
• Decrease in dose level dispensed including change from 150 mg bid to 100 mg bid, change 
from 100 mg bid to 150 mg qd and change from 150 mg qd to 100 mg qd, respectively 
The expected number of doses, actual number of doses, number of missed doses, and percent 
compliance will be summarized by time interval and overall using descriptive statistics. Percent 
compliance is defined as the actual number of doses (tablets) the patient took during the time 
period divided by the total number of tablets expected to be taken, multiplied by 100. 
The duration of dosing of fostamatinib and the mean total daily dose will be summarized using 
descriptive statistics and displayed in waterfall plots. In addition, the number and percentage of 
following subgroups of  patients will be presented  
• Patients with at least 3 months of duration of dosing of fostamatinib 
• Patients with at least 6 months of duration of dosing of fostamatinib 
• Patients with at least 12 months of duration of dosing of fostamatinib 
• Patients with at least 18 months of duration of dosing of fostamatinib 
• Patients with at least 24 months of duration of dosing of fostamatinib 
 
The number and percentage of patients with at least one dose interruption with duration less than 
or equal to 2 days, greater than 2 days, and of unknown duration, and the number and percent of 
patients with a dose interruption followed by early termination, with at least one dose 
interruption due to adverse events, and with any dose interruption will be presented. Among 
patients with at least one dose interruption, the total number and mean number per patient of 
dose interruptions with duration less than or equal to 2 days, greater than 2 days, and of unknown 
duration, and the total number and mean number per patient of dose interruptions due to adverse 
events will be presented.   
 
 
  


 
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10.0 
EFFICACY ANALYSES 
10.1 
Primary Efficacy Endpoint 
10.1.1 Version 1 
The first version of the primary efficacy endpoint is defined in Section 4.4 and applies for all 
patients entering C-935788-049 study.  It will be summarized using counts and percentages, 
together with a 95% exact (Clopper-Pearson) confidence interval for the true percentage of 
Version 1 responders.  
10.1.2 Version 2 
The second version of the primary efficacy endpoint is defined in Section 4.4 and applies for all 
patients randomized to placebo in  either C-935788-047 or C-935788-048 studies and entering 
C-935788-049 study.   
These endpoints will be summarized based on a shift table (Table 3 below) presenting shifts in 
responder status from placebo treatment in the C-935788-047 or C-935788-048 studies to 
fostamatinib treatment in the C-935788-049 study using counts and percentages, together with 
95% exact (Clopper-Pearson) confidence intervals for the true percentage of Version 2 
responders. In addition, the following hypothesis test will be conducted: 
H0:  P01– P10 = 0  vs.  Ha: P01– P10 ≠ 0 ,  
Where P01 denotes true proportions of non-responders from placebo patients in C-935788-047 or 
C-935788-048 studies who become Version 2 responders in C-935788-049 study and  
P10 denotes true proportions of stable responders from placebo patients in C-935788-047 or C-
935788-048 studies who become Version 2 non-responders in C-935788-049 study. 
here P01 and P10 are estimated by    
c
a+b+c+d    and 
b
a+b+c+d , respectively, where a, b, c and d are 
number of patients as defined in Table 3 below 
Table 3. Shift of Response Status For Version 2 Response 
Placebo Patients in C-935788-047 or C-935788-048 Studies Who Entered C-935788-049 Study 
 
 
Version 2 Responders in C-935788-049 Study 
 
 
Yes 
No 
Total 
Stable Responder in     
C-935788-047 or C-
935788-048 Studies 
Yes 
a 
b 
a+b 
No 
c 
d 
c+d 
Total 
a+c 
b+d 
a+b+c+d 


 
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The p-value of the null hypothesis test for H0:  P01– P10 = 0 will be calculated using a 2-sided 
exact McNemar’s test with a significance level of 0.05.  The 95% confidence intervals for the 
difference in proportion of P01– P10 will be calculated using normal approximation method. 
10.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints are as follows:  
10.2.1 Duration of Platelet Response  
Duration of platelet response is defined in Section 4.4. It will be analyzed using the Kaplan-
Meier method, and the Kaplan-Meier estimate of the median duration of platelet response will be 
presented together with the 95% confidence interval for the true median. The descriptive 
summary for the duration of platelet response will also be presented with number (n) of patients 
with non-missing duration of platelet response and mean/ standard deviation (SD)/ 25th 
percentile/ median/ 75th percentile/ minimum/maximum of duration of platelet response. 
In addition, the duration of platelet response will also be analyzed for the following subgroups of 
patients: 
• C-935788-047 or C-935788-048 fostamatinib subjects who were C-935788-049 primary 
efficacy endpoint version 1 responders 
• all C-935788-049 primary efficacy endpoint version 1 responders 
• C-935788-047 or C-935788-048 placebo patients who were C-935788-049 primary 
efficacy endpoint version 2 responders.  
The same analyses as mentioned above will be conducted for the duration of platelet response 
based on the additional definitions as mentioned in Appendix 14.2.   
10.2.2 Total Duration of Platelet Response  
The total duration of platelet response is defined in Section 4.4 and will be analyzed in the 
similar way as duration of platelet response as mentioned in Section 10.2.1 . 
The same analyses as mentioned above will be conducted for the total duration of platelet 
response based on the additional definitions as mentioned in Appendix 14.2.   
10.2.3 Reduction in the Dose of Concomitant ITP Therapy  
This endpoint is defined in Section 4.4. The patient level listing of concomitant ITP use during 
the present study will be provided. 
 
10.3      Additional Efficacy Analyses  
Platelet count will be summarized by scheduled visit using descriptive statistics. Platelet count 
will also be summarized by  
• Study C-935788-047/C-935788-048 primary efficacy endpoint responder status,  


 
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• Study C-935788-047/C-935788-048 primary efficacy endpoint responder status and C-
935788-049 primary efficacy version 2 responder status. This is for C-935788-047/C-
935788-048 placebo patients entering C-935788-049 study 
• For study C-935788-049 primary efficacy endpoint version 1 responders. This is for all 
C-935788-047/C-935788-048 patients entering C-935788-049 study 
The summaries above will be performed by prior study treatment group in C-935788-047/ C-
935788-048 studies and overall. 
For each of exploratory efficacy endpoints mentioned in Appendix 14.1, frequencies and 
percentages of patients achieving the endpoint (Yes) will be provided.  
 
11.0 
SAFETY ANALYSES 
The safety endpoints of this study are defined in Section 4.5. 
11.1 
Adverse Events 
Analyses of adverse events (AEs) will include all adverse events in the present study, not just 
treatment emergent AEs (e.g., if a placebo patient has an AE starting in C-935788-047/C-
935788-048 studies and continuing in the present study, this AE will be included in the analyses) 
. Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
19.1).  The number of events and the number and percentage of patients with at least 1 adverse 
event, at least one severe AE, at least one moderate or severe AE, at least 1 serious adverse event 
(SAE), at least 1 treatment related adverse event, at least one adverse event leading to dose 
reduction, at least one adverse event leading to dose interruption, at least one adverse event 
leading to drug withdrawal, and at least one adverse event leading to death will be presented. 
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. Among patients with at least one 
AE, the mean number of AEs per patient will also be presented. The number and percentage of 
patients with adverse events of interest [any gastrointestinal (GI) complaints (nausea, vomiting, 
diarrhea, abdominal pain), overall and separately, infection, hypertension, neutropenia, 
transaminase elevation, and bilirubin elevation] will be presented. For the AEs of nausea, 
vomiting, abdominal pain, and infection, Rigel will specify preferred terms that fit into these 
categories. AEs, SAEs, AEs of interest, AEs leading to dose reduction, AEs leading to dose 
interruption, AEs leading to drug withdrawal, and AEs leading to death will be summarized at 
the patient level by MedDRA system organ class (SOC) and preferred term using frequencies 
and percentages. AEs will also be tabulated at the event level and the patient level by severity 


 
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and by causal relationship to study drug. AEs of interest will be tabulated at the event level and 
the patient level by severity. 
Regarding diarrhea (as reported by SMQ 19.1), the following additional analyses will be 
performed: 
• A patient's maximum diarrhea severity grade for the post-baseline period will be 
summarized using counts and percentages.  
• A patient level of listing for diarrhea that include the diarrhea severity grade, diarrhea 
start and end dates and duration of diarrhea in the present study will be provided.   
 
11.2 
Clinical Laboratory Tests 
Descriptive statistics will be presented by scheduled visit for the actual values and the changes 
and percentage changes from baseline for each selected quantitative laboratory test (hematology, 
serum chemistry, and liver function test). Actual values of categorical urinalysis test results will 
be summarized by scheduled visit. Lab values that are out of normal range will be flagged in the 
data listings. 
Box plots indicating mean and median as well as the 25th and 75th percentiles, reference plots, 
and spaghetti plots will be presented by study scheduled visit for both raw values and changes 
from baseline.   
Descriptive  statistics for the actual values, changes from baseline, and maximum value observed 
post baseline will be presented by scheduled visit in the present study.  In addition, two types of 
shift tables based on lab values classified per Common Terminology Criteria for Adverse Events 
(CTCAE) Grade Version 5.0 will be provided as follows: 
• Grades based on baseline lab values vs. the grades based on the worst post-baseline lab 
values observed in the present study,  
• Grades based on baseline lab values vs. the grades based on the last post-baseline lab 
value observed in the present study. 
These two types of shift table summaries above will be applied to the following selected lab 
parameters, respectively:  
• Liver function tests (i.e., ALT, AST, total bilirubin and indirect bilirubin) 
• Absolute neutrophil count (ANC) 
• Alkaline Phosphatase 
Regarding lab values of ALT, the following additional analyses will be performed: 
• Descriptive statistics for the average number of events of lab value increasing from 
baseline for each patient. 


 
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• Frequencies and percentages for number of patients with the events of lab value 
increasing from baseline  
Same additional analyses will be performed for AST. 
11.3 
Vital Signs 
Descriptive statistics will be presented by scheduled visit for the actual values and the changes 
and percentage changes from baseline for each vital sign. The maximum post baseline systolic 
blood pressure categories ( < 140 mmHg, 140 - < 160 mmHg, 160 - <180 mmHg and  ≥ 180 
mmHg) will be summarized using counts and percentages. This analysis will also be performed 
by baseline use of anti-hypertensives (yes/no). The anti-hypertensives are the medications with 
any of the following ATC codes at baseline: C02 (anti-hypertensives), C03 (diuretics), C04 
(peripheral vasodilators), C07 (beta blocking agents), C08 (calcium channel blockers), and C09 
(agents acting on the rennin-angiotensin system). These analyses will be repeated for maximum 
post baseline diastolic blood pressure categories (< 90 mmHg, 90 - < 100 mmHg, 100 - <110 
mmHg and  ≥ 110 mmHg). 
The number and percentage of following types of patients will be presented: 
• Patients with systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg at consecutive visits 
(2 or more visits, 3 or more visits) of present study 
• Patients with systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg anytime during the 
post-baseline of present study 
• Patients with systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg at consecutive visits 
(2 or more visits, 3 or more visits) of present study 
• Patients with systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg anytime during the 
post-baseline of present study 
• Patients with systolic BP ≥ 180 mmHg or diastolic BP ≥ 110 mmHg at consecutive visits 
(2 or more visits, 3 or more visits) of present study 
• Patients with systolic BP ≥ 180 mmHg or diastolic BP ≥ 110 mmHg anytime during the 
post-baseline of present study 
 
In addition, shifts based on new guidance in blood pressure (Appendix 14.3 ) from normal, 
elevated, Stage 1, Stage 2 and hypertensive crisis at baseline to normal, elevated, Stage 1, Stage 
2 and hypertensive crisis for the maximum observed value, and the last value post baseline will 


 
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be tabulated.  The maximum observed blood pressure and the last blood pressure post baseline 
will be based on both scheduled and unscheduled visits. 
Box plots indicating mean and median as well as the 25th and 75th percentiles, reference plots, 
and spaghetti plots will be presented by scheduled visit for both raw values and changes from 
baseline.   
11.4 
IBLS and WHO Bleeding Scale Scores 
 The IBLS will be analyzed as follows: 
• The mean of the IBLS scores across 9 anatomical sites and across visits during the 24-
month treatment period in present study will be summarized using descriptive statistics.   
• The highest IBLS score across the 9 anatomical sites and the total IBLS score will be 
summarized by visit. 
 
The WHO bleeding scale will be analyzed as follows: 
• The mean of the WHO bleeding scale across visits during the 24-month treatment period 
in present study will be summarized using descriptive statistics.  
In addition, both IBLS bleeding scale and WHO bleeding scale analyses mentioned above will 
be performed by prior study treatment group and overall.  
11.5 
Physical Examination 
Abnormal physical exam (PE) findings will be summarized by body system and visit using 
counts and percentages.   
11.6 
Karnofsky Performance Status (KPS)  
Karnofsky Performance Status Scale results, both raw and change and percentage change from 
baseline, will be summarized by visit using descriptive statistics. 
11.7 
Concomitant Medications 
Concomitant medications (non-ITP) and ITP concomitant medications will be summarized at the 
patient level by World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) 
class 3 and preferred term using counts and percentages. 
12.0 OTHER ANALYSES 
12.1 
Pharmacokinetics 
A separate document will describe the analyses of pharmacokinetic data.  


 
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12.2 
SF-36 
Descriptive statistics will be presented by scheduled visit for the actual values and the changes 
from baseline for the following: 
• Eight domains: physical functioning, role physical, bodily pain, general health, vitality, 
social functioning, role emotional, and mental health, respectively 
• Two summary scores: physical health summary and mental health summary, respectively 
• Proportions of patients with change from baseline ≥ 8 at month 12 for each domain and 
summary score, respectively, will be presented   
12.4 
Protocol Deviations 
Protocol deviations will be maintained in the trial master file and will be listed and discussed in 
the clinical study report. 
12.5 
Rescue Therapy 
A rescue therapy event is defined based on the medication administration start date. Two or more 
rescue medications started on the same day are counted as one rescue therapy event. Only rescue 
medications administered on or after the first dose of study drug in the present study are 
included.  
The number of rescue therapy events per patient will be summarized using descriptive statistics 
for the following: 
• Placebo patients of the C-935788-047/C-935788-048 study who received rescue therapy 
prior to Week 10 (Day 73)  
• Placebo patients of the C-935788-047/C-935788-048 study who received rescue therapy 
after Week 10 
  
The number and percentage of patient who received any rescue therapy in the present study will 
be summarized  for  
• the placebo patients of the C-935788-047/C-935788-048 study who received rescue 
therapy prior to Week 10 (Day 73)  
• the placebo patients of the C-935788-047/C-935788-048 study who received rescue 
therapy after Week 10,  
• all patients in C-935788-049 study 
 
In addition, the number of patients who received any rescue therapy will be summarized using 
counts and percentages, and the number of rescue therapy events per patient for all patients who 


 
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received any rescue therapy will be summarized using descriptive statistics.  These analyses 
above will be conducted by prior study treatment group and overall.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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13.0 
REFERENCES 
Whelton, et al., Guideline for the Prevention, Detection, Evaluation, and Management of High 
Blood Pressure in Adults,   American College of Cardiology, 2017 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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14.0 
APPENDICES 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
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14.2 
Additional Definitions of Duration of Platelet Response and Total Duration of 
Platelet Response 
The additional definitions of duration of platelet responses are presented as follows:   
1) The length of time from when the patient first achieves a platelet count of at least 
50,000/μL until the loss of platelet response, which is defined as the earlier time of (the 
first of two consecutive visits with platelet counts < 30,000/µL that are at least 4 weeks 
apart or the first use of rescue therapy after first achieving a platelet count of at least 
50,000/μL) 
2) The length of time from when the patient first achieves a platelet count of at least 
50,000/μL until the loss of platelet response, which is defined as the earlier time of (the 
first of two consecutive visits with platelet counts < 20,000/µL that are at least 4 weeks 
apart or the first use of rescue therapy after first achieving a platelet count of at least 
50,000/μL) 
3) The length of time from when the patient first achieves a platelet count of at least 
30,000/μL until the loss of platelet response, which is defined as the earlier time of (the 
first of two consecutive visits with platelet counts < 30,000/µL that are at least 4 weeks 
apart or the first use of rescue therapy after first achieving a platelet count of at least 
30,000/μL) 
4) The length of time from when the patient first achieves a platelet count of at least 
30,000/μL until the loss of platelet response, which is defined as the earlier time of (the 
first of two consecutive visits with platelet counts < 20,000/µL that are at least 4 weeks 
apart or the first use of rescue therapy after first achieving a platelet count of at least 
30,000/μL) 
 
Patients who drop out of the study before achieving a platelet response [i.e., achieving a platelet 
count of ≥ 50,000/μL for definition 1)-2) or ≥ 30,000/μL for definitions 3) - 4)] will be assigned 
a value of 0 for this endpoint. Patients who drop out of the study by the time of database lock 
while still maintaining a platelet response will be censored as of the time of the last platelet 
measurement prior to drop out of study respectively. Similarly, patients who remain in the study 
by the time of database lock while still maintaining a platelet response will be censored as of the 
time of the last platelet measurement prior to the time of database lock. For patients who have 
achieved and are maintaining a platelet response but who have discontinued treatment due to 
lack of efficacy or to an AE by the time of database lock,  duration of platelet response will be 
defined as the time from first achieving a platelet response [i.e., achieving a platelet count of ≥ 
50,000/μL for definition 1)-2) or ≥ 30,000/μL for definitions 3)- 4)]  until discontinuation of 
treatment. 
 
For each of additional definitions of duration of platelet responses 1)-4) above, the total duration 
of platelet response will be defined as the sum of all durations of platelet responses. 
 


 
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14.3 
New Categories of Blood Pressure in Adults  
The following new blood pressure (BP) categories is based on 2017 Guideline (see Section 13.0) 
for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults 
BP Categories 
Systolic BP (SBP) 
 
Diastolic BP (DBP) 
Normal 
< 120 mmHg 
and 
<  80 mmHg 
Elevated 
120 – 129 mmHg 
and 
<  80 mmHg 
Stage 1 
130 – 139 mmHg 
or 
80 – 89 mmHg 
Stage 2 
≥ 140 mmHg 
or 
≥ 90 mmHg 
Hypertensive Crisis 
Higher than 180 mmHg 
or 
Higher than 120 mmHg 
Note: Individuals with SBP and DBP in 2 categories should be designated to the higher BP 
category.