Conditions: Chemotherapy Induced Anemia
Keywords: Anemia Chemotherapy induced anemia Myelosuppressive chemotherapy Non-Myeloid malignances
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 92
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out if roxadustat (also known as FG-4592) is safe and effective for the treatment of anemia in participants receiving chemotherapy treatment for cancer.

Detailed description:
This study consists of three periods:

1. Screening Period up to 28 days
2. Treatment Period of up to16 weeks
3. A Follow-up period of 4 weeks.

Arms:
arm 1: Participants will receive roxadustat as an oral tablet, 3 times per week (TIW) for up to a maximum of 16 weeks.

Interventions: intervention 1: Roxadustat
Intervention descriptions: intervention 1: Roxadustat will be administered per schedule specified in the arm description.

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
TITLE PAGE 
A Phase 2 Open Label Study Investigating the 
Efficacy and Safety of Roxadustat (FG-4592) for 
Treatment of Anemia in Patients Receiving 
Chemotherapy Treatment for Non-Myeloid 
Malignancies 
PROTOCOL NUMBER: 
FGCL-4592-092 
PHASE: 
Phase 2 
STUDY SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158 USA 
KEY SPONSOR CONTACT(S): 
IND NUMBER: 
 
 
Direct: 
 
Mobile: 
 
E-mail: 
142993
STUDY DRUG: 
Roxadustat (FG-4592) 
INDICATION: 
Treatment of Anemia Caused by Chemotherapy 
ORIGINAL PROTOCOL: 
AMENDMENT 1: 
AMENDMENT 2: 
AMENDMENT 3: 
02 April 2019 
16 July 2019 
30 January 2020 
22 May 2020 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and proprietary to FibroGen, Inc. No 
part of this document or any of the information contained herein may be transmitted, disclosed, 
shared, reproduced, published or utilized by any persons without prior written authorization by 
FibroGen, Inc. 
Confidential 
Page 1 of 76 
NCT #NCT04076943


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INVESTIGATOR SIGNATURE PAGE 
STUDY ACKNOWLEDGEMENT 
A Phase 2 Open Label Study Investigating the Efficacy and Safety of Roxadustat (FG-4592) for 
Treatment of Anemia in Patients Receiving Chemotherapy Treatment for Non-Myeloid 
Malignancies 
 
FGCL-4592-092 
 
Amendment 3: 22 May 2020 
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the current Investigator’s Brochure (IB), 
and I agree that it contains all necessary details for me and my staff to conduct this study as 
described. I will conduct this study as outlined herein and will make a reasonable effort to 
complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by FibroGen, Inc. I will discuss this material with them to ensure that they 
are fully informed about the drugs and the study. 
I will conduct the trial in accordance with the guidelines of Good Clinical Practice (GCP) 
including the archiving of essential documents, the Declaration of Helsinki, and any applicable 
local health authority, and Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) requirements. 
 
 
 
 
 
Investigator Name (Printed) 
Institution 
 
 
 
Signature 
Date 
 
 
Please return a copy of this signature page to FibroGen (or designee). Please retain the original 
for your study files. 


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CONFIRMATION OF PROTOCOL APPROVAL
Amendment 3 Protocol Date: 22 May 2020 
This protocol is approved by FibroGen. 
te
FibroGen, Inc.
te


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SUMMARY OF MAJOR PROTOCOL AMENDMENT CHANGES 
Amendment 3 
 
In addition to the major changes listed below, minor editorial changes were made throughout the 
document to correct typographical errors and to improve consistency and clarity. 
 
Description of Change 
Rationale for Change 
Section(s) 
Affected 
Upon evaluating the pharmacodynamics 
(hemoglobin) responses after 4 weeks of therapy 
with the starting dose of 2.0 mg/kg in initial 20 
patients, it has been determined to increase the 
starting dose for newly enrolled patients by one level 
i.e. from 2.0 mg/kg to 2.5 mg/kg level as majority of 
the initial 20 patients required a dose increase at 
Week 5, per dose adjustment rule. 
To achieve optimal Hb 
response with the starting dose 
Synopsis 
3.3.1; 5.1; 
7.1.1 
Exclusion #17 was updated from: 
“Known, active or chronic gastrointestinal bleeding” 
to “Known, active or chronic gastrointestinal 
bleeding” 
The criterion has been revised 
to exclude all types of 
active/chronic bleeding 
Synopsis; 
6.2 
Section 7.1.5.2 Chemotherapy Treatments has been 
updated to the following (changed text is italicized): 
“If Paclitaxel (e.g. Taxol® or Abraxane®) is given as 
part of a chemotherapy regimen, roxadustat dosing 
should be held for 24 hours before and after 
treatment (time 0 = start of infusion) with this drug. 
Roxadustat dosing frequency may be adjusted, as 
needed.” 
The current suggested 48 hour 
interval between roxadustat and 
paclitaxel administration was 
added as a precautionary step as 
paclitaxel is known to have 
drug-drug interaction with 
several different drugs. 
However, upon further in-house 
review of paclitaxel PK, 
FibroGen considers the 
potential for DDI with 
roxadustat relatively 
insignificant if the interval 
between roxadustat and 
paclitaxel is reduced to 24 
hours. FibroGen is reducing the 
48 hour interval to 24 hours and 
clarifying the window start time 
as the start of infusion. 
7.1.5.2 
Paclitaxel PK sub-study has been added under 
Section 8.2.4.2 to evaluate the effect of 
roxadustat timing of administration on the 
pharmacokinetics of paclitaxel. 
This PK sub study will help us 
to determine the impact 
roxadustat timing of 
administration on paclitaxel PK 
(drug-drug-interaction) and 
whether there is a need for an 
interval between roxadustat and 
8.2.4.2 


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Additional details are provided in Appendix 6 
paclitaxel administration to 
avoid drug-drug-interaction, if 
any, in patients who may be 
taking both Roxadustat and 
Paclitaxel concomitantly. 
Appendix 6 has been added to describe Paclitaxel 
PK study including instruction for collecting PK 
samples for patients taking Roxadustat and 
Paclitaxel concomitantly: 
PK collection time points were 
defined for patients taking part 
in the optional sub-study 
investigating the potential effect 
of Roxadustat on the 
pharmacokinetics of paclitaxel. 
Appendix 6 
Secondary efficacy endpoints and Subgroup 
analysis have been revised 
For better understanding the 
effects of roxadustat on efficacy 
parameters and PK properties 
of roxadustat and paclitaxel 
Synopsis 
4.2.2 
4.2.5 


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1. 
PROTOCOL SYNOPSIS 
 
PROTOCOL SYNOPSIS 
Study Title: 
A Phase 2 Open Label Study Investigating the Efficacy and Safety of 
Roxadustat (FG-4592) for Treatment of Anemia in Patients Receiving 
Chemotherapy Treatment for Non-Myeloid Malignancies 
Protocol Number: 
FGCL-4592-092 
Investigational Product: 
FG-4592 (Roxadustat) 
Study Phase: 
Phase 2 
Indication: 
Treatment of Anemia Caused by Chemotherapy 
Number of Patients Planned: Up to approximately 100 
Number of Sites Planned: 
Approximately 10-20 (United States Only) 
OBJECTIVES 
Primary Objective: 
• To evaluate the efficacy of roxadustat for the treatment of anemia in patients receiving 
multi-cycle treatments of myelosuppresssive chemotherapy. 
Secondary Objectives: 
• Evaluate the safety of roxadustat 
• Evaluate the impact of roxadustat on RBC transfusion requirements 
• Evaluate effect of roxadustat on biological indicators:, hemoglobin, hematocrit, 
reticulocytes, hepcidin, serum iron, ferritin, transferrin saturation and total iron binding 
capacity 


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ENDPOINTS 
Primary Efficacy Endpoint: 
• The primary efficacy endpoint is maximum change in hemoglobin within 16 weeks from 
baseline without RBC transfusion 


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Secondary Efficacy Endpoints: 
• Mean change in hemoglobin from baseline to week 16 (without RBC transfusion) 
• Change in hemoglobin from baseline at) week 8, 12, 16 (without RBC transfusion) 
• Proportion of patients who achieved a ≥1 g/dL increase in hemoglobin from baseline 
through week 16 
• Time to achieve a ≥1 g/dL increase in hemoglobin from baseline 
• Proportion of patients who achieved a ≥1.5 g/dL increase in hemoglobin from baseline 
through week 16 
• Proportion of patients who achieved a hematopoietic response at any time in the study 
(defined as an increase in Hb of 1.5 g/dL OR attaining a Hb of 11 g/dL) 
• Proportion of patients who achieved a ≥2.0 g/dL increase in hemoglobin from baseline 
through week 16 
• Number (%) of patients who had a RBC transfusion from beginning of Week 5 (Day 29) to 
week 16 
Additional Efficacy Endpoints: 
• Proportion of patients who achieved a ≥1 g/dL increase in hemoglobin from baseline 
through week 8 and 12 
• Proportion of patients who achieved a ≥1.5 g/dL increase in hemoglobin from baseline 
through week 8 and 12 
• Number (%) of patients who require transfusion as medical intervention and/or ESA 
(erythropoiesis stimulating agent) as a rescue agent. [Time Frame: baseline to week 16] 
• Percentage of Participants by Tumor Type With Improvement in FACIT-F (fatigue) and 
Increase in Hemoglobin ≥1 g/dL [Time Frame: baseline to week 16] 
• Change from Baseline in Quality of life as measured by: 
Functional Assessment of Cancer Therapy-Anemia (FACT-An) test [Time Frame: baseline 
to week 8 and 16] 
Exploratory Evaluations: 
• Effect on hepcidin and iron metabolism 
• Effect on cholesterol parameters and lipid metabolism 
Subgroup Analyses: 
• Tumor type 
• Chemotherapy regimen [i.e. platinum vs non-platinum] 
• Other clinically relevant characteristics 
• Roxadustat PopPk 


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• Paclitaxel DDI 
STUDY DESIGN 
This is a Phase 2 Open Label Study Investigating the Efficacy and Safety of Roxadustat (FG-4592) 
for Treatment of Anemia in Patients Receiving Chemotherapy Treatment for Non-Myeloid 
Malignancies. Approximately 100 patients will be enrolled. 
STUDY PERIODS 
Screening Period: 
All screening procedures are to be completed within 28 days prior to Study Day 1. Patients will be 
evaluated per the protocol inclusion/exclusion criteria to determine eligibility for participation in this 
trial. Protocol assessments will be completed during screening visits in accordance with Schedule of 
Assessments (SOA) to establish a baseline profile, including; demographics, medical history, clinical 
status and disease stage for each patient. Patients determined to be eligible for participation will be 
enrolled in the trial and will receive roxadustat in an open-label manner. The starting dose for the 
initial 20 patients will be 2.0 mg/kg. After the initial 20 patients are enrolled, starting dose(s) for 
additional patients will be selected by the sponsor, informed by the data available from earlier 
patients treated in the study. The selected starting dose level will not exceed the highest dose level 
received by any individual patient in the study up to that point and will be within the maximum dose 
allowed in the protocol. Additionally, the sponsor will review clinical efficacy and safety response 
on an ongoing basis and take into account potential impact of certain baseline patient characteristics 
or chemotherapy regimens (such as from patients on a platinum vs non-platinum containing regimen) 
on treatment response in the selection of patients of baseline characteristics and starting dose(s) of 
subsequent patients. Lastly, if there is more than one starting dose cohort open for enrollment at the 
same time for a certain subgroup, such as platinum (or non-platinum) treatment group, patients will 
be randomized to receive a starting dose. A comprehensive table of potential doses is contained in 
the protocol body and in Appendix 2. 
Upon evaluating the pharmacodynamics (hemoglobin) responses after 4 weeks of therapy with the starting 
dose of 2.0 mg/kg in initial 20 patients, it has been determined to increase the starting dose for newly enrolled 
patients by one level i.e. from 2.0 mg/kg to 2.5 mg/kg level to achieve optimal hemoglobin response. 
Treatment Period: 
Patients will undergo 16 weeks of study treatment with roxadustat. Study visits are scheduled every 2 
weeks. Patients’ clinical status and safety will be regularly evaluated. Efficacy assessments will be 
performed routinely to evaluate patients’ quality of life and disease state. If disease progression 
occurs during the treatment period, patients will be discontinued from study treatment and continue 
in the follow-up period. 
Follow-up Period: 
All patients who complete 16 weeks (of treatment with study medication) will undergo a 4-week 
follow-up period after the last dose of study medication. 


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Patients who discontinue study medication early (for any reason whatsoever) will have a 4-week 
follow-up visit after stopping study medication. 
PATIENT ELIGIBILITY CRITERIA 
Inclusion Criteria: 
1. Diagnosis of non-myeloid malignancy. Current documentation of disease burden (e.g. CT 
scan) within 3 months prior to enrollment (Day 1). 
2. Anemia caused by cancer treatment (myelosuppressive chemotherapy) defined as Hb ≤10.0 
g/dL at screening 
3. Planned concurrent treatment of cancer (myelosuppressive chemotherapy) for at least 8 
additional weeks 
4. Age ≥ 18 years 
5. Body weight ≥ 45 kg and < 150 kg 
6. ECOG performance status of 0, 1, or 2 at last screen visit 
7. Patient must be capable of giving written informed consent 
8. Understand and sign informed consent; be willing to comply with all study procedures 
9. Estimated life expectancy ≥ 6 months at enrollment (Day 1) 
Exclusion Criteria: 
1. Patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome 
is cure 
2. Patients who are only receiving hormonal products, biological products, novel 
immunosuppressive products (such as PD-1 and PD-L1 checkpoint inhibitors) or targeted 
biological or radiation therapy to treat/manage their cancer. (Patients receiving concomitant 
myelosuppressive therapy if not intended for cure may be allowed to participate) 
3. Patients who prefer a Red Blood Cell (RBC) transfusion as treatment of anemia at time of 
study entry, over receiving the investigational drug Roxadustat 
4. Received an RBC transfusion or ESA within 4 weeks of enrollment (Day 1) 
5. Alanine aminotransferase (AST) > 3 x upper limit of normal (ULN), OR aspartate 
aminotransferase (ALT) > 3 x ULN, OR total bilirubin (TBL) > 1.5 x ULN – will exclude a 
patient from entering the study (patients with TBL up to 2x ULN may be allowed if 
ALT/AST are within normal limit and investigator has no safety concerns) 
6. Inadequate iron stores as defined as ferritin < 50 ng/mL 
7. Any investigational drug within 8-weeks prior to Day 1 Treatment or plans to use any of these 
medications during the course of clinical trial participation 
8. Anticipated use of dapsone during the study 


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9. Clinically significant anemia due to other etiologies such as iron deficiency, vitamin B12 or 
folate deficiency, autoimmune or hereditary hemolysis or anemia, hemorrhage, or hereditary 
anemia such as sickle cell anemia or thalassemia 
10. Active infection(s) requiring chronic antibiotic therapy 
11. Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min based on 4-variable MDRD 
equation 
12. Thromboembolic event (deep vein thrombosis (DVT), pulmonary embolism, myocardial 
infarction, stroke, transient ischemic attack (TIA) within previous 6 months of screening 
13. Significant heart disease, including New York Heart Association (NYHA) Class III or IV 
congestive heart failure, uncontrolled hypertension or hypotension, or significant valvular or 
endocardial disease that would put the patient at risk for thromboembolism 
14. Clinically significant or uncontrolled ongoing inflammatory/autoimmune disease (e.g., 
rheumatoid arthritis, Crohn’s disease, celiac disease, etc.) 
15. History of significant liver disease or active liver disease 
16. Major surgery planned during the treatment period 
17. Known, active or chronic bleeding 
18. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
19. Clinically significant or uncontrolled medical condition that would affect the patient's ability 
to participate in the study or confound the study's efficacy or safety results 
20. History of leukemia (current or historical Chronic Lymphocytic Leukemia may be allowed) 
21. Previous recipients of roxadustat or another hypoxia-inducible factor prolyl hydroxylase 
inhibitor (HIF-PHI) 
22. Pregnant or breastfeeding females 
STUDY TREATMENT 
Dose and Mode of Administration: 
Roxadustat: 
Tablets with strengths of 20 mg, 50 mg ,100 mg and 150 mg 
Route of Administration: 
Oral (all tablets must be administered whole). 
Patients will receive roxadustat, at a starting dose of 2.0 mg/kg TIW with actual dose (in mg) based 
on body weight at Day 1 of treatment, per table below. 
Starting dose for initial 20 patients: 


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Dose 
Level 
Group 
Roxadustat 
Dose Level 
( mg/kg) 
45 to < 70 
kg 
70 - 100 
kg 
> 100 kg 
1 
2.0 
100 mg 
TIW 
150 mg 
TIW 
200 mg TIW 
Starting dose for newly enrolled patients: 
Upon evaluating the pharmacodynamics (hemoglobin) responses after 4 weeks of therapy with the starting 
dose of 2.0 mg/kg in initial 20 patients, it has been determined to increase the starting dose for newly enrolled 
patients by one level i.e. from 2.0 mg/kg to 2.5 mg/kg level to achieve optimal hemoglobin response. 
Dose adjustment evaluation will be made every 4 weeks, and dose will be titrated to Hb level and 
rate of Hb change according to Appendix 2. 
Principal Investigator (PI) and/or treating physician will determine when to transfuse a patient based 
on clinical judgement. 
Evaluation for dose modification/adjustment will occur every 4 weeks. Any potential dose 
escalation/dose reduction will be at pre-defined dose step increments. 
After the initial 20 patients are enrolled, starting dose(s) for additional patients will be selected by the 
sponsor, informed by the data available from earlier patients treated in the study. The selected 
starting dose level will not exceed the highest dose level received by any individual patient in the 
study up to that point and will be within the maximum dose allowed in the protocol. 
Additionally, the sponsor will review clinical efficacy and safety response on an ongoing basis and 
take into account potential impact of certain baseline patient characteristics or chemotherapy 
regimens (such as from patients on a platinum vs non-platinum containing regimen) on treatment 
response in the selection of patients of baseline characteristics and starting dose(s) of subsequent 
patients. Lastly, if there is more than one starting dose cohort open for enrollment at the same time 
for a certain subgroup, such as platinum (or non-platinum) treatment group, patients will be 
randomized to receive a starting dose. A comprehensive table of potential doses is contained in the 
protocol body and in Appendix 2. Finally, starting doses will not be adjusted for platinum containing 
or non-platinum containing regimens until 8 patients in a group have been dosed at a specific dose 
level. 
Dose 
Level 
Group 
Roxadustat 
Dose Level 
( mg/kg) 
45 to < 70 
kg 
70 - 100 
kg 
> 100 kg 
1 
2.5 
150 mg 
TIW 
200 mg 
TIW 
250 mg TIW 


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In the event that chemotherapy is modified or withheld or discontinued, as per standard of care, the 
dosing schedule of roxadustat should be maintained through the 16 week treatment period, and 
patients will continue in the follow-up period. 
Other Important Information: 
Best supportive care (BSC) including RBC transfusion is permitted to ensure patient’s safety. 
Principal Investigator (PI) and site staff will utilize their own institutional criteria to determine when 
to transfuse a patient. 
Use of any ESA during the study (epoetin alfa, epoetin beta, darbepoetin, Mircera, or others; see 
Appendix 5) is not permitted. Patients who receive an ESA will be discontinued from further 
treatment with study medication. 
See the Investigator’s Brochure for additional information pertaining to roxadustat. 
STATISTICAL METHODS 
The sample size of the study was not determined by formal power calculations. All analyses will be 
exploratory for different dose level. 
The following analysis populations are defined and will be used for the statistical analysis: 
• All enrolled or ITT: consisted of all patients enrolled in the roxadustat treatment period, 
regardless of whether patients received any roxadustat. 
• Full analysis set (FAS): consisted of all enrolled patients who receive at least one dose of 
roxadustat, have a baseline Hb and at least one corresponding on-treatment Hb 
assessment, and will be used for all efficacy analyses 
• Efficacy Evaluable (EE): consisted of all enrolled patients who receive at least one dose 
of roxadustat for at least 4 weeks, and have at least one Hb value after 4 weeks or longer, 
obtained within 2 weeks of last dose. 
• Safety Population (SAF): consisted of all patients who received at least one dose of 
roxadustat. This population will be for all assessments of safety and tolerability 
The efficacy analysis will be based on both the Full Analysis Set (FAS) population and Efficacy 
Evaluable (EE) Population. 
Analyses of the safety data will be based on the Safety Population. 
Baseline Hb value for efficacy analysis is defined as the mean of Screening (central laboratory) Hb 
values and Day 1 (central laboratory) Hb value. 
Data Analyses 
Up to approximately 100 patients will be enrolled in the study, with various diagnoses of non- 
myeloid malignancies. 
Primary efficacy analysis 


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The primary efficacy analysis will be based on the EE and FAS population using an observed data 
approach. The primary efficacy parameter is defined as maximum change in hemoglobin in 16 weeks 
without RBC transfusion. 
Maximum Change from baseline will be summarized by using descriptive statistics. Maximum 
change from baseline will also be analyzed using Analysis of covariance using cancer types as a class 
variable and the baseline Hb as a covariate. Least Square Means will be calculated from the model 
and tested against 0 for each cancer type and overall. 
Secondary efficacy analyses 
The mean change from baseline hemoglobin (without a RBC transfusion) will be summarized using 
descriptive statistics by visit. This will also be analyzed similar to the model used for the primary 
endpoint. 
In addition, missing hemoglobin data, either because of a missed visit or collected within 4 weeks 
after a RBC transfusion will be imputed with the last-observation-carried-forward (LOCF) approach. 
The Number (%) of patients meeting various criteria specified in the protocol as secondary endpoints 
will also be summarized using the Clopper–Pearson confidence limits approach. 
The percentages of patients who have a hematopoietic response, who receive at least one RBC 
transfusion will be estimated using the Kaplan–Meier (KM) method. 
Safety Analysis 
Adverse events, laboratory, vital signs, ECGs data will be descriptively summarized and/or listed. 
Change from baseline values may be calculated for selected vital sign and ECG parameters. Shift 
tables may also be constructed. 
Additional endpoints may be detailed with corresponding statistical analysis methods specified in a 
Statistical Analysis Plan (SAP). 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
and the applicable regulatory requirement(s), including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
1. 
PROTOCOL SYNOPSIS .............................................................................................6 
TABLE OF CONTENTS ...............................................................................................................15 
2. 
LIST OF ABBREVIATIONS .....................................................................................20 
3. 
INTRODUCTION ......................................................................................................23 
3.1. 
Chemotherapy Induced Anemia (CIA) .......................................................................23 
3.1.1. 
Epidemiology of Chemotherapy Induced Anemia .....................................................23 
3.1.2. 
Etiology of Chemotherapy Induced Anemia ..............................................................24 
3.1.3. 
Clinical Features of Chemotherapy Induced Anemia .................................................24 
3.1.4. 
Current Treatment of Chemotherapy Induced Anemia ..............................................24 
3.2. 
Roxadustat ..................................................................................................................24 
3.2.1. 
Mechanism of Action of Roxadustat ..........................................................................24 
3.2.2. 
Clinical Experience with Roxadustat ..........................................................................25 
3.2.3. 
Pharmacology (PK/PD) of Roxadustat .......................................................................26 
3.3. 
Rationale for Roxadustat in Chemotherapy Induced Anemia ....................................27 
3.3.1. 
Rationale for Roxadustat Dose and Dosage Regimen ................................................28 
3.3.2. 
Risks/Benefit Assessment of Roxadustat Treatment in This Study ...........................28 
3.4. 
Nonclinical Studies .....................................................................................................29 
3.4.1. 
Roxadustat in Cisplatin-induced-anemia in Sprague Dawley Rats ............................29 
3.4.2. 
Preclinical Tumor Models ..........................................................................................30 
3.4.3. 
Carcinogenicity Studies ..............................................................................................30 
3.4.4. 
Preclinical Safety Summary........................................................................................31 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................32 
4.1. 
Objectives ...................................................................................................................32 
4.1.1. 
Primary Objective .......................................................................................................32 
4.1.2. 
Secondary Objectives .................................................................................................32 
4.2. 
Endpoints ....................................................................................................................32 
4.2.1. 
Primary Efficacy Endpoint .........................................................................................32 
4.2.2. 
Secondary Efficacy Endpoints ....................................................................................32 
4.2.3. 
Additional Efficacy Endpoints ...................................................................................33 


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Roxadustat 
Protocol FGCL-4592-092 
Confidential 
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4.2.4. 
Exploratory Evaluations .............................................................................................33 
4.2.5. 
Subgroup Analyses .....................................................................................................33 
4.3. 
Safety Assessments .....................................................................................................33 
5. 
INVESTIGATIONAL PLAN .....................................................................................34 
5.1. 
Overall Study Design ..................................................................................................34 
5.1.1. 
Estimated Study Duration ...........................................................................................35 
5.2. 
Treatment Assignment ................................................................................................37 
5.2.1. 
Enrollment ..................................................................................................................37 
5.2.2. 
Treatment Assignment ................................................................................................37 
5.3. 
Blinding ......................................................................................................................37 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................38 
6.1. 
Patient Inclusion Criteria ............................................................................................38 
6.2. 
Patient Exclusion Criteria ...........................................................................................38 
6.3. 
Patient Withdrawal Criteria ........................................................................................39 
6.4. 
Replacement of Study Patients ...................................................................................40 
6.5. 
Study Termination ......................................................................................................40 
7. 
TREATMENT OF PATIENTS ..................................................................................41 
7.1. 
Study Treatment ..........................................................................................................41 
7.1.1. 
Roxadustat ..................................................................................................................41 
7.1.2. 
Chemotherapy .............................................................................................................43 
7.1.3. 
Dose Administration and Modifications .....................................................................43 
7.1.4. 
Treatment Compliance ................................................................................................43 
7.1.5. 
Concomitant Medications, Procedures, and Nondrug Therapies ...............................43 
7.1.5.1. 
Prohibited Concomitant Medications .........................................................................43 
7.1.5.2. 
Chemotherapy Treatments ..........................................................................................43 
7.1.5.3. 
Other Potential Drug Interactions ...............................................................................43 
7.1.5.4. 
Phosphate Binders ......................................................................................................43 
7.1.5.5. 
Statins .........................................................................................................................43 
7.1.5.6. 
Supplemental Iron Use ...............................................................................................44 
7.1.5.7. 
Contraception Requirements ......................................................................................44 
7.2. 
Study Drug Materials and Management .....................................................................44 
7.2.1. 
FibroGen Investigational Product (Roxadustat) .........................................................44 
7.2.2. 
Study Drug Packaging and Labeling ..........................................................................45 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
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7.2.3. 
Study Drug Storage .....................................................................................................45 
7.2.4. 
Study Drug Administration .........................................................................................45 
7.2.5. 
Overdose, Emergency Procedures, and Management of Overdose ............................45 
7.2.6. 
Study Drug Handling and Disposal ............................................................................45 
8. 
ASSESSMENTS OF EFFICACY ..............................................................................46 
8.1. 
Study Assessments ......................................................................................................46 
8.1.1. 
Screening Period .........................................................................................................46 
8.1.2. 
16-Week Treatment Period .........................................................................................46 
8.1.3. 
Follow-up Period ........................................................................................................46 
8.1.4. 
Missed Visits ..............................................................................................................46 
8.1.5. 
Unscheduled Visits .....................................................................................................47 
8.1.6. 
Early Withdrawal from Treatment ..............................................................................47 
8.2. 
Assessments ................................................................................................................47 
8.2.1. 
Vital Signs (Including Weight and Height) ................................................................47 
8.2.2. 
Physical Exam ............................................................................................................47 
8.2.3. 
Electrocardiogram (ECG or EKG) .............................................................................47 
8.2.4. 
Laboratory Evaluations ...............................................................................................47 
8.2.4.1. 
Central Laboratory Evaluations ..................................................................................48 
8.2.4.2. 
Pharmacokinetics and Pharmacodynamics .................................................................48 
8.2.4.3. 
Eastern Cooperative Oncology Group (ECOG) .........................................................49 
8.2.5. 
Patient Reported Outcomes (PROs) ...........................................................................49 
8.2.5.1. 
FACIT-F .....................................................................................................................49 
8.2.5.2. 
FACT-An ....................................................................................................................49 
9. 
ASSESSMENTS OF SAFETY ..................................................................................50 
9.1. 
Background .................................................................................................................50 
9.2. 
Definitions ..................................................................................................................50 
9.2.1. 
Definition of an Adverse Event (AE) .........................................................................50 
9.2.2. 
Definition of a Serious Adverse Event (SAE) ............................................................50 
9.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events.........................51 
9.3.1. 
Adverse Event Reporting Period ................................................................................51 
9.3.2. 
Adverse Event Eliciting/Reporting .............................................................................51 
9.3.3. 
Assessing Adverse Event Severity .............................................................................52 
9.3.4. 
Assessing the Adverse Event’s Relationship to Study Drug ......................................52 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
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9.3.5. 
Reporting Serious Adverse Events .............................................................................53 
9.3.5.1. 
Reporting Serious Adverse Events to the Institutional Review Board / 
Independent Ethics Committee ...................................................................................54 
9.3.5.2. 
Deaths .........................................................................................................................54 
9.3.6. 
Pregnancies: Reporting and Follow-up of Patients .....................................................54 
9.3.7. 
Abnormal Laboratory Findings ..................................................................................55 
9.3.8. 
Safety Monitoring .......................................................................................................55 
9.3.8.1. 
Data Monitoring Committee (DMC) ..........................................................................55 
10. 
STATISTICS ..............................................................................................................56 
10.1. 
Sample Size Determination ........................................................................................56 
10.2. 
Analysis Populations ..................................................................................................56 
10.2.1. 
All Enrolled or Intent-to-Treat (ITT) Population........................................................56 
10.2.2. 
Full Analysis Set (FAS) Population............................................................................56 
10.2.3. 
Efficacy Evaluable (EE) Population ...........................................................................56 
10.2.4. 
Safety (SAF) Population .............................................................................................56 
10.3. 
Statistical Analysis ......................................................................................................56 
10.3.1. 
General Considerations ...............................................................................................56 
10.3.2. 
Patient Enrollment and Disposition ............................................................................56 
10.3.3. 
Demographics and Baseline Characteristics ...............................................................56 
10.3.4. 
Efficacy Analyses .......................................................................................................57 
10.3.4.1. 
Analysis of the Primary Endpoint ...............................................................................57 
10.3.4.2. 
Analysis of the Secondary and Additional Endpoints ................................................57 
10.3.5. 
Exploratory Analyses ..................................................................................................57 
10.3.6. 
Safety Analyses...........................................................................................................58 
10.4. 
Interim Analysis ..........................................................................................................58 
10.5. 
Statistical Analysis Plan..............................................................................................58 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................59 
11.1. 
Data Quality Assurance ..............................................................................................59 
11.2. 
Audit and Inspection ...................................................................................................59 
12. 
ETHICS ......................................................................................................................60 
12.1. 
Ethical Considerations ................................................................................................60 
12.2. 
Communication with the Institutional Review Board or Independent Ethics 
Committee ...................................................................................................................60 
12.3. 
Patient Information and Consent ................................................................................60 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
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Protocol FGCL-4592-092 
Confidential 
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12.4. 
Patient Confidentiality ................................................................................................61 
13. 
DATA HANDLING AND RECORD KEEPING ......................................................62 
13.1. 
Source Documents ......................................................................................................62 
13.2. 
Direct Access to Source Documents...........................................................................62 
13.3. 
Data Collection, Handling, and Verification ..............................................................62 
13.4. 
Protocol Deviations ....................................................................................................62 
13.5. 
Retention of Data ........................................................................................................62 
13.6. 
Financial Disclosure ...................................................................................................63 
14. 
PUBLICATION POLICY ..........................................................................................64 
15. 
REFERENCES ...........................................................................................................65 
APPENDICES ...............................................................................................................................66 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .................................................................67 
APPENDIX 2. ROXADUSTAT DOSE LEVELS AND DOSE ADJUSTMENT 
RULES .......................................................................................................................69 
APPENDIX 3. ECOG ASSESSMENT SCALE ......................................................................71 
APPENDIX 4. LIVER FUNCTION MONITORING ............................................................72 
APPENDIX 5. ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) ..........................74 
APPENDIX 6. ROXADUSTAT AND PACLITAXEL PHARMACOKINETICS 
SUB-STUDY ..............................................................................................................75 
 
LIST OF TABLES 
Table 1: 
Starting Dose, Route, and Administration ..................................................................41 
Table 2. 
Roxadustat Dose Levels .............................................................................................42 
Table 3. 
Recommended Maximum Daily Dose of Statins .......................................................44 
Table 4. 
Laboratory Tests .........................................................................................................48 
 
LIST OF FIGURES 
Figure 1. 
Circulating EPO Exposure with Roxadustat-treated CKD & ESRD Patients 
versus Reported ESA Dosing Patterns in ESRD 2005 and 2009................................27 
Figure 2. 
Roxadustat in Cisplatin-induced-anemia Response ....................................................29 
Figure 3. 
Roxadustat in Cisplatin-induced-anemia Creatinine Levels .......................................30 
Figure 4. 
Study Schema .............................................................................................................36 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
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2. 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
~ 
Approximately 
AB 
Antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BM 
Bone Marrow 
BP 
Blood Pressure 
BSC 
Best Supportive Care 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CHr 
Reticulocyte Hemoglobin Content 
CIA 
Chemotherapy Induced Anemia 
CKD 
Chronic Kidney Disease 
Cmax 
Maximum Concentration 
CRF 
Case Report Form 
DD 
Dialysis-dependent 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
ECG/EKG 
Electrocardiogram 
EE 
Efficacy Evaluable 
EOT 
End of Treatment 
EPO 
Erythropoietin 
ESA 
Erythropoiesis-stimulating Agent 
ESRD 
End-stage Renal Disease 
FACT-An 
Functional Assessment of Cancer Therapy-Anemia 
FACIT-F 
Functional Assessment of Chronic Illness Therapy- 
Fatigue 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 21 of 76 
 
 
 
FAS 
Full analysis Set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transferase 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
HIF 
Hypoxia-inducible Factor 
HIF-PH 
Hypoxia-inducible Factor Prolyl Hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl hydroxylase inhibitor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IU 
International Unit 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LFT 
Liver Function Test 
LOCF 
Last Observation Carried Forward 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MDRD 
Modification of Diet in Renal Disease 
MDS 
Myelodysplastic Syndromes 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 22 of 76 
 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Sample Size 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
PTT/PT 
Prothrombin Time/Partial Thromboplastin Time 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Events 
Tbili 
Total Bilirubin 
TEAE 
Treatment-emergent Adverse Event 
TESAE 
Treatment-emergent Serious Adverse Event 
TIA 
Transient ischemic Attack 
TIBC 
Total Iron Binding Capacity 
TIW 
Three Times Weekly 
TSAT 
Transferrin Saturation 
UIBC 
Unsaturated Iron-binding Capacity 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
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3. 
INTRODUCTION 
Roxadustat (the investigational study drug) is a new chemical entity (NCE) which belongs to a 
new pharmacological class of small molecule enzyme inhibitors (hypoxia inducible factor 
prolyl hydroxylase inhibitor, HIF-PHI). It is a potent and reversible inhibitor of the prolyl 
hydroxylase enzymes that regulate the stability of the hypoxia-inducible factor (HIF) for 
regulation of erythropoiesis. Roxadustat has been investigated for the treatment of CKD anemia 
in multiple phase 2 studies and phase 3 studies, and all consistently showed robust efficacy and 
acceptable safety profile to date. Furthermore, when roxadustat was tested in a rodent model of 
chemotherapy induced anemia, it was efficacious. In light of the unmet medical need in 
Chemotherapy-Induced Anemia (CIA) where patients have limited choices all of which are 
suboptimal, we aim to develop a new therapeutic option. This study proposes to evaluate the use 
of roxadustat in the treatment of Chemotherapy-Induced Anemia. 
 
3.1. 
Chemotherapy Induced Anemia (CIA) 
Chemotherapy-Induced Anemia is anemia from reduction in red blood cell production by the 
bone marrow due to myelosuppression by chemotherapeutic agents. The anemia due to 
myelosuppressive effect of chemotherapy leads to a decrease in patient’s hemoglobin level. As 
oxygen is critical to survival of all cells in the body, a reduction in oxygen-carrying capacity, 
measured as low Hb level, can have significant impact on the function of various organs and 
risks depending on the severity of anemia. The most common manifestations of anemia are 
fatigue, low energy, and poor quality of life. In severe cases of CIA when the anemia becomes 
life-threatening, blood transfusion may be given if available; in this case, the patient may be 
subjected to the risk of infection and/or immunogenic reactions associated with RBC transfusion. 
Patient outcome could be compromised if the dose and frequency of chemotherapeutic regimen 
were to be reduced in order to reduce its myelosuppressive effects to address the severe anemia. 
 
3.1.1. 
Epidemiology of Chemotherapy Induced Anemia 
Anemia is one of the most common consequences of chemotherapeutic agents where incidence 
of anemia is over 60% and prevalence is 30% to 90% in the same patient population particularly 
in those patients undergoing multiple rounds of chemotherapy. The incidence and severity of 
chemotherapy-related anemia depend on a variety of factors, including (but not limited to) the 
type of chemotherapy, schedule and intensity of therapy administered. Other factors are whether 
the patient has received prior myelosuppressive treatment, radiation therapy or both. There is 
relatively higher incidence of mild-to-moderate than severe anemia. However, elderly cancer 
patients may show higher severity of clinical symptoms of anemia even at higher hemoglobin 
levels than do younger people or anemic patients without cancer. Retrospective reviews of 
incidence of anemia that required RBC transfusions in patients with nonmyeloid malignancies 
who received cytotoxic chemotherapy indicate that the highest frequency occurs in those patients 
with lymphomas, lung tumors, and gynecologic (ovarian) or genitourinary tumors in which the 
incidence may be as high as 50%-60%. The proportion of anemic (hemoglobin <11 g/dL) 
patients increased from 17% before the first chemotherapy cycle to 35% by the sixth cycle of 
treatment, with 49% and 51% of the patients with ovarian and lung tumors, respectively, anemic 
by the sixth cycle of chemotherapy. The mean hemoglobin concentration at which a transfusion 
was given decreased progressively with each treatment cycle. 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 24 of 76 
 
 
 
3.1.2. 
Etiology of Chemotherapy Induced Anemia 
Chemotherapeutic agents induce anemia through directly impairing hematopoiesis, including 
synthesis of RBC precursors, in the bone marrow. In addition, nephrotoxic effects of particular 
cytotoxic agents (e.g., platinum-containing agents) can also lead to anemia through decreased 
renal production of erythropoietin. Platinum-based regimens, commonly used in lung, ovarian, 
and head and neck cancers, are well known to induce anemia caused by combined bone marrow 
suppression and kidney toxicity. The myelosuppressive effects of some cytotoxic agents are 
likely to accumulate over the course of repeated cycles of treatments, resulting in a steady 
worsening of anemia with additional chemotherapy cycles. An increase in the fraction of grades 
2 and 3 anemia was associated with increasing number of chemotherapy cycles. 
 
3.1.3. 
Clinical Features of Chemotherapy Induced Anemia 
Anemia is a common cause of morbidity in cancer. Because anemia of chronic disease is 
prevalent in cancer patients, mild anemia is common before initiation of treatment. Anemia 
generally worsens over time, over repeated cycles of cytotoxic chemotherapies. The anemia 
associated with chemotherapy are normochromic, normocytic but with inappropriately low 
reticulocyte count. Serum Iron and Iron-binding capacity are low. Bone marrow (BM) 
morphology reveals normal erythroid precursor with normal or slightly increased stainable iron. 
Erythroid progenitors (BFU-E & CFU-E) size, number and degree of hemoglobinization are 
normal while the BM still maintains normal sensitivity to erythropoietin (EPO). CIA is 
characterized by decrease in hemoglobin (Hb) concentration, RBC count and / or packed cell 
volume to subnormal levels. 
 
3.1.4. 
Current Treatment of Chemotherapy Induced Anemia 
The current treatment options for CIA are limited, and thus the anemia in most patients with CIA 
remain untreated. Although ESA has been approved for the treatment of CIA, its use has 
decreased precipitously due to safety concerns of risk of tumor progression, death, and 
cardiovascular risk. Such risks are associated with the high doses of ESA used in CIA (about 
3X to 5X of doses for CKD anemia). RBC transfusions are sometimes used for treating severe 
CIA, but patients would be exposed to the risks of infection and immunogenic reactions 
associated with RBC transfusions. Reduction in chemotherapy use may decrease the 
myelosuppressive effects, but patients’ outcome could also be compromised. Given the 
limitations in the current choices, a new efficacious, safe, and convenient treatment option for 
CIA is needed. 
3.2. 
Roxadustat 
3.2.1. 
Mechanism of Action of Roxadustat 
Roxadustat (FG-4592) is an orally administered inhibitor of HIF-PHI. FG-4592 increases 
cellular levels of HIF. HIF is a transcription factor that is believed to be the key element in the 
body’s oxygen sensing mechanism (Semenza, 2000). HIF regulates expression of genes that 
modulate the acute and chronic responses to hypoxia. In addition, HIF-responsive genes regulate 
a wide range of processes, including erythropoiesis, iron metabolism, oxidation, cellular 
metabolism, glycolysis, vasculogenesis, cell cycle progression, and apoptosis. 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
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FG-4592 is a potent and reversible HIF-prolyl hydroxylase inhibitor that transiently induces HIF 
stabilization and leads to a functional HIF transcriptional response that mimics the erythropoietic 
response associated with exposure of humans to intermittent hypoxia. Thus, FG-4592 
pharmacologically stimulates erythropoiesis through the HIF pathway and in a manner consistent 
with the body’s normal homeostatic response to anemia, but under normal oxygenation 
conditions. 
The physiologic mechanisms underlying the effects of FG-4592 on erythropoiesis are distinct 
from that of ESAs. These differences result in several potential advantages over ESAs beyond 
the convenience of oral therapy, including: 
• Transient increase of circulating endogenous erythropoietin levels at or near 
physiologic levels 
• Improved iron metabolism and bioavailability 
• Effective erythropoiesis in the presence of inflammation 
• Increase in the number of EPO receptors in the bone marrow 
• Improvement in lipid profile 
3.2.2. 
Clinical Experience with Roxadustat 
A total of 22 Phase 2 and 3 clinical efficacy and safety studies have been completed and three 
studies are ongoing at the time of this submission. As of the 07 September 2019 data cut-off, 
13063 patients (943 healthy patients, 5994 patients with NDD-CKD, and 6126 patients with DD- 
CKD) have been randomized in the roxadustat CKD clinical development program. An 
estimated total of 7821 patients received roxadustat, 3129 patients received active comparator 
(epoetin alfa or darbepoetin alfa), and 2113 patients received placebo. Over 11,000 subjects 
have enrolled into Phase 3 studies. 
 
There are > 3200 CKD patients exposed to roxadustat for >= 1 year, and of whom about half 
have received roxadustat for >=2 years. There is a small number of patients receiving roxadustat 
for > 5 years. Long term studies suggest durability of erythropoietic effect. There have been no 
safety concerns to date, inclusive of thorough QT study which tested roxadustat dose up to 
5 mg/kg in healthy volunteers, with no evidence of QTc prolongation. The anemia correction 
response rates in anemic CKD patients not on dialysis (Studies FGCL-4592-041, 
FGCL-4592-047, FGCL-4592-808) and those starting dialysis therapy (FGCL-4592-053, ASP- 
1517-CL-302) were >90%. 
Roxadustat has also been shown to maintain Hb levels when ESA has been withdrawn in 
dialysis-dependent (DD) end stage renal disease (ESRD) patients who previously depended on 
ESA for Hb maintenance (Studies FGCL-4592-040, FGCL-4592-048, FGCL-4592-806, and 
ASP-1517-CL-307). In CKD patients, the roxadustat dose requirement and achieved Hb levels 
are not impacted by baseline C-reactive protein level (CRP), a measure of inflammation, which 
is suggestive of roxadustat’s ability to overcome the dampening effect of inflammation on 
erythropoiesis (FGCL-4592-053, FGCL-4592-806).This is a challenge for ESA use for anemia in 
inflamed patients as higher ESA dose was used and the Hb level achieved were still lowered in 
patients with elevated CRP in study 808. Anemia of inflammation affects various patient 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
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populations with chronic diseases, including those with cancer. Roxadustat also overcomes the 
iron dysregulation in CKD patients to enable iron utilization for erythropoiesis, by reducing the 
hepcidin level, and also lowering serum ferritin levels. 
Comprehensive safety information can be found in the Investigator’s Brochure. 
 
3.2.3. 
Pharmacology (PK/PD) of Roxadustat 
Supra-physiological recombinant human erythropoietin (rhEPO) levels may be a contributing 
factor in the increased cardiovascular and thrombotic risk observed in ESA treated CKD patients 
and the very high doses of ESA required (up to five times the dose required in anemia associated 
with CKD) potentially contribute to ESA’s cancer progression risks in oncology patients. 
Roxadustat, a HIF-PHI mechanism impacting multiple parts of the erythropoietic pathway, has 
been shown to expose CKD patients to much lower plasma EPO levels than ESA when 
achieving comparable erythropoietic effects, and the transient peak levels of EPO level with 
roxadustat doses used in CKD patients are within the range of physiologic adaptation. Figure 1 
depicts the impact of environment on plasma EPO levels: with a range from 10 to 15 mIU/mL in 
healthy patients at sea level, while EPO levels triggered by physiologic adaptation to phlebotomy 
are in the range of 15 to 250 mIU/mL (Goldberg, 1993, Maeda, 1992), and adaptation to 
moderate high altitude (4500 m) showed mean levels up to 70 mIU/mL (Milledge, 1985), to 
doses used in CKD patients on dialysis (far right). The off-label ESA use for treatment of anemia 
in MDS patients are typically at doses comparable to the EPO hypo-responsive ESRD-dialysis 
patients (such as those at or above the highest dose quartile in Figure 1) that leads to two orders 
of magnitude above the normal physiologic range of EPO. Exposure to high ESA levels are 
thought to be associated with higher risks to off-target effects of ESA. Roxadustat has a potential 
to address anemia need with more physiologic EPO exposure. 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
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Figure 1. 
Circulating EPO Exposure with Roxadustat-treated CKD & ESRD Patients 
versus Reported ESA Dosing Patterns in ESRD 2005 and 2009 
 
 
1Cmax data for roxadustat estimated for a subset of 243 patients who achieved Hb response and were dosed at 
expected therapeutic doses; 2Milledge & Cotes (1985); 3Goldberg et al. (1993), Maeda et al. (1992); 
4 Kato et al. (1994); 5Based on Flaharty et al. (1990) 
Furthermore, the roxadustat intermittent dosing regimen (three times weekly, TIW) enables the 
HIF system to reset before the next round of stabilization which enhances the durability of its 
therapeutic effect by avoiding tachyphylaxis while minimizing the risk of off-target effects on 
the HIF biology. 
 
3.3. 
Rationale for Roxadustat in Chemotherapy Induced Anemia 
The unmet medical need with CIA exists because of the unintended side-effect of anemia 
induced by chemotherapy’s effect on bone marrow suppression. However, the treatment options 
to address CIA are limited. Of the 3 options, RBC transfusion, ESA which leads to 
supraphysiologic levels of endogenous erythropoietin, and/or dose reduction of the 
chemotherapy treatments, each has its major shortcoming. Therefore, in the US, CIA is left 
mostly untreated and RBC transfusion has become patients’ last resort. 
Roxadustat has the potential to address this unmet medical need in light of its positive efficacy 
demonstrated in multiple phase 2 and some phase 3 studies, with acceptable safety profile. The 
results from the preclinical model using cisplatin induced anemia suggest roxadustat has the 
potential for CIA therapy. 
This study is an open label study investigating the efficacy and safety of roxadustat (FG-4592) 
for the treatment of anemia in patients receiving multiple cycles / rounds of chemotherapy 
treatments for Non-Myeloid malignancies. This will include anemic patients, with Hb ≤ 10 g/dL, 
in those who may require RBC transfusion, with treatment duration of 16 weeks. The primary 
efficacy will be evaluated after 16 weeks of treatment (Appendix 1– Schedule of Assessments). 


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3.3.1. 
Rationale for Roxadustat Dose and Dosage Regimen 
For the treatment of anemia in patients undergoing multiple rounds of chemotherapy, roxadustat 
will be administered orally three times per week (TIW) and its dose will be titrated to achieve the 
target response. This study will provide the information for selection of optimal starting dose of 
roxadustat. In anemia therapy, the goal is to increase Hb level to ~ 11 +/- 1 g/dL. Dose 
requirement is individualized, and dose titration will be needed to optimize treatment results. 
Roxadustat dose selection in CIA is informed by the learnings from CKD anemia preclinical and 
clinical trials experience. The roxadustat dose shown effective in preclinical CIA model is the 
same as the dose used in the 5/6 nephrectomy preclinical model of CKD anemia. The starting 
dose of ~ 2.0 mg/kg in the first 20 patients in this study is one that is efficacious in about 80% of 
CKD patients, and no safety concern observed. After every 4 weeks of treatment at a dose level 
of roxadustat, dose requirement will be evaluated and dose modification will be made according 
to Appendix 2. The maximum permitted dose will be the same as that allowed in the CKD 
program of 400 mg or 3.5 mg/kg TIW (whichever is lower). The highest roxadustat dose studied 
in healthy volunteers is 5.0 mg/kg in TQT study, and there was no safety concern. There has not 
been a maximal tolerated dose in this program. 
Upon evaluating the pharmacodynamics (hemoglobin) responses after 4 weeks of therapy with the 
starting dose of 2.0 mg/kg in initial 20 patients, it has been determined to increase the starting dose for 
newly enrolled patients by one level i.e. from 2.0 mg/kg to 2.5 mg/kg level to achieve optimal 
hemoglobin response. The maximum permitted dose will remain the same i.e. 400 mg or 3.5 
mg/kg TIW (whichever is lower). 
 
 
3.3.2. 
Risks/Benefit Assessment of Roxadustat Treatment in This Study 
Patients with anemia have a shortage of oxygen carrier, hemoglobin. Depending on the severity 
of anemia, CIA can lead to fatigue, poor QOL, and when severe, it could be life-threatening. 
Thus, interventions such as blood transfusions, ESA use, or modification of chemotherapy 
regimen could be chosen by treating physicians in the management of cancer patients with CIA. 
Yet, each of these intervention has its inherent risks: blood transfusion carries risks of 
transfusion reaction, infection, and there may be limitation of blood supply; ESA use is 
associated with documented increased risk of death, MI, stroke, and tumor progression; and 
reduction in chemotherapy doses could lead to less favorable outcome for the patient. It is 
important to highlight that the risk with ESA in treatment of CIA is related to the very high doses 
required in cancer patients who suffer from myelosuppression superimposing on their varying 
degrees of anemia of inflammation where ESA is ineffective. The tumor progression risks and 
CV risks of ESA are associated with exposure to the high concentrations of exogenous 
recombinant EPO in the blood, at orders of magnitude above physiologic range. 
The potential benefits of roxadustat include halting the reduction in Hb level and correction of 
anemia, thus reduction of pRBC transfusions, and avoiding the need to alter planned 
chemotherapy regimen to enable patients to maximal benefit of treatment. These altogether will 
result in the relief of signs and symptoms associated with anemia, the avoidance of the risks 
associated with RBC transfusions, improvement in quality of life for these cancer patients, and 
achieving the benefit from the optimal dose of chemotherapy treatment. In contrast to ESA, 
patients are exposed to endogenous erythropoietin at levels at or near physiologic range to avoid 


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the ESA-dose related risks, and roxadustat is expected to be efficacious regardless of
inflammation as observed in CKD studies. Roxadustat is expected to overcome the inhibitory
effect of inflammation of chronic disease on erythropoiesis, improve erythropoietic progenitor
cells’ response to erythropoietin, facilitate the mobilization of iron and ultimately lead to
improved erythropoiesis. Furthermore, oral route of administration of roxadustat offers
convenience to patients.
In the experience of roxadustat for treatment of CKD anemia, it has been found well tolerated
and highly efficacious in a number of phase 2 and phase 3 studies. New Drug Applications have
been submitted to China and to Japan. Adverse events profile is provided in the IB. This will be
the first study of roxadustat for treatment of CIA for proof of concept and for dose selection.
Given the extensive clinical experience with roxadustat for treatment of CKD anemia with
encouraging efficacy and safety data, in addition to the positive preclinical data from CIA animal
models, we believe the benefit of testing roxadustat in patients with CIA in this study far
outweighs the risks. We believe roxadustat has the potential to address the unmet medical need
in patients suffering from CIA.
3.4.
Nonclinical Studies
In addition to the usual preclinical toxicology studies to support human use of roxadustat, a
number of preclinical studies have been conducted for the evaluation of efficacy of roxadustat
for treatment of CIA and studies were also conducted for the assessment of safety especially in
the oncology setting.
3.4.1.
Roxadustat in Cisplatin-induced-anemia in Sprague Dawley Rats
A single dose of cisplatin was administered IV on day 0 and roxadustat was administered via oral
gavage on days 0, 2, 4, 7, 9, and 11 with the first dose given ~2 hours before cisplatin to Sprague
Dawley rats. The treatment arms included vehicle, roxadustat 20 mg/kg or 40 mg/kg, dose
response in anemia correction was noted on Day 14, per figure 2 below.
Figure 2.
Roxadustat in Cisplatin-induced-anemia Response
Furthermore, roxadustat may mitigate nephrotoxic effect of cisplatin based on serum creatinine
levels per Figure 3 below.


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Figure 3.
Roxadustat in Cisplatin-induced-anemia Creatinine Levels
It appears roxadustat can treat cisplatin induced anemia and reduce the nephrotoxic effect of
cisplatin in this rodent model.
3.4.2.
Preclinical Tumor Models
To assess the potential cancer risk of roxadustat, 12 tumor studies in rodents with roxadustat had
been completed. These studies included xenograft, syngeneic, or spontaneous tumors of lung,
colon, breast, pancreas, of ovarian, renal, prostate and leukemic origin, and melanoma, several of
which are reported to be dependent on vascular endothelial growth factor, or VEGF, a protein
that can be regulated by HIF for which increased levels have potentially been linked to increased
tumor growth. The doses of FG-4592 used in these studies ranged from 6 to 80 mg/kg, up to
5 times the high dose in Phase 3 (2.5 mg/kg). No effect on tumor promotion was observed with
roxadustat in any of the studies. In addition, roxadustat had no effect on tumor initiation or
metastasis in the studies in which these end-points were also measured. Five other HIF-PH
inhibitors from our HIF-PHI library have been evaluated in many of the same rodent tumor
models as roxadustat, as well as some additional ones (35 studies of six HIF-PH inhibitors in
18 models total), with no observed effect on tumor initiation, promotion or metastasis.
Specifically, no tumor-related findings were observed when FG-4592 was evaluated in a
VEGF-sensitive mouse model of spontaneous breast cancer. Intermittent treatment of FG-4592
and another HIF-PH inhibitor, FG-4497, were evaluated in the MMTV-Neundl-YD5 (NeuYD)
transgenic mouse model of breast cancer, in which a significant elevation in markers of
erythropoiesis were observed without any evidence of promotion of tumor initiation,
progression, or metastasis (Seely 2017).
Finally, no significant increases in plasma VEGF levels have been observed in any of our
nonclinical studies at clinically relevant erythropoietic doses of roxadustat.
3.4.3.
Carcinogenicity Studies
Results of genotoxicity and 2-year rodent carcinogenicity studies showed FG-4592 to be both
nonmutagenic and noncarcinogenic and thus likely a low risk for carcinogenic potential.
In genotoxicity studies, FG-4592 demonstrated no mutagenic potential in the mouse
micronucleus assay or in the presence or absence of metabolic activators (S9 fraction) as tested
in the bacterial reverse mutation (five Escherichia or Salmonella strains) assay and in the
chromosomal aberration assay.


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Two-year repeat oral TIW administration of FG-4592 to mice and rats produced no adverse 
effects on survival or evidence of a carcinogenic effect using up to and including the highest 
doses administered, 60 mg/kg and 10 mg/kg in mice and rats, respectively. Exposure levels 
(Cmax and AUC) of FG-4592 in the 2-year rodent bioassays were greater than in the human 
plasma collected from the healthy human volunteer clinical trial FGCL-4592-016. Based on the 
in vitro FG-4592 protein binding ratios in mice and rats which were demonstrated to be lower 
than in humans, the free (non-protein bound) exposure multiples between exposure at the 
NOAELs in the rodent studies and at the highest dose administered in the repeated dose clinical 
trial would be greater (~10 and 2 times higher) in mice and rats respectively based on in vitro 
free fraction than those estimated using total drug exposure. 
 
3.4.4. 
Preclinical Safety Summary 
The results of the chronic toxicity studies, the ICH battery of genotoxicity studies, and the rodent 
carcinogenicity studies showed no evidence of an increased risk of carcinogenicity following up 
to two years repeated TIW dosing of FG-4592. 
Conclusion from preclinical studies: preclinical evidence suggest FG-4592 does not present a 
carcinogenicity risk. 
Summaries of all completed, nonclinical studies for roxadustat can be found in the current 
version of the Investigator’s Brochure. 


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4. 
OBJECTIVES AND ENDPOINTS 
4.1. 
Objectives 
4.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of roxadustat in the treatment of 
anemia in patients undergoing multi-cycle myelosuppressive chemotherapy treatment of cancer. 
 
4.1.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• Evaluate the safety of roxadustat in this patient population 
• Evaluate the impact of roxadustat on RBC transfusion requirements 
• Evaluate the effect of roxadustat on several biological indicators including, but not 
limited to: erythropoietin, hemoglobin, hematocrit, reticulocytes, hepcidin, serum 
iron, ferritin, transferrin saturation and total iron binding capacity 
 
4.2. 
Endpoints 
Central lab Hb values will be censored for 4 weeks following a blood/pRBC transfusion during 
the treatment period for all efficacy analyses. 
 
4.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is maximum change in hemoglobin in 16 weeks from baseline 
without RBC transfusion. 
 
4.2.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this trial are: 
• Mean change in hemoglobin level from baseline to week 16 (without RBC 
transfusion) 
• Change in hemoglobin from baseline through week 8, 12, 16 (without RBC 
transfusion) 
• Proportion of patients who achieved a ≥1 g/dL increase in hemoglobin from baseline 
through week 16 
• Time to achieve a ≥1 g/dL increase in hemoglobin from baseline 
• Proportion of patients who achieved a ≥1.5 g/dL increase in hemoglobin from 
baseline through week 16 
• Proportion of patients who achieved a hematopoietic response at any time in the study 
(defined as an increase in Hb of 1.5 g/dL OR attaining a Hb of 11) 
• Proportion of patients who achieved a ≥2 g/dL increase in hemoglobin from baseline 
through week 16 


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• Number (%) of patients who had a RBC transfusion from beginning of Week 5 (Day 
29) to week 16 
 
4.2.3. 
Additional Efficacy Endpoints 
• Proportion of patients who achieved a ≥1 g/dL increase in hemoglobin from baseline 
through week 8 and 12 
• Proportion of patients who achieved a ≥1.5 g/dL increase in hemoglobin from 
baseline through week 8 and 12 
• Number (%) of patients that require transfusion as medical intervention and/or ESA 
(erythropoiesis stimulating agent) as a rescue agent. [Time Frame: 16 weeks] 
• Percentage of Participants by Tumor Type With Improvement in FACIT-F (fatigue) 
and Increase in Hemoglobin ≥ 1 g/dL [Time Frame: baseline to week 16] 
• Change from Baseline in Quality of life as measured by: 
Functional Assessment of Cancer Therapy-Anemia (FACT-An) test 
[Time Frame: baseline to week 8 and 16] 
 
4.2.4. 
Exploratory Evaluations 
• Effect on hepcidin and iron metabolism 
• Effect on cholesterol parameters and lipid metabolism 
4.2.5. 
Subgroup Analyses 
• Tumor Type 
• Chemotherapy regimen [i.e. platinum vs non-platinum] 
• Other clinically relevant characteristics 
• Roxadustat PopPK 
• Paclitaxel DDI 
4.3. 
Safety Assessments 
Safety will be assessed by evaluating the following over the 16-week treatment plus 4-week 
follow-up periods of the study: 
• Adverse Event and Serious Adverse Event Reporting 
• Number (%) of patients receiving transfusions 
• Various clinical laboratory measurements/values. 


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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Design 
This is a Phase 2, open label study. The study will evaluate the efficacy of roxadustat for the 
treatment of anemia in patients receiving multi-cycle treatments of myelosuppressive 
chemotherapy. A total of up to 100 patients will be enrolled in this trial, across approximately 
10-20 study centers in the United States. 
This trial has three study periods: 
• Screening (up to 28 days) 
• 16-week Treatment with roxadustat 
• 4-week Follow-Up 
All screening procedures are to be completed within 28 days prior to Study Day 1. Patients will 
be evaluated per the protocol inclusion/exclusion criteria to determine eligibility for participation 
in this trial. Protocol assessments will be completed during screening visits in accordance with 
Schedule of Assessments (SOA) to establish a baseline profile, including; demographics, 
medical history, clinical status and disease stage for each patient. Eligible patients will be 
enrolled in the trial and receive roxadustat in an open-label manner. The starting dose for the 
initial 20 patients will be 2.0 mg/kg, with dose titration to Hb levels every 4 weeks. Starting 
dose(s) for subsequent patients will be selected by the sponsor, informed by the data available 
from earlier patients treated in the study. 
Upon evaluating the pharmacodynamics (hemoglobin) responses after 4 weeks of therapy with the 
starting dose of 2.0 mg/kg in initial 20 patients, it has been determined to increase the starting dose for 
newly enrolled patients by one level i.e. from 2.0 mg/kg to 2.5 mg/kg level to achieve optimal 
hemoglobin response. The maximum permitted dose will remain the same i.e. 400 mg or 3.5 
mg/kg TIW (whichever is lower). 
The selected starting dose level of subsequent patients will not exceed the highest dose level 
received by any individual patient in the study up to that point and will be within the maximum 
dose allowed in the protocol. Additionally, the sponsor will review clinical efficacy and safety 
response on an ongoing basis and take into account potential impact of certain baseline patient 
characteristics or chemotherapy regimens (such as from patients on a platinum vs non-platinum 
containing regimen) on treatment response in the selection of subsequent patients of such 
characteristics and starting dose(s) of subsequent patients. This may result in different starting 
dose revisions for each group. Lastly, if there is more than one starting dose cohort open for 
enrollment at the same time for a certain subgroup, such as a platinum (or non-platinum) 
treatment subgroup, patients will be randomized to receive a starting dose. A comprehensive 
table of potential doses is contained in the protocol body and in Appendix 2. Finally, starting 
doses will not be adjusted for platinum containing or non-platinum containing regimens until 8 
patients in a group have been dosed at a specific dose level. 
Patients will undergo 16 weeks of study treatment with roxadustat. Study visits are scheduled 
every 2 weeks. Patients’ clinical status will be regularly evaluated. If disease progression occurs 
during the treatment period, patients will be discontinued from study treatment and should 
continue to be followed for safety evaluation throughout the follow-up period. 


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All patients who complete 16 weeks of treatment with study medication will undergo a 4-week 
follow-up period after the last dose of study medication. 
Patients who discontinue study medication early (for any reason whatsoever) will have a 4-week 
follow-up visit after stopping study medication. See Section 8.0 for details. A schematic 
overview of the study is provided in Figure 4. Study Schema A detailed overview of assessments 
and the timing of assessments is provided in Appendix 1 
 
5.1.1. 
Estimated Study Duration 
It is anticipated that enrollment will be complete within 9-12 months from first patient enrolled. 
All patients will complete up to 16 weeks of study treatment and at least 28 days of safety 
follow-up. Therefore, it is anticipated that the entire duration of the study will be approximately 
1 to 1.5 years from time of first patient enrolled. 


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Roxadustat 
Protocol FGCL-4592-092 
 
Figure 4. 
Study Schema 
 


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5.2. 
Treatment Assignment 
5.2.1. 
Enrollment 
Approximately (up to) 100 patients will be enrolled into this study 
No stratification is planned for this study, however sub-groups analyses will be performed as 
described in the separate statistical analysis plan (SAP). Sub-Groups of interest will include the 
following: 
• Tumor type 
• Chemotherapy regimen [i.e. platinum vs non-platinum] 
• Other clinically relevant characteristics 
Importantly, the initial 8 patients in each of the platinum and non-platinum containing groups 
will all receive the initial starting dose of 2.0 mg/kg. Data from each group will be examined 
separately to determine the need of a potential dose step increase for each group. It is possible 
that one group will have a dose increase and the other group will remain at the initial starting 
dose level. 
 
5.2.2. 
Treatment Assignment 
All patients will receive roxadustat. 
 
5.3. 
Blinding 
Not applicable to this open-label study. 


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6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1. 
Patient Inclusion Criteria 
In order to be eligible for inclusion in this trial, a patient must meet all of the following: 
1. Diagnosis of non-myeloid malignancy. Current documentation of disease burden (e.g. 
CT scan) within 3 months prior to enrollment (Day 1) 
2. Anemia caused by cancer treatment (myelosuppressive chemotherapy), defined as 
Hb ≤ 10.0 g/dL at screening 
3. Planned concurrent treatment of cancer (myelosuppressive chemotherapy) for at least 8 
additional weeks 
4. Age ≥18 years 
5. Body weight ≥45 kg and < 150 kg 
6. ECOG performance status of 0, 1, or 2 at last screen visit 
7. Patient must be capable of giving written informed consent 
8. Understand and sign informed consent; be willing to comply with all study procedures 
9. Estimated life expectancy ≥ 6 months at enrollment (Day 1) 
 
6.2. 
Patient Exclusion Criteria 
Patients will be ineligible for and excluded from this trial if any of the following apply: 
1. Patients with cancer receiving myelosuppressive chemotherapy when the anticipated 
outcome is cure 
2. Patients who are only receiving hormonal products, biological products, novel 
immunosuppressive products (such as PD-1 and PD-L1 checkpoint inhibitors) or targeted 
biological or radiation therapy to treat/manage their cancer. (Patients 
receiving concomitant myelosuppressive therapy if not intended for cure may be allowed 
to participate) 
3. Patients who prefer a Red Blood Cell (RBC) transfusion as treatment of anemia at time of 
study entry, over receiving the investigational drug Roxadustat 
4. Received an RBC transfusion or ESA within 4 weeks of enrollment (Day 1) 
5. Alanine aminotransferase (AST) >3 x upper limit of normal (ULN), OR aspartate 
aminotransferase (ALT) >3 x ULN, OR total bilirubin (TBL) >1.5 x ULN– will exclude a 
patient from entering the study (patients with TBL up to 2x ULN may be allowed if 
ALT/AST are within normal limit and investigator has no safety concerns) 
6. Inadequate iron stores as defined as ferritin < 50 ng/mL 
7. Any investigational drug within 8-weeks prior to Day 1 Treatment or plans to use any of 
these medications during the course of clinical trial participation 
8. Anticipated use of dapsone during the study 


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9. Clinically significant anemia due to other etiologies such as iron deficiency, vitamin B12 
or folate deficiency, autoimmune or hereditary hemolysis or anemia, hemorrhage, or 
hereditary anemia such as sickle cell anemia, thalassemia, or MDS 
10. Active infection(s) requiring chronic antibiotic therapy 
11. Estimated Glomerular Filtration Rate (eGFR) <30 mL/min based on 4-variable MDRD 
equation 
12. Thromboembolic event (deep vein thrombosis (DVT), pulmonary embolism, myocardial 
infarction, stroke, transient ischemic attack (TIA) within previous 6 months of screening 
13. Significant heart disease, including New York Heart Association (NYHA) Class III or IV 
congestive heart failure, uncontrolled hypertension or hypotension, or significant valvular 
or endocardial disease that would put the patient at risk for thromboembolism 
14. Clinically significant or uncontrolled ongoing inflammatory/autoimmune disease (e.g., 
rheumatoid arthritis, Crohn’s disease, celiac disease, etc.) 
15. History of significant liver disease or active liver disease 
16. Major surgery planned during the treatment period 
17. Known, active or chronic bleeding 
18. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
19. Clinically significant or uncontrolled medical condition that would affect the patient's 
ability to participate in the study or confound the study's efficacy or safety results 
20. History of leukemia (current or historical Chronic Lymphocytic Leukemia may be 
allowed) 
21. Previous recipients of roxadustat or another hypoxia-inducible factor prolyl hydroxylase 
inhibitor (HIF-PHI) 
22. Pregnant or breastfeeding females 
 
6.3. 
Patient Withdrawal Criteria 
Patients may withdraw from study treatment at any time. 
Reasons for discontinuing the patient from study treatment include the following: 
• Progressive Disease 
• Adverse Event 
• Lost to Follow-Up 
• Use of any ESA (Appendix 5) during the study 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Major protocol deviation that substantially affects patient safety or assessment of 
efficacy endpoints 


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• Withdrawal of Consent 
Discontinued patients should be evaluated in the clinic for EOT visit, followed for safety and 
continue in the follow-up period. 
 
6.4. 
Replacement of Study Patients 
Patients will not be replaced in this study. 
 
6.5. 
Study Termination 
FibroGen reserves the right to close any investigational site(s) or terminate the study at any time 
for any reason. Reasons for the closure of the study site or termination of a study by FibroGen 
may include (but are not limited to): 
• Successful completion of the study at the investigational site 
• The required number of patients for the study has been recruited 
• Failure of the Investigator to comply with the protocol, GCP guidelines or local 
requirements 
• Safety concerns 
• Inadequate recruitment of patients by the Investigator 


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7. 
TREATMENT OF PATIENTS 
7.1. 
Study Treatment 
Roxadustat is administered as an oral tablet, TIW for up to a maximum of 16 weeks overall study 
treatment period. If dosing delays occur due to AEs or scheduling conflicts, for example, it is 
acceptable to hold (not give) roxadustat for one single instance not to exceed a 2-week period. 
Dosing visits should occur in accordance with the SOA outlined in Appendix 1 whenever 
possible, regardless of delays in chemotherapy dosing. Dosing of roxadustat should continue 
even if the planned courses of chemotherapy are halted. 
Information regarding storage and handling is found in the FG-4592 Investigator’s Brochure and 
the IP Manual. 
 
7.1.1. 
Roxadustat 
The dose, route and schedule for the administration of roxadustat is provided below in Table 1 as 
well as in Appendix 2. 
Table 1: 
Starting Dose, Route, and Administration 
 
Dose 
Level 
Group 
Roxadustat 
dose level 
( mg/kg) 
45 to <70 
kg 
70 - 100 kg 
> 100 kg 
1 
2.0 
100 mg 
TIW 
150 mg 
TIW 
200 mg TIW 
 
Dose adjustment evaluation will be made every 4 weeks, and dose will be titrated to Hb level and 
rate of Hb change according to Appendix 2. Dose escalation decisions are based on results from 
LOCAL Hb testing. This can either be hemocue (supplied by FibroGen) or via local lab as long 
as there is real time turnaround of results to prevent patient inconvenience. 
Additional information on dose escalation steps and other potential starting dose levels is given 
in Appendix 2 as well as the table below. 


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Table 2. 
Roxadustat Dose Levels 
 
Body 
Weight 
Dose Levels 
Approx. 
1.0 mg/kg 
Approx. 
1.5 mg/kg 
Approx. 
2.0 mg/kg 
Approx. 
2.5 mg/kg 
Approx. 
3.0 mg/kg 
Approx. 
3.5 mg/kg 
45 - < 70 kg 
50 mg TIW 
70 mg TIW 
100 mg 
TIW 
150 mg 
TIW 
200 mg 
TIW* 
250 mg 
TIW* 
70-100 kg 
100 mg 
TIW 
120 mg 
TIW 
150 mg 
TIW 
200 mg 
TIW 
250 mg 
TIW 
300 mg 
TIW* 
>100 kg 
120 mg 
TIW 
150 mg 
TIW 
200 mg 
TIW 
250 mg 
TIW 
300 mg 
TIW 
350 mg 
TIW 
 
Principal Investigator (PI) and/or treating physician will determine when to transfuse a patient 
based on clinical judgement. 
Evaluation for dose modification/adjustment will occur every 4 weeks. Any potential dose 
escalation/dose reduction will be at pre-defined dose step increments. 
After the initial 20 patients are enrolled, starting dose(s) for additional patients will be selected 
by the sponsor, informed by the data available from earlier patients treated in the study. 
Starting dose for newly enrolled patients: 
Upon evaluating the pharmacodynamics (hemoglobin) responses after 4 weeks of therapy with the 
starting dose of 2.0 mg/kg in initial 20 patients, it has been determined to increase the starting dose for 
newly enrolled patients by one level i.e. from 2.0 mg/kg to 2.5 mg/kg level to achieve optimal 
hemoglobin response. 
 
 
Dose 
Level 
Group 
Roxadustat 
Dose Level 
( mg/kg) 
45 to < 70 
kg 
70 - 100 
kg 
> 100 kg 
1 
2.5 
150 mg 
TIW 
200 mg 
TIW 
250 mg TIW 
 
 
The selected starting dose level will not exceed the highest dose level received by any individual 
patient in the study up to that point and will be within the maximum dose allowed in the 
protocol. Additionally, the sponsor will review clinical efficacy and safety response on an 
ongoing basis and take into account potential impact of certain baseline patient characteristics or 
chemotherapy regimens (such as from patients on a platinum vs non-platinum containing 
regimen) on treatment response in the selection of patients of baseline characteristics and starting 
dose(s) of subsequent patients. Lastly, if there is more than one starting dose cohort open for 
enrollment at the same time for a certain subgroup, such as platinum (or non-platinum) treatment 


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group, patients will be randomized to receive a starting dose. A comprehensive table of potential 
doses is contained in the protocol body and in Appendix 2. 
 
7.1.2. 
Chemotherapy 
The dose, route, and schedule for administration of any chemotherapeutic agent will be decided 
and administered per treating physicians according to standard treatment algorithms. 
 
7.1.3. 
Dose Administration and Modifications 
See Study IP Manual for details regarding dose preparation and administration. 
Roxadustat can be given either before or after chemotherapy, but timing should be consistent 
throughout the course of the study. 
In the event that chemotherapy is modified, withheld, or terminated as per standard of care, the 
dosing schedule of roxadustat should be maintained. 
 
7.1.4. 
Treatment Compliance 
Roxadustat will be dispensed by qualified personnel at the investigational sites; dosing history 
and study medication reconciliation will be documented in the corresponding case report form 
(CRF). 
 
7.1.5. 
Concomitant Medications, Procedures, and Nondrug Therapies 
 
7.1.5.1. 
Prohibited Concomitant Medications 
Use of ESAs (Appendix 5) and Dapsone in any dose amount is prohibited in the course of the 
study. Androgens and iron-chelating agents (eg, deferoxamine, deferiprone, or deferasirox 
therapy) are also prohibited in the course of the study. However, other regular supportive care as 
clinically indicated is permitted during this trial. 
 
7.1.5.2. 
Chemotherapy Treatments 
If Paclitaxel (e.g. Taxol® or Abraxane®) is given as part of a chemotherapy regimen, roxadustat 
dosing should be held for 24 hours before and after treatment (time 0 = start of infusion) with 
this drug. Roxadustat dosing frequency may be adjusted, as needed. 
 
7.1.5.3. 
Other Potential Drug Interactions 
Dose adjustments of strong modulators of CYP2C8 (e.g. gemfibrozil, clopidogrel) and UGT 
enzymes per physician judgment are allowed. 
 
7.1.5.4. 
Phosphate Binders 
When coadministered with roxadustat, in a clinical pharmacology study, the bioavailability of 
roxadustat was reduced. Patients should be advised to discuss with the Investigator when 
changing the dose or dosing time of their phosphate binder while taking study medication. 
 
7.1.5.5. 
Statins 
When coadministered with roxadustat, in clinical pharmacological studies, 
hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) exposure was increased 2- to 3- 


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fold. Investigators should consider this interaction and local prescribing information when 
deciding on the appropriate statin dose for individual patients, bearing in mind the impact of 
ethnicity, other concomitant medications, renal and hepatic function. Goals of lipid lowering 
treatment should be maintained as clinically indicated. The dose of statins should not exceed the 
recommended daily dose in Table 3 below. 
Table 3. 
Recommended Maximum Daily Dose of Statins 
 
Statins 
Recommended Maximum Dose (mg/day) 
Atorvastatin 
40 
Simvastatin 
5 
Rosuvastatin 
5 
Pravastatin 
40 
Fluvastatin 
20 
Pitavastatin 
2 
Lovastatin 
20 
 
7.1.5.6. 
Supplemental Iron Use 
Oral iron supplementation is allowed. IV iron use is prohibited, but may be considered if patient 
is iron-deficient and unresponsive to oral iron supplementation and lacking erythroid response to 
study medication.  This would require discussion with the Medical Monitor. 
 
7.1.5.7. 
Contraception Requirements 
Female patients of childbearing potential are required to use double barrier contraception 
methods during the entire conduct of the study and for 3 months after the last dose of study drug. 
Male subjects with female partners of childbearing potential who are not using birth control as 
described above must use a barrier method of contraception (e.g., condom) if not surgically 
sterile (i.e., vasectomy). 
For patients discontinuing study medication prematurely, it is recommended that they continue to 
practice contraceptive methods for 12 weeks following the last dose of study treatment. 
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be reported. 
 
7.2. 
Study Drug Materials and Management 
Additional details regarding study drug material and management can be found in the Study 
Investigational Product (IP) Manual. 
 
7.2.1. 
FibroGen Investigational Product (Roxadustat) 
Roxadustat is supplied by FibroGen as red-coated, oval tablets for oral administration, in 
strengths of 20 mg, 50 mg, 100 mg, and 150 mg. The excipients include lactose monohydrate, 
microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, and colorant 
Red Opadry II. All ingredients used for manufacture of roxadustat comply with US and 
European Union compendia or regulatory standards. Strengths are different in size and 
debossing reflects the strength (i.e., 20, 50, 100 and 150 mg). 


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7.2.2. 
Study Drug Packaging and Labeling 
Labels will be prepared and will comply with Good Manufacturing Practice and local regulatory 
guidelines. 
 
7.2.3. 
Study Drug Storage 
Roxadustat tablets should be stored at room temperature between 15°C and 30°C (59ºF to 86ºF). 
Roxadustat should be stored in a securely locked area to which access is limited to appropriately 
authorized study personnel. 
 
7.2.4. 
Study Drug Administration 
All patients will take doses TIW for the entire duration of the study unless frequency adjustment 
is needed for concomitant Paclitaxel use. Roxadustat will be dispensed to patients with 
instructions for self-administration of the tablets orally on each dosing day, according to the 
dosing schedule. The tablets are to be swallowed whole.  Tablets should not be cut. 
First dose of roxadustat should be administered on Day 1 after completion of all procedures 
including laboratory draws. Study drug doses should be administered at least 2 days apart, and 
no more than 4 days apart.  Dosing should occur at approximately the same time of day. 
Roxadustat can be taken with water and with or without food. 
 
7.2.5. 
Overdose, Emergency Procedures, and Management of Overdose 
The maximum tolerated dose of roxadustat has not been established in humans. For the purpose 
of this study, the maximum allowed roxadustat dose is set at 400 mg or 3.5 mg/kg/dose, 
whichever is lower. Any dosing of study medication in this study exceeding the maximum 
allowed roxadustat dose should be reported within 24 hours. The Medical Monitor should be 
contacted as soon as possible. Symptoms associated with overdosing, if any, will be reported as 
adverse events. 
In the event of suspected roxadustat overdose, the patient should receive supportive care and 
monitoring. The Sponsor’s Medical Monitor should be contacted as applicable. 
 
7.2.6. 
Study Drug Handling and Disposal 
All study drug provided by the Sponsor should be retained at the site until otherwise instructed in 
writing by the Sponsor (or designee). The Sponsor (or designee) will perform drug 
accountability and reconciliation for all study drug received at the site prior to approving study 
drug return/destruction. Upon completion of accountability/reconciliation or upon completion of 
the study or termination of the investigational site, all used, unused, partially used study drug, 
and all study drug that was not dispensed will be shipped to a destruction site designated by the 
Sponsor (or designee) for destruction. Study drug may be destroyed on site according to 
local/institutional policies by the pharmacy/authorized staff with approval from Sponsor (or 
designee). Please refer to the IP Manual for additional information on study drug accountability. 


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8. 
ASSESSMENTS OF EFFICACY 
8.1. 
Study Assessments 
A signed and dated IRB/IEC-approved informed consent must be obtained before any study- 
specific assessments are performed. Assessments that are part of routine care are not considered 
study-specific and may be used at screening to determine eligibility. All patients will be screened 
for eligibility before enrollment. Only eligible patients will enrolled into the study. 
 
8.1.1. 
Screening Period 
All screening procedures must be performed within 28 days of Day 1. Study procedures to be 
performed during the screening period can be found in the Schedule of Assessments 
(Appendix 1). Central laboratory results will be used to determine eligibility. No IWRS system 
will be utilized for this study. All enrolled patients will be entered in the clinical database 
(EDC). 
Current disease burden measurement at baseline is required to be done within 3 months of 
enrollment (Day 1), documented in CRF, and the scans or other reports (used for disease burden 
documentation), as applicable, be available for comparison if needed: 
1. For tumor lesion(s) which are measurable by RECIST criteria, relevant imaging stud(ies) 
of choice to be determined by PI, i.e. CT, MRI, ultrasound, etc, is/are required. 
2. For bone lesion (not measurable by RECIST), a bone scan is required. 
 
8.1.2. 
16-Week Treatment Period 
All enrolled patients will have clinic visits at a scheduled frequency of every 2 weeks throughout 
the 16-week period. Assessments will be done as outlined in the Schedule of Assessments in 
Appendix 1. 
 
8.1.3. 
Follow-up Period 
All patients enrolled will have a safety follow-up visit approximately 28 days after the last dose 
of study treatment. After the protocol-required reporting period (28 days after the last dose), the 
investigator does not need to actively monitor patients for serious adverse events (SAEs). 
However, if the investigator becomes aware of a SAE that may be possibly related to study 
treatment after the protocol-required reporting period, the investigator may report the event to 
FibroGen as outlined in Section 9.0. SAEs reported outside of the protocol-required reporting 
period will be captured within the safety database only as clinical trial cases for the purposes of 
expedited reporting. 
 
8.1.4. 
Missed Visits 
Study treatment may be withheld/interrupted due to safety reasons, resulting in a “missed” visit. 
These visits may be rescheduled to accommodate interruptions within a total window of + 4 
weeks over the course of the study. Adjustments to the dosing schedule for roxadustat should be 
discussed with the study Medical Monitor. If a visit is missed and not rescheduled, it will be 
captured accordingly in the clinical database. 


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8.1.5. 
Unscheduled Visits 
Unscheduled visits/assessments may be required at the discretion of the Investigator. 
Unscheduled visit data will be captured accordingly in the clinical database. 
 
8.1.6. 
Early Withdrawal from Treatment 
Patients who prematurely discontinue the study should be strongly encouraged to complete the 
final evaluations scheduled for the EOT visit as specific in the SOA (Appendix 1). These 
patients must be followed for safety for 28 days following their last dose of study drug. 
Discontinued patients will continue in the Follow-up period and be followed for progression, 
survival and additional anti-cancer therapies. 
 
8.2. 
Assessments 
Refer to the Schedule of Assessments (Appendix 1) for details regarding the timing and 
frequency of study assessments. 
 
8.2.1. 
Vital Signs (Including Weight and Height) 
Vital signs to be collected include; heart rate, blood pressure, respirations and temperature: 
• Heart rate should be collected as beats/min 
• Systolic and diastolic blood pressure should be collected from patients in seated 
position 
• Respirations should be collected as breaths/min 
• Temperature should be taken as oral or tympanic and captured as °F or °C 
Weight is collected during screening and Day 1. Dosing is based at patient’s weight at Day 1 of 
treatment. Height is collected during screening only. 
 
8.2.2. 
Physical Exam 
A full physical exam is required during screening, EOT and at the Follow-Up visit. A full 
physical exam may include, but is not limited to, review of the following systems: 
• General Appearance, HEENT, Lungs, Heart, Chest & Back, Abdomen, Extremities, 
Neurologic, Skin 
 
8.2.3. 
Electrocardiogram (ECG or EKG) 
EKGs will be performed in accordance with institutional standards at Week 1/Day 1 prior to 
randomization, EOT and 4-week Follow-up. 
 
8.2.4. 
Laboratory Evaluations 
Details regarding sample collection, preparation and transport can be found in the central lab 
manual. Importantly, dose adjustments/escalations will be made based on results from LOCAL 
Hb testing. This can either be hemocue (supplied by FibroGen) or via local lab as long as there 
is real time turnaround of results to prevent patient inconvenience. However, if in PI’s opinion, 
the local lab value does not accurately reflect patient’s current condition, PI may delay 
adjustment until central lab result is available. 


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A set of serum and plasma samples may be drawn and stored for future analysis of relevant 
select biomarkers. Donation of these samples is optional and will be sought through a separate 
informed consent form. No genetic testing will be performed for the diagnosis of genetic 
disorders on these samples. 
 
8.2.4.1. 
Central Laboratory Evaluations 
The following labs will be evaluated by a central laboratory in accordance with the SOA 
(Appendix 1): 
Table 4. 
Laboratory Tests 
 
CBC: 
Chemistry Panel: 
Absolute neutrophil count (ANC) 
Bicarbonate 
Eosinophils 
BUN 
Erythrocyte count (RBC) 
Calcium 
Hematocrit 
Creatinine 
INR 
Chloride 
PTT/PT 
Magnesium 
Hemoglobin 
Glucose 
Leukocyte count (WBC) 
ALP 
Lymphocytes 
ALT 
Mean corpuscular volume 
AST 
Monocytes 
Bilirubin, total 
Neutrophils 
Albumin 
Platelets 
Phosphorous 
CRP 
Potassium 
Other: 
Sodium 
Hepcidin 
Abbreviations: 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CBC = complete blood count; CRP = C-reactive protein; INR = international 
normalized ratio, PT/PTT = prothrombin time/partial thromboplastin time; RBC = red blood cell; 
WBC = white blood cell. 
Central lab results obtained during the screening period will be used to determine patient 
eligibility for participation in the trial. Central lab results will be reviewed by the investigator 
for clinical significance and to determine appropriate reporting of adverse events 
(see Section 9.3.7). 
Local labs results may be used to evaluate patient condition prior to dosing. Local lab results 
will not be captured in the clinical database except for local Hb testing. These local Hb values 
will be recorded in the CRF and used for dose adjustment assessments only. Clinically 
significant local lab findings during the study, if any, should be confirmed via central lab. If 
situation permits, a sample should be sent to the central lab at the same time for study record. 
 
8.2.4.2. 
Pharmacokinetics and Pharmacodynamics 
Roxadustat Population PK sub-study: 


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There will be a population PK sub-study for roxadustat in this protocol. Sites will not be 
required to participate in the pharmacokinetic/pharmacodynamics (PK/PD) portion of the study. 
Patients at sites that have been qualified to participate in the PK/PD portion of the study will sign 
an additional informed consent form if they wish to participate in the PK/PD sub-study. Patients 
are NOT required to participate in the sub-study, and this decision will NOT make them 
ineligible for the overall study protocol.   Samples will be taken after 4 weeks of treatment at 
each dose level at 1 or 2 pre-dose sample times and at 1-4 hours post-dose (ideally on the same 
day as the pre-dose sample but not required). In addition, two samples should be taken at > 5 
hours after dosing (may be at different clinic visits consequent with other assessments). 
Accuracy of time of most recent dosing and sampling is important to capture. 
Paclitaxel PK sub-study: 
There will be a PK sub-study to evaluate the effect of roxadustat timing of administration on the 
pharmacokinetics of paclitaxel in this protocol. Patients are NOT required to participate in the 
sub-study, and this decision will NOT make them ineligible for the overall study protocol. Sites 
will not be required to participate in the pharmacokinetic sub-study. Patients at sites that have 
been qualified to participate in the PK portion of the study will sign an informed consent if they 
wish to participate in the sub-study. 
Additional details are provided in Appendix 6 for PK sub-study to investigate the potential effect 
of Roxadustat on the pharmacokinetics of paclitaxel. 
 
8.2.4.3. 
Eastern Cooperative Oncology Group (ECOG) 
These scales and criteria are used by doctors and researchers to assess how a patient's disease is 
progressing, to assess how the disease affects the daily living abilities of the patient, and to 
determine appropriate treatment and prognosis (Oken, 1982). The ECOG performance scale will 
be used to evaluate patient’s performance status during screening and throughout the trial. 
See Appendix 3. 
 
8.2.5. 
Patient Reported Outcomes (PROs) 
Patient reported outcome (PRO) data will be collected in all patients to evaluate the most 
important patient reported symptoms, treatment related symptoms and functional impacts that 
may be responsive to treatment. FACIT-F (fatigue) and FACT-An (anemia) questionnaires will 
be administered as specified in the SOA (see Appendix 1). All questionnaires should be 
completed by patients PRIOR to any procedures/treatments performed on that study day. 
8.2.5.1. 
FACIT-F 
FACIT-F, a subset of FACT-An, is a health related quality of life questionnaire (HRQOL) 
assessing fatigue and anemia-related concerns in people with chronic illness including cancer. 
The most current validated version of this questionnaire will be used for this study. This 
questionnaire will be collected at baseline (Day 1), and at various times as described in the SOA. 
 
8.2.5.2. 
FACT-An 
FACT-An is a HRQOL instrument that specifically addresses symptoms of anemia related to 
cancer- therapy and has been validated in diverse cancer populations. This questionnaire will be 
collected at baseline (Day 1), and at various times as described in the SOA. 


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9. 
ASSESSMENTS OF SAFETY 
9.1. 
Background 
Adverse event reports from investigators are the critical building blocks to the development of 
the safety profile of the Study Drug. Patients will be asked non-leading questions in general 
terms to determine the occurrence of AEs, according to the schedule outlined in Appendix 1. In 
addition, all AEs reported spontaneously during the course of the study will be recorded. The 
investigator must immediately (within 24 hours of awareness) report to the sponsor or designated 
safety management vendor all SAEs, regardless of whether the investigator believes they are 
related to the study drug. 
 
9.2. 
Definitions 
9.2.1. 
Definition of an Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence in a clinical trial patient. The 
event does not necessarily have a causal relationship with study treatment. The investigator is 
responsible for ensuring that any adverse events observed by the investigator or reported by the 
patient as defined in the study protocol are recorded in the patient’s medical record. The 
definition of adverse events includes worsening of a pre-existing medical condition. Worsening 
indicates that the pre-existing medical condition (e.g., diabetes, migraine headaches and gout) 
has increased in severity, frequency, and/or duration, and/or has an association with a 
significantly worse outcome. A pre-existing condition that has not worsened during the study or 
involves an intervention such as elective cosmetic surgery or a medical procedure while on 
study, is not considered an adverse event. (Section 9.3.1). 
 
9.2.2. 
Definition of a Serious Adverse Event (SAE) 
A serious adverse event is any adverse event or suspected adverse reaction that results in any of 
the following outcomes: 
• Death, 
• A life-threatening AE (i.e., if in the view of the investigator or sponsor, the patient 
was at immediate risk of death at the time of the event). Life-threatening does not 
refer to an event which hypothetically might have caused death if it were more 
severe, 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
• A congenital anomaly or birth defect, or 
• Is considered a medically important event not meeting the above criteria, but which 
may jeopardize a patient or may require medical or surgical intervention to prevent 
one of the other criteria listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, and blood dyscrasias or convulsions that do not result in inpatient 
hospitalization. 


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Please note that death is an outcome, not an event; the primary cause of death would be the 
adverse event. 
Surgical procedures, per se, are not SAEs. The condition requiring the surgical procedure, 
however, may be an SAE. 
Scheduled or pre-planned hospitalization or prolongation of a hospitalization due to standard of 
care assessments and procedures (including elective procedures) do not warrant reporting as 
adverse events unless resulting observations are deemed by the Investigator to meet the 
definition of an adverse event. 
 
9.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
9.3.1. 
Adverse Event Reporting Period 
The safety reporting period begins after the patient has signed the informed consent and ends 28 
days after the last dose of study drug. It is only required that SAEs be reported prior to first 
dose, while all AEs (serious and non-serious) be reported thereafter. The investigator should 
notify FibroGen of any death or other SAEs occurring after a patient has discontinued or 
terminated study participation that may reasonably be related to this study (Section 9.3.5). 
Pregnancy reporting requirements are outlined in Section 9.3.6. 
Adverse events will be followed until resolved, stable, or until the patient’s last study visit or 
patient is lost to follow-up. 
 
9.3.2. 
Adverse Event Eliciting/Reporting 
During the AE reporting period, study site personnel will query each patient at each visit to 
actively solicit any AE occurring since the previous visit. All AEs will be collected in response 
to a general question about the patient’s well-being and any possible changes from the BL or 
previous visit, but shall not be specifically solicited. There will be no directed questioning for 
any specific AE. This does not preclude the site from collecting and recording any AEs reported 
by the patient to site personnel at any other time. 
Whenever possible, diagnoses should be recorded when signs and symptoms are due to a 
common etiology, as determined by qualified medical study staff. The investigator is responsible 
for reviewing laboratory test results and determining whether an abnormal value in an individual 
study patient represents a clinically significant change from the patient’s baseline values. In 
general, abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events. However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events. Where 
applicable, clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. The investigator is expected to follow reported adverse events until stabilization or 
reversibility. 


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The following attributes must be assigned to each AE: 
• Description (Investigator’s verbatim term describing the event) 
• Dates of onset and resolution 
• Severity 
• Relationship to study drug 
• Outcome 
• Action taken regarding study drug 
• Other treatment required 
• Determination of “seriousness” 
9.3.3. 
Assessing Adverse Event Severity 
AEs, including abnormal clinical laboratory values, should be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for AE (CTCAE) v 4.0 guidelines. For terms not 
specified as part of NCI CTCAE, the following guidelines should be used to determine grade: 
All AEs will be assessed for severity using the following criteria: 
• Grade 1, Mild: Asymptomatic or mild symptoms which the patient finds easily 
tolerated. The event is of little concern to the patient and/or of little-or-no clinical 
significance; intervention not indicated. 
• Grade 2, Moderate: The patient has enough discomfort to cause interference with or 
change in some of their age-appropriate instrumental activities of daily living 
(e.g., preparing meals, shopping for groceries or clothes, using the telephone, 
managing money); local or noninvasive intervention indicated. 
• Grade 3, Severe: The patient is incapacitated and unable to work or participate in 
many or all usual activities. The event is of definite concern to the patient and/or 
poses substantial risk to the patient’s health or well-being; likely to require medical 
intervention and/or close follow-up, including but not limited to hospitalization or 
prolongation of hospitalization. 
• Grade 4, Life-threatening: The patient was at immediate risk of death from the 
event as it occurred. 
• Grade 5, Death: Fatal AE. 
9.3.4. 
Assessing the Adverse Event’s Relationship to Study Drug 
Most of the information about the safety of a drug prior to marketing comes from clinical trials; 
therefore, AE reports from investigators are critically important. The assessment of whether an 
AE is causally related to the study drug(s) using an evidence-based approach is critical in order 
to appropriately describe the safety profile study drug(s). Default reporting of individual events 
as possibly related is uninformative and does not meaningfully contribute to the development of 
the study drug’s safety profile. 


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The investigator must provide an evidence-based assessment of the relationship of the AE to 
study drug in accordance with the guidance below. Absence of an alternative cause would not 
normally be considered sufficient evidence to assess an event as related to study drug. 
• Related: 
− Any event for which there is sufficient evidence to suggest that the study drug 
may have caused the event. For example, an unanticipated medical condition 
occurs which resolves with study drug interruption and re- occurs with re- 
administration of study drug; another example is a typical drug-related medical 
condition such as a rash that occurred shortly after first dose of study drug. 
• Not Related: 
− The event represents a pre-existing underlying disease that has not worsened on 
study 
− The event has the same characteristics of a known side-effect associated with a 
co-medication 
− The event is an anticipated medical condition of anticipated severity for the study 
population 
− The most plausible explanation for the event is a factor that is independent of 
exposure to study drug 
 
9.3.5. 
Reporting Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by the 
investigator or reported by the patient that occur after signing of the informed consent/assent 
through 28 days after the last dose of roxadustat are recorded in the patient’s medical record and 
are submitted to FibroGen. All SAEs must be submitted to FibroGen within 24 hours following 
the investigator’s knowledge of the event via the SAE report form. 
If a patient is permanently withdrawn from protocol required therapies because of a serious 
adverse event, this information must be submitted to FibroGen. FibroGen will report serious 
adverse events and/or suspected unexpected serious adverse reactions as required to regulatory 
authorities, investigators/institutions, and central IRBs/IECs in compliance with all reporting 
requirements according to local regulations and Good Clinical Practice (GCP). 
There is no requirement to monitor study patients for serious adverse events following the 
protocol-required reporting period or after end of study. However, these serious adverse events 
can be reported to FibroGen. In some countries (e.g. European Union [EU] member states), 
investigators are required to report serious adverse events that they become aware of after end of 
study. If serious adverse events are reported, the investigator is to report them to FibroGen 
within 24 hours following the investigator’s knowledge of the event. Serious adverse events 
reported outside of the protocol-required reporting period will be captured within the safety 
database as clinical trial cases for the purposes of expedited reporting; these cases will not be 
included in the clinical study report. 
To report an SAE, the investigator must complete an SAE Report Form and fax or email the 
completed form to the Sponsor or its designated safety management vendor. 


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Full details of the SAE should also be recorded on the medical records and in the CRF. The 
following minimum information is required: 
• Patient number, sex and age 
• The date of report 
• A description of the SAE (event, seriousness of the event) 
• Causal relationship to the study drug 
• Follow-up information for the event should be sent promptly. 
For each SAE observed, the investigator should obtain all of the information available about the 
event, including (but not limited to): hospital discharge diagnoses, hospital discharge note, death 
certificate, appropriate laboratory findings (including autopsies and biopsy results), and clinical 
examinations (including radiological examinations and clinical consultations). 
 
9.3.5.1. 
Reporting Serious Adverse Events to the Institutional Review 
Board / Independent Ethics Committee 
The investigator is responsible for notifying his/her Institutional Review Board (IRB) or Ethics 
Committee (EC) of SAEs in accordance with local regulations. The Sponsor, or its designated 
safety vendor, will provide a copy of expedited safety reports to the investigator that it intends to 
submit to global regulatory authorities. 
 
9.3.5.2. 
Deaths 
The investigator will report the fatal event to the Sponsor’s medical monitor. The investigator 
must provide a causal assessment of the relationship of the event to the study drug according to 
the guidance in Section 9.3.5. 
If the death occurred within the AE collection and reporting period (signed ICF to 4 weeks after 
last dose) and meets the reporting criteria, the investigator must submit the SAE Report Form in 
the same manner as described above in Section 9.3.5. If the investigator becomes aware of a 
death occurring after the AE reporting period and considers it related to roxadustat, it will be 
reported as an SAE. 
 
9.3.6. 
Pregnancies: Reporting and Follow-up of Patients 
The outcome of all pregnancies for female patients should be followed up and documented as 
described. A Pregnancy Report Form must be completed and submitted to Sponsor or designated 
safety management vendor within 24 hours of the investigator becoming aware of the pregnancy. 
The investigator must follow-up to completion of the pregnancy to ascertain its outcome 
(e.g. spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) and whether any AEs occur during the pregnancy or birth. The outcome 
of the pregnancy must be reported by the investigator on a Pregnancy Outcome Report Form, 
which should be sent to the Sponsor and/or its designated safety vendor within 24 hours of the 
investigator becoming aware of the outcome. 
Pregnancy itself is not an AE unless there is a suspicion that the investigational product under 
study may have interfered with the effectiveness of a contraceptive medication. Pregnancies are 
followed up to outcome even if the patient was discontinued from the study. Congenital 


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abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. 
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should if possible be followed up and documented as described. To 
capture information about a pregnancy from the partner of a male patient, the male patient’s 
partner consent must be obtained to collect information related to the pregnancy and outcome 
(should be handled on a case by case basis with IRB/IEC approval); the male patient should not 
be asked to provide this information. 
If a lactation case occurs while the female patient is taking protocol-required therapies, report the 
lactation case to FibroGen. In addition to reporting a lactation case during the study, 
investigators should monitor for lactation cases that occur after the last dose of protocol-required 
therapies through 3 months after the last dose of roxadustat. Any lactation case should be 
reported to FibroGen’s Safety within 24 hours of the investigator’s knowledge of event. 
9.3.7. 
Abnormal Laboratory Findings 
An abnormal laboratory finding in absence of any other signs or symptoms is not necessarily an 
AE. The investigator must review and assess all results provided by the central laboratory 
throughout the study in a timely manner, and determine whether any abnormal laboratory values 
are clinically significant (CS) or not clinically significant (NCS), and whether there are 
associated signs and symptoms. Laboratory abnormalities should be considered clinically 
significant when they occur after taking study medication, reflect a meaningful change from the 
screening value(s), and require active management (e.g., abnormalities that require study 
treatment dose modification, discontinuation, more frequent follow-up assessments, etc.). 
Clinically significant laboratory abnormalities will be reported as AEs. If the abnormal 
laboratory finding is accompanied by signs or symptoms, report the signs and symptoms as the 
AE in lieu of the abnormal laboratory value. If a diagnosis is available, report the diagnosis. 
 
9.3.8. 
Safety Monitoring 
 
9.3.8.1. 
Data Monitoring Committee (DMC) 
No data monitoring committee will be established for this open label Phase 2 study. 


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10. 
STATISTICS 
10.1. 
Sample Size Determination 
Up to approximately 100 patients will be enrolled into this study. The sample size is determined 
by clinical judgment, not by statistical power analysis. 
 
10.2. 
Analysis Populations 
10.2.1. 
All Enrolled or Intent-to-Treat (ITT) Population 
Defined as all patients enrolled in the roxadustat treatment period, regardless of whether patients 
received any study drug. 
 
10.2.2. 
Full Analysis Set (FAS) Population 
Defined as all enrolled patients who receive at least one dose of roxadustat, have a baseline Hb 
and at least one corresponding on-treatment Hb assessment. The FAS population will be used for 
efficacy analyses. 
 
10.2.3. 
Efficacy Evaluable (EE) Population 
Defined as all enrolled patients who receive roxadustat for at least 4 weeks, and have at least one 
Hb value after 4 weeks or longer, obtained within 2 weeks of last dose. 
The EE population will be primarily used for efficacy analyses. 
 
10.2.4. 
Safety (SAF) Population 
Defined as all patients who took at least one dose of study medication. The primary analysis of 
safety will be based on the Safety population. 
 
10.3. 
Statistical Analysis 
10.3.1. 
General Considerations 
Summary statistics will consist of number of patients (N), means, standard deviations, medians, 
and minimum and maximum values for continuous variables, and counts and percentages for 
categorical variables. For efficacy endpoints, the standard error and 95% confidence intervals 
will be added as part of the descriptive summaries. Tables will summarize all efficacy and safety 
measures by time point, if appropriate. All analyses will be based on available data unless 
otherwise specified. 
 
10.3.2. 
Patient Enrollment and Disposition 
Patient enrollment and disposition will be presented for all enrolled patients. The total number 
and percent of patients who completed or discontinued, and reasons for early discontinuation, 
will be summarized. 
 
10.3.3. 
Demographics and Baseline Characteristics 
Demographics (age, race, sex), baseline characteristics (e.g., height, weight), and patient disease 
characteristics will be summarized for the ITT population and safety population. 


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Descriptive statistics will be calculated for continuous variables (age and weight) and frequency 
counts and percentages will be tabulated for categorical variables (e.g., sex, race, and body mass 
index). 
 
10.3.4. 
Efficacy Analyses 
 
10.3.4.1. Analysis of the Primary Endpoint 
Hemoglobin results obtained from the central laboratory will be used for all efficacy analyses. 
Baseline Hb is defined as the mean of the central laboratory Hb values prior to the first dose of 
study drug. 
The primary efficacy analysis will be based on the EE and FAS population using an observed 
case dataset. The primary efficacy parameter, defined as maximum change in hemoglobin from 
baseline in 16 weeks without RBC transfusion, will be summarized by using descriptive 
statistics. Hb values within 4 weeks after a RBC transfusion will be censored. 
The mean change from baseline hemoglobin (without a RBC transfusion) will be summarized 
using descriptive statistics by visit. Maximum change from baseline will also be analyzed using 
Analysis of covariance using Cancer types as a class variable and the baseline Hb as a covariate. 
Least Square Means will be calculated from the model and tested against 0 for each cancer type 
and overall. 
In addition, missing hemoglobin data, either because of a missed visit or collected within 4 
weeks after a RBC transfusion will be imputed in the last-observation-carried-forward (LOCF) 
approach. 
Number (%) of patients meeting specific criteria specified in the protocol as secondary efficacy 
endpoints will also be summarized descriptively and the Clopper – Pearson confidence limits 
approach will be used. 
The percentages of patients who have a hematopoietic response, who receive at least one RBC 
transfusion will also be summarized descriptively and estimated using the Kaplan–Meier (KM) 
method. 
 
10.3.4.2. Analysis of the Secondary and Additional Endpoints 
The mean change from baseline hemoglobin (without a RBC transfusion) will be summarized 
using descriptive statistics by visit. This will also be analyzed similar to the model used for the 
primary endpoint. 
Additional efficacy analyses will use the EE and FAS populations. Number (%) of patients 
require transfusion/ESA will be summarized descriptively. Change from baseline in quality of 
life composite scores (as well as selected subscale scores, if applicable) will be summarized 
descriptively. 
 
10.3.5. 
Exploratory Analyses 
Changes from baseline in iron parameters, lipid parameters, hepcidin levels, cholesterol 
parameters and biomarkers will be summarized descriptively. 
Subgroup analyses of primary and secondary endpoints will be performed. 


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10.3.6. 
Safety Analyses 
All patients who received any dose of study drug will be included in the safety analyses. 
All safety assessment data, including laboratory assessments (with special emphasis on Hb 
response and LFTs), vital signs, ECGs, AEs, concomitant medications and therapies will be 
summarized by time point of collection as appropriate. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
A treatment emergent adverse event (TEAE) is defined as any new or worsening of an existing 
condition occurred after the first dose of the study medication and within 28 days after the last 
dose of study medication. TEAEs will be tabulated to examine their frequency, severity, organ 
systems affected and relationship to study treatment. Deaths, SAEs, AEs leading to study or 
treatment discontinuation will be listed or tabulated separately. 
Laboratory tests, vital sign measurements, ECG parameters, as well as the changes from baseline 
will be summarized descriptively by assessment time point. Clinically significant changes from 
baseline in these safety parameters will be identified. Shift tables will summarize changes for 
selected laboratory measures. 
Medications used prior to and during the study will be coded using The World Health 
Organization Drug Dictionary (WHODrug). Prior and concomitant medications will be tabulated 
by therapeutic class and generic name. 
 
10.4. 
Interim Analysis 
The study will have no formal interim analysis with statistical inference. Safety and efficacy will 
be monitored on an ongoing basis. 
 
10.5. 
Statistical Analysis Plan 
A detailed Statistical Analysis Plan (SAP) will be finalized prior to data analysis. The Statistical 
Analysis Plan (SAP) will include detailed analysis methods, statistical models, definitions, as 
well as data handling rules. The SAP will document additional exploratory endpoints that are not 
specified in the protocol. Any significant changes to the analyses described in this protocol will 
be highlighted in the SAP. Deviations in analyses from the SAP will be detailed in the Clinical 
Study Report. 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
Data Quality Assurance 
Quality assurance and quality control systems will be implemented and maintained with 
Standard Operating Procedures by FibroGen and its designee(s), as appropriate, to ensure that 
this clinical study is conducted and data are generated, documented (recorded) and reported in 
compliance with the protocol, ICH E6 (GCP), and other applicable regulations. 
This study will be monitored by FibroGen or designee in accordance with GCP, and may be 
audited or reviewed by an independent Quality Assurance department, IRB/IEC, and/or 
regulatory authorities. This implies that monitors and auditors/inspectors will have the right to 
inspect the study sites at any time during and/or after completion of the study and will have 
direct access to data/source documents, including the patient's file. By participating in this study, 
Investigators agree to this requirement. 
The purpose of trial monitoring is to verify the following: 
• The rights and well-being of human patients are protected. 
• The reported data are accurate, complete, and verifiable from source documents. 
• All data are collected, tracked, and submitted by the site to FibroGen or designee, 
including unscheduled and missed assessments 
• The reported data are reconciled across all data sources (e.g., laboratory, safety, IRT, 
clinical databases). 
• The conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s). 
Measures will be undertaken to protect the confidentiality of records that could identify patients, 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements. 
 
11.2. 
Audit and Inspection 
Authorized representatives of the sponsor, a regulatory authority, and/or an IRB/IEC may visit 
the investigator site to perform audits or inspections, including source data verification and 
source documentation review. The Investigator will allow the sponsor auditor (or designee), 
regulatory authority or ethics committee representative to inspect the drug storage area, study 
drug stocks, drug accountability records, patient charts (e.g. medical records) and study source 
documents, and other records relative to study conduct. 
The purpose of an audit or inspection is to systematically and independently examine all study- 
related activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, ICH GCP guidelines, 
and any applicable regulatory requirements. 
The investigator must contact the sponsor, or its third party representative (CRO), immediately if 
notified by a regulatory authority of an inspection pertaining to this study. 


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12. 
ETHICS 
12.1. 
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirements, the 
International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice 
(GCP), the Declaration of Helsinki, any other applicable regulatory requirements, and 
Institutional Review Board (IRB) or independent ethics committee (IEC) requirements. 
 
12.2. 
Communication with the Institutional Review Board or Independent 
Ethics Committee 
This protocol, the Informed Consent Form, the Investigator’s Brochure, and any information to 
be given to the patient must be submitted to a properly constituted IRB/IEC by the investigator 
for review and approved by the IRB/IEC before the study is initiated and before any 
investigational product is shipped to the investigator. In addition, any patient recruitment 
materials must be approved by the IRB/IEC before the material is used for patient recruitment. 
The investigator is responsible for obtaining re-approval by the IRB/IEC annually or as required 
by the policies and procedures established by the IRB/IEC. Copies of the investigator’s annual 
report and other required reports submitted to the IRB/IEC and copies of the IRB/IEC 
continuance of approval must be furnished to FibroGen or designee. A copy of the signed FDA 
Form 1572 or other qualified investigator statement (as required) must also accompany the above 
approval letter provided to FibroGen. 
Investigators are also responsible for promptly informing the IRB/IEC of any protocol changes 
or amendments, changes to the Investigator’s Brochure, and other safety-related communications 
from FibroGen or its designee. Written documentation of IRB/IEC approval must be received 
before the amendment is implemented. 
Investigators must maintain a list of appropriate qualified persons to whom the investigator has 
delegated significant trial-related duties and update the list as staff and their delegated 
responsibilities change. 
 
12.3. 
Patient Information and Consent 
Prior to participation in any study-specific procedures, the patient must sign (note: all references 
to “patient” in this section refers to the study patient or his/her legally acceptable representative) 
an IRB/IEC-approved written Informed Consent Form in his/her native language. The approved 
written informed consent must adhere to all applicable laws in regards to the safety and 
confidentiality of the patients. To obtain and document informed consent, the Investigator 
should comply with applicable regulations, and adhere to ICH GCP standards and the ethical 
principles in the Declaration of Helsinki (October 2008). 
The language in the written information about the study should be as non-technical as practical 
and should be understandable to the patient. Before informed consent is obtained, the 
Investigator should provide the patient ample time and opportunity to inquire about the study and 
to decide whether or not to participate. 
All questions about the study should be answered to the satisfaction of the patient. The written 
Informed Consent Form should be signed and personally dated by the patient and the person who 


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conducted the informed consent discussion, with any additional signatures obtained as required 
by applicable local regulations and IRB/IEC requirements. Each patient will be informed that 
participation is voluntary and that he/she can withdraw from the study at any time. All patients 
will receive a copy of the signed and dated Informed Consent Form. 
If there are any changes to the IRB/IEC approved ICF during the patients’ participation in the 
study, the revised ICF must receive the IRB/IEC’s written approval before use and patients must 
be re-consented to the revised version of the ICF. 
Guidance for Clinical Teams: For studies conducted in the United States, each patient must 
provide his or her consent for the use and disclosure of personal health information under the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) regulations by signing a 
HIPAA Authorization Form. The HIPAA Authorization Form may be part of the ICF or may be 
a separate document. IRB review may or may not be required for the HIPAA Authorization 
Form according to study site policies. 
 
12.4. 
Patient Confidentiality 
The confidentiality of records that could identify patients should be protected, respecting the 
privacy and confidentiality rules in accordance with applicable regulatory requirements. 
Patient medical information obtained as part of this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent and HIPAA Authorization Form 
or separate authorization to use and disclose personal health information signed by the patient, or 
unless permitted or required by law. The patient may request in writing that medical information 
be given to his/her personal physician. 
The processing of personal data in pursuit of this study will be limited to those data that are 
reasonably necessary to investigate the utility of the study medications used in this study. These 
data will be processed with adequate precautions to ensure confidentiality according to local 
laws. 
FibroGen ensures that the personal data are: 
• collected for a specified and legitimate purpose 
• processed fairly and lawfully 
• accurate and up to date 
Explicit consent for the processing of personal data will be obtained prospectively from the 
participating patient. FibroGen and/or designees whose responsibilities require access to 
personal data agree to keep the identity of study patients confidential. This confidentiality will 
be maintained throughout the complete data processing. 
Study patients will be entitled to request confirmation of the existence of personal data held by 
FibroGen and will have the right to rectify erroneous or inaccurate data prior to database lock. 


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13. 
DATA HANDLING AND RECORD KEEPING 
13.1. 
Source Documents 
Source documents are original documents, data, and records necessary for the reconstruction and 
evaluation of the clinical study. The investigator or designee will prepare and maintain adequate 
and accurate source documents. These documents are designed to record all observations and 
other pertinent data for each patient enrolled in this clinical study. Source documents must be 
adequate to reconstruct all data transcribed onto the CRFs and resolved queries. 
13.2. 
Direct Access to Source Documents 
The investigator must provide direct access to source data and source documents for trial-related 
monitoring, audits, IRB/IEC review, and regulatory authority inspection. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are important to 
the evaluation of the study. The investigator is obligated to inform and obtain the consent of the 
patient to permit such individuals to have access to his/her study-related records, including 
personal information and medical records. 
13.3. 
Data Collection, Handling, and Verification 
All required data will either be entered onto CRFs by authorized site personnel or will be 
provided as a data transfer from authorized service providers (such as laboratory results from a 
central laboratory). Data will be entered or uploaded into a validated, clinical database compliant 
with 21 CFR Part 11 regulations. 
All patient data will be reviewed by Sponsor and/or designee. Data that appear inconsistent, 
incomplete or inaccurate will be queried for site clarification. 
Medical history, adverse events and medications will be coded using industry standard 
dictionaries (e.g., MedDRA and World Health Organization Drug [WHODrug]) Dictionary. 
The investigator is responsible for reviewing, verifying, and approving all patient data (i.e. CRFs 
and queries) throughout the duration of the study and prior to study completion, ensuring that all 
data are verifiable with source documents. 
 
13.4. 
Protocol Deviations 
Unless there is a safety concern, there should be no deviations or violations of the study protocol. 
In the event of a safety concern, the Investigator or designee must document and explain the 
reason for any deviation from the approved protocol. The Investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
participants without prior IRB/IEC approval. Immediately after the implemented deviation or 
change, the Investigator must submit a report explaining the reasons for the protocol violation or 
deviation to the IRB/IEC, FibroGen, and to the regulatory authorities, if required. 
 
13.5. 
Retention of Data 
A FibroGen representative will inform the Investigator in writing when it is acceptable to dispose 
of any study records. To enable evaluation and/or audits from regulatory authorities or FibroGen 
or designee, the Investigator agrees to keep records, including the identity of all participating 


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patients (eg, patient identification code list and all source documents), all original signed ICFs, 
copies of all CRFs, original laboratory reports, detailed records of drug disposition and all 
essential documents for the conduct of a clinical study. To comply with international 
regulations, the records should 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 until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
However, the Investigator may need to retain these documents for a longer period if required by 
the applicable regulatory requirements or by an agreement with FibroGen. 
 
13.6. 
Financial Disclosure 
The Investigator’s disclosable financial interests must be obtained prior to initiation of the study 
site, at completion of the study at the investigational site, and 1 year following study completion. 
The Investigator should promptly update this information if any relevant changes occur during 
the above described period. 
Disclosable financial interests will be recorded on the Investigator Financial Disclosure Form. 
Any Investigator(s) added as investigational staff to the form FDA 1572 must complete the 
Investigator Financial Disclosure Form at the beginning of his/her participation in the study. The 
Investigator Financial Disclosure Form for any Investigator(s) leaving the clinical site prior to 
study completion will be obtained prior to study completion. 


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14. 
PUBLICATION POLICY 
A detailed explanation of FibroGen’s publication policy is described in the Clinical Trial 
Agreement. 


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15. 
REFERENCES 
 
Flaharty KK, Caro J, Erslev A, et al. (1990) Pharmacokinetics and erythropoietic response to 
human recombinant erythropoietin in healthy men. Clin Pharmacol Ther 47: (5):557-564 
Goldberg MA, Schneider TJ, Khan S, Petersen JR (1993) Clinical validation of an RIA for 
natural and recombinant erythropoietin in serum and plasma. Clin Biochem 26: (3):183-189 
Kato, A., Hishida A, Kumagai H, Furuya R, et al. (1994) Erythropoietin production in patients 
with chronic renal failure. Ren Fail 16: (5): 645-651 
Maeda H, Hitomi Y, Hirata R, et al. (1992) The effect of phlebotomy on serum erythropoietin 
levels in normal healthy subjects. Int J Hematol 55: (2):111-115 
Milledge JS, Cotes PM (1985) Serum erythropoietin in humans at high altitude and its relation to 
plasma renin. J Appl Physiol 59: (2):360-364 
Oken, et.al. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J 
Clin Oncol 5:649-655, 1982 
Seely, et.al. Hypoxia (2017) 5:1-9 
Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to 
hypoxia. J Appl Physiol 88: (4):1474-1480 


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APPENDICES 


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Appendix 1. Schedule of Assessments 
 
Procedures 
Screening 
Treatment Weeks 
Follow-up 
28 days 
+3 days1 
+7 days 
S1 
S2 
Week 1 Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
WK4 
EOT15 
Informed consent signature 
x 
Eligibility Review 
x 
Med History/Demographics 
x 
Physical Exam 
x 
x 
x 
Weight, height 
x 
x 
x 
HbsAg,anti-HCV AB, HIV 
x 
B12, Folate 
x 
ECG2 
x 
x 
x 
Vital signs3 
x 
x 
x 
x 
x 
x 
x 
ECOG Score4 
x 
x 
x 
x 
Serum Lipid Panel 
x 
x 
x 
x 
LFTs5 
x 
x 
x 
x 
x 
x 
x 
Serum chemistry6 
x 
x 
x 
x 
x 
x 
x 
PT, PTT, INR 
x 
x 
x 
Hepcidin 
x 
x 
x 
x 
x 
x 
Serum hCG pregnancy test7 
x 
C-reactive protein 
x 
x 
CBC8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Local Hemoglobin 
x 
x 
x 
x 
Reticulocyte count; CHr 
x 
x 
x 
x 
x 
x 
Iron Biomarkers9 
x 
x 
x 
x 
x 
Exploratory biomarkers10 
x 
x 
x 
x 
HRQoL Questionnaires11 
x 
x 
x 
x 
x 
Study drug dosing12 
x 
x x x x x x x x x 
x 
x 
x 
x 
x 
Study drug dispensation 
x 
x 
x 
x 
Dose adjustment review13 
x 
x 
x 
AEs/Con Meds/Procedures 
x 
x 
x 
x x x x x x x x x 
x 
x 
x 
x 
x 
x 
x 
PK sub-study14 
x 
x 
x 
x 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
 
 
Footnotes: 
1. Windows for procedures listed are +/- 3days unless otherwise stated. 
2. ECG: no clinically significant findings per PI review at screen period. 
3. Vital signs include BP, HR, RR, temperature. If possible, use the same device for BP measurement over the course of the study. Weight at 
registration/Day 1 will be used for determination of starting dose. 
4. ECOG score: must be 0, 1, or 2 at last screen visit. 
5. LFTs = AST, ALT, TBili, alkaline phosphatase. ALT >3 x ULN, OR AST >3 × (ULN), OR TBili > 1.5 × ULN (patients with Total Bilirubin up to 2x 
ULN may be allowed if ALT/AST are within normal limit and investigator has no safety concerns) will exclude a patient from entering the study (see 
Appendix 4 for liver monitoring information). 
6. Serum chemistry = sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, phosphorus, LDH, albumin (Central Lab). 
See Table 4 for laboratory tests. 
7. Pregnancy Test: must be negative for women of child bearing capacity at screening. 
8. CBC = Hb, HCT, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), 
RBC, WBC, platelets, differential; Regarding Central Lab Hb values: Two Hb values are obtained at Screening Visit 1 and 2, only 1 of 2 value needs to 
meet the Hb ≤ 10.0 g/dL criteria. 
9. Iron biomarkers = serum iron, ferritin, transferrin, TIBC, TSAT, and UIBC. 
10. Exploratory biomarkers (optional) – 2 x 4ml of blood will be collected pre-dose for the preparation of plasma and serum samples for future analysis 
11. HRQoL questionnaires will be FACIT-F and FACT-An. 
12. Study drug dosing: begins on the first day of dosing (Day 1/Week 1). All study procedures must be completed prior to administration of the 1st dose of 
study treatment. Dosing should occur at approximately the same time of day. Roxadustat can be taken with water with or without food. The dose of 
statins should not exceed the protocol-recommended daily dose in the protocol. 
13. Dose adjustment review will be performed every 4 weeks for potential upward dose adjustment. 
14. Samples for Pharmacokinetics will be taken at times described in the protocol text in Section 8.2.4.2.   PK samples will be collected at each dose level 
for each patient. An “X” in the above table for PK samples on weeks 9 and 13, indicates POTENTIAL days for samples, but will only actually be taken 
if there is a dose adjustment at that visit and at week 16/EOT if there is a dose adjustment between week 13 and week 16/EOT. If there is only one dose 
level for a patient during the study then PK is only collected once at week 5. 
15. EOT visit should be scheduled at the end of Week 16. Last dose of study drug must be prior to EOT assessments. 
 
 
 
 
 
Confidential 
Page 68 of 76 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 69 of 76 
 
 
Appendix 2. Roxadustat Dose Levels and Dose Adjustment Rules 
Dose adjustment will follow as described in the table below. The down titration of the dose is 
allowed at any time. The maximum dose of study medication is capped at 3.5 mg/kg per dose or 
400 mg, whichever is lower. The table below shows all possible dose levels in the study. 
 
Body 
Weight 
Dose Levels 
Approx. 
1.0 mg/kg 
Approx. 
1.5 mg/kg 
Approx. 
2.0 mg/kg 
Approx. 
2.5 mg/kg 
Approx. 
3.0 mg/kg 
Approx. 
3.5 mg/kg 
45 - <70 kg 
50 mg TIW 
70 mg TIW 
100 mg 
TIW 
150 mg 
TIW 
200 mg 
TIW* 
250 mg 
TIW* 
70-100 kg 
100 mg 
TIW 
120 mg 
TIW 
150 mg 
TIW 
200 mg 
TIW 
250 mg 
TIW 
300 mg 
TIW* 
>100 kg 
120 mg 
TIW 
150 mg 
TIW 
200 mg 
TIW 
250 mg 
TIW 
300 mg 
TIW 
350 mg 
TIW* 
* Patients body weight MAY require a lower dose than listed in the table above, due to the 
potential for the maximum dose being exceeded.  The dose given should be at one dose level 
immediately below what is in the above table. In some cases, a dose escalation will NOT be 
allowed. If a patient requires a further decrease from what is listed in the table above, the 
medical monitor should be consulted. 
If there is ANY question as to the appropriate dose to administer contact the CRA or medical 
monitor. 
Dose Adjustment 
Following commencement of study treatment, patients are evaluated for response after 4 weeks 
and the roxadustat dose will be adjusted per the table below. After each dose adjustment, the 
patient remains on the dose level for a minimum of 4 weeks before further adjustment is 
permitted. 
The following dose adjustment algorithm will apply to patients during the treatment phase of the 
study. In addition, the down titration of the dose is allowed at any time. 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 70 of 76 
 
 
At any time during the Treatment Period if Hb increases by ≥2.5 g/dL within 4 weeks, the dose 
should be reduced by one dose level. 
**Dose Adjustment for Excessive Hematopoiesis 
 
Hemoglobin (Hb) Values 
Change in Hb 
from 4 weeks 
earlier (g/dL) 
Hb <10.5 g/dL 
Hb 10.5 to 12.0 g/dL Hb >12.0 to <13.0 
g/dL 
Hb ≥13.0 g/dL 
< -1.0 * 
(or had RBC 
transfusion within 4 
weeks) 
↑ 
↑ 
No change** 
Hold, then resume dosing 
when: 
Hb <12 g/dL, at a dose that 
is reduced by one-dose level 
Patients are to return 
weekly to monitor Hb until 
dosing can be resumed 
-1.0 to 1.0 
↑ 
No change 
↓ 
> 1.0 
No change 
↓ 
↓ 
* A change in Hb from 4 weeks earlier of < -1.0 g/dL means a Hb value that is lower by more than 1.0 g/dL 
compared to 4 weeks earlier, e.g., a Hb of 9.4 g/dL compared to 10.6 g/dL 4 weeks earlier 
** 
Continue to dose-hold 
 
 
Dose Reduction 
The down titration of the study treatment is allowed at any time per investigator discretion, but a 
dose reduction must be performed if any of the following criteria are met: 
a. Hb >12 g/dL; or 
b. Rate of rise of Hb ≥2.5 g/dL over 4 weeks. 
 
Hb levels should be retested for confirmation every 2 weeks after a dose reduction 
Reduction should be to one dose level lower than the dose at which the patient is receiving. 
 
 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 71 of 76 
 
 
Appendix 3. ECOG Assessment Scale 
 
Grade ECOG 
 
0 
Fully Active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
light or sedentary nature, e.g., light house work, office work 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 72 of 76 
 
 
Appendix 4. Liver Function Monitoring 
The guidelines described in this section are intended to enable early detection and action 
following abnormal liver function test (LFT) results. Any patient enrolled in a clinical study 
with active drug therapy and reveals an increase of serum aminotransferases (AT) to > 3 × upper 
limit of normal (ULN), or bilirubin > 2 × ULN, should undergo detailed testing (including at 
least alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase 
[ALP], and total bilirubin [TBL]) for further evaluation and follow-up. Alerts will be generated 
by the central lab to inform the investigator, study monitor and study team. Testing should be 
repeated within 48-72 hours of notification. Patients should be asked if they have any symptoms 
suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities should be characterized as follows: 
 
ALT or AST 
Total Bilirubin 
Moderate 
> 3× ULN 
Or 
> 2× ULN 
Severe 
> 3× ULN 
And 
> 2× ULN 
Abbreviations: 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. 
Hy’s Law: Drug-induced jaundice caused by hepatocellular injury, without a significant obstructive component, has a 
high rate of bad outcomes, from 10% to 50% mortality (or transplant). The two “requirements” for Hy’s Law are: 
1) Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase in transaminase elevations 
higher than 3 times the upper limit of normal (“2 × ULN elevations are too common in treated and untreated Patients to 
be discriminating”). 2) Cases of increased bilirubin (at least 2 × ULN) with concurrent transaminase elevations at least 
3 × ULN and no evidence of intra- or extrahepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s 
syndrome: Temple, R (2006) Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 15: (4):241- 
243 
 
In addition, the patient should be considered to have severe hepatic abnormalities for any of the 
following: 
• ALT or AST > 8× ULN 
• ALT or AST > 5× ULN for more than 2 weeks 
• ALT or AST > 3× ULN and international normalized ratio (INR) > 1.5 (if INR testing 
is applicable/evaluated). 
• ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up. 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 73 of 76 
 
 
Follow-up Procedures 
Patients with confirmed abnormal liver function results should be closely monitored and 
followed as described below. If close monitoring for LFTs in a patient is not possible, study 
drug should be discontinued. 
Repeat LFTs 2-3 times weekly, then weekly or less until abnormalities stabilize or return to 
within normal limits. LFTs should include ALT, AST, TBL and ALP 
In addition, evaluate the patient for potential causes, which may include the following: 
• Detailed history of symptoms and prior or concurrent diseases 
• Concomitant drug use, including nonprescription medications, herbal and dietary 
supplements, alcohol or recreational drug use, or special diets 
• Exposure to environmental chemical agents 
• Rule out acute viral hepatitis Types A,B,C,D,E; autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; biliary tract disease 
• Obtain additional tests as appropriate: e.g., INR, gamma glutamyltransferase (GGT) 
or direct bilirubin; ultrasound or other imaging to assess biliary tract disease 
• Consider gastroenterology or hepatology consultations 
In general, in the absence of an explanation for increased LFTs, such as viral hepatitis, 
preexisting or acute liver disease or exposure to other agents associated with liver injury, the 
study drug should be discontinued. 
Discontinuation of treatment should be considered if: 
• ALT or AST > 8 × ULN 
• ALT or AST > 5 × ULN for more than 2 weeks 
• ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated) 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
Once LFTs return to normal, and depending on whether there is an explanation for the LFT 
elevations, study drug dosing may resume, after discussion with the Medical Monitor 
See also: FDA Guidance for Industry, titled: “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluations”, issued July 2009 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 74 of 76 
 
 
Appendix 5. Erythropoiesis-Stimulating Agents (ESAs) 
Prohibited ESAs include (but are not limited to) the following: 
• darbepoetin 
• Mircera (methoxy polyethylene glycol epoetin beta) 
• epoetin alfa 
• epoetin beta 
• epoetin delta 
• epoetin theta 
• epoetin omega 
• hematide 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 75 of 76 
 
 
Appendix 6. Roxadustat and Paclitaxel Pharmacokinetics Sub-Study 
This optional PK sub-study will investigate the potential effect of Roxadustat timing of 
administration on the pharmacokinetics of paclitaxel. 
Participation in this sub-study is voluntary. Patients are NOT required to participate, and this 
decision will NOT make them ineligible for the overall study protocol. 
Patients who agree to participate in this sub-study will have different timing of Roxadustat 
dosing in connection with administration of paclitaxel (including Abraxane®) for the duration of 
the PK sub-study.  Roxadustat dosing for these patients will be as follows: 
• Dosing of Roxadustat will be separated from paclitaxel administration by 
approximately 24 hours or 1 day for the initial paclitaxel dose. 
• Dosing of Roxadustat will be separated from paclitaxel administration by 
approximately 48 hours or 2 days for the next paclitaxel dose. 
• Dosing of Roxadustat will have no separation from paclitaxel administration 
(dosed on same day) for the next paclitaxel dose. 
 
Collection of Samples for Paclitaxel PK assessments: 
 
 
Paclitaxel 
Alone 
1-Day Interval between 
paclitaxel & roxadustat 
dosing 
2-Day Interval 
between paclitaxel & 
roxadustat dosing 
Same-Day 
paclitaxel & 
roxadustat dosing 
Roxadustat 
Administra 
tion 
Roxadustat 
given 1 
Day 
before 
Paclitaxel 
Roxadustat 
given 1 
Day after 
Paclitaxel 
Roxadust 
at given 
2-Days 
before 
Paclitaxel 
Roxadustat 
given 2- 
Days after 
Paclitaxel 
Roxadustat will be 
administered after 
collecting pre- 
transfusion sample 
PK Sample 
Collection 
Samples 
should be 
collected 
during 
screening 
(before Day 
1) 
Samples 
collected 
on the day 
of 
paclitaxel 
dosing 
Samples 
collected 
on the day 
of 
roxadustat 
dosing 
Samples 
collected 
on the day 
of 
paclitaxel 
dosing 
Samples 
collected 
on the day 
of 
roxadustat 
dosing 
Samples collected 
on the day of 
paclitaxel/roxadustat 
dosing 
Before start 
of infusion 
X 
X 
X 
X 
Within 30 
minutes 
after end of 
transfusion 
X 
X 
X 
X 


DocuSign Envelope ID: 78AB005C-E4B7-44BD-BE12-24416589097B 
DocuSign Envelope ID: F3BFD5A3-C713-484B-AB8C-0593506CF8EA 
Roxadustat 
Protocol FGCL-4592-092 
Confidential 
Page 76 of 76 
 
 
 
2 hours 
after end of 
transfusion 
X 
X 
X 
X* 
Before 
roxadustat 
dosing 
X 
X 
1-hour 
after 
roxadustat 
dosing 
X 
X 
3-hours 
after 
roxadustat 
dosing 
X 
X 
X* 
*These samples may be combined if in close proximity 
 
Upon completion of the paclitaxel PK sub study, roxadustat dosing should be held for 24 hours 
before and after treatment with paclitaxel (time 0 = start of infusion) for the remainder of the 
study. Roxadustat dosing frequency may be adjusted, as needed. 

SAP_001.pdf: 
Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
FibroGen, Inc. 
Confidential and Proprietary 
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00 
Page 1 of 58 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A Phase 2 Open Label Study Investigating the Efficacy and Safety of 
Roxadustat (FG-4592) for Treatment of Anemia in Patients Receiving 
Chemotherapy Treatment for Non-Myeloid Malignancies 
PROTOCOL NUMBER: 
FGCL-4592-092 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158 USA 
Version 
1.0 
Release Date: 
7/9/2021 Final 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and proprietary to FibroGen, Inc. No part 
of this document or any of the information contained herein may be transmitted, disclosed, shared, 
reproduced, published or utilized by any persons without prior written authorization by FibroGen, Inc. 
NCT #NCT04076943


Veeva Document Number: FG-CLPLN-0032
Version: 1.0
Status: Approved
Approved Date(GMT-8:00): 14 Jul 2021
FG-CLPLN-0032
FGCL-4592-092
Statistical Analysis Plan
FibroGen, Inc.
Confidential and Proprietary
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00
Page 2 of 58
Signature:
Date:
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
Approvals 
I have reviewed and accepted the information in this document to be a true and accurate 
representation of the Statistical Analysis Plan, for Study FGCL-4592-092, Amendment 3. 
Initiator:
Reviewed by: 
Signature:
Date:
Date:
Signature:
Date:
Signature:
Date:
Signature:
Signature Significance
The following significance is lent to the signatures on the Approvals page of this document. 
Signatory 
Significance
Initiator
By signing, the author is attesting that the content of the document is
complete and accurate.
*See appended final page for 21CFR Part 11 compliant
*See appended final page for 21CFR Part 11 compliant
*See appended final page for 21CFR Part 11 compliant approval
*See appended final page for 21CFR Part 11 compliant
*See appended final page for 21CFR Part 11 compliant approval


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
FibroGen, Inc. 
Confidential and Proprietary 
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00 
Page 3 of 58 
 
 
 
 
Reviewer 
By signing, the reviewer is attesting that the document’s approach and 
contents are compliant with the study protocol, all appropriate, regulatory 
requirements, and other significant guidelines. This individual(s) has 
reviewed the document for accuracy and completeness. 


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
FibroGen, Inc. 
Confidential and Proprietary 
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00 
Page 4 of 58 
 
 
 
CHANGE HISTORY 
 
Version 
Date 
Description 


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
FibroGen, Inc. 
Confidential and Proprietary 
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00 
Page 5 of 58 
 
 
 
 
 
TABLE OF CONTENTS 
1 
Introduction ........................................................................................................................... 12 
2 
Study Objectives ................................................................................................................... 13 
3 
Study Design ......................................................................................................................... 14 
3.1 
Overview ....................................................................................................................... 14 
3.2 
Study Population ........................................................................................................... 14 
3.3 
Sample Size Determination ........................................................................................... 14 
3.4 
Randomization and Treatment Blinding ....................................................................... 15 
3.5 
Study Treatment ............................................................................................................ 15 
3.6 
Study Assessments ........................................................................................................ 15 
3.7 
Protocol Amendments ................................................................................................... 16 
3.8 
Changes from the Protocol............................................................................................ 17 
4 
Study Endpoints and Definitions .......................................................................................... 19 
4.1 
Primary Efficacy Endpoint ............................................................................................ 19 
4.2 
Secondary Efficacy Endpoints ...................................................................................... 19 
4.3 
Additional Efficacy Endpoints ...................................................................................... 20 
4.4 
Exploratory Evaluations ................................................................................................ 20 
4.5 
Subgroup Analyses ....................................................................................................... 20 
4.6 
PK Parameters and Biomarkers .................................................................................... 21 
4.7 
Safety Parameters .......................................................................................................... 21 
5 
General Statistical Considerations ........................................................................................ 22 
5.1 
Statistical Hypothesis Testing ....................................................................................... 22 
5.2 
Analysis Populations ..................................................................................................... 22 
5.2.1 All Enrolled or Intent-to-Treat (ITT) Population ...................................................... 22 
5.2.2 Full Analysis Set (FAS) ............................................................................................ 22 
5.2.3 Efficacy Evaluable (EE)............................................................................................ 22 
5.2.4 Safety (SAF) Population ........................................................................................... 22 
5.2.5 PK Analysis Set (PKS) ............................................................................................. 22 
5.3 
Handling of Dropouts or Missing Data ......................................................................... 22 
5.3.1 Handling Missing Hb Assessment ............................................................................ 22 
5.3.2 Handling Missing/Incomplete AE Onset Date.......................................................... 22 
5.3.3 Handling Missing/Incomplete CM Start/Stop Dates ................................................ 23 


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
FibroGen, Inc. 
Confidential and Proprietary 
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00 
Page 6 of 58 
 
 
5.4 
Adjustment for Covariates ............................................................................................ 23 
5.5 
Definition of Baseline ................................................................................................... 23 
5.6 
Analysis Visit Window ................................................................................................. 23 
5.6.1 Hb Analysis Visit Window ....................................................................................... 23 
5.6.2 CHr, Hepcidin, and PRO Analysis Visit Window .................................................... 24 
5.6.3 Iron Marker and Lipid Analysis Visit Window ........................................................ 24 
5.6.4 Safety Assessment Analysis Visit Window .............................................................. 25 
5.7 
Pooling Data of Study Sites .......................................................................................... 25 
5.8 
General Layout.............................................................................................................. 25 
5.9 
Data Errata and Hard-Coding ....................................................................................... 25 
6 
Statistical Analyses ............................................................................................................... 26 
6.1 
Subject Enrollment and Disposition ............................................................................. 26 
6.2 
Protocol Deviations ....................................................................................................... 26 
6.3 
Demographic and Baseline Characteristics .................................................................. 26 
6.3.1 Demographic and Other Baseline Variables ............................................................. 26 
6.3.2 Baseline Parameters .................................................................................................. 26 
6.3.3 Medical History ........................................................................................................ 27 
6.3.4 Tumor Type and Disease Burden ............................................................................. 27 
6.3.5 Prior and Concomitant Medications ......................................................................... 27 
6.4 
Study Treatment and Other Intervention ...................................................................... 29 
6.4.1 Study Drug Exposure ................................................................................................ 29 
6.4.2 Treatment Compliance .............................................................................................. 29 
6.4.3 RBC Transfusions ..................................................................................................... 29 
6.5 
Efficacy Analyses ......................................................................................................... 30 
6.5.1 Primary Efficacy Analysis: Maximum Hb Change from Baseline ........................... 30 
6.5.2 Secondary Analyses of Hb Change from Baseline ................................................... 30 
6.5.3 Analysis of Other Secondary Endpoints ................................................................... 30 
6.5.4 Exploratory Analyses ................................................................................................ 31 
6.5.5 Subgroup Analyses ................................................................................................... 31 
6.6 
PK Analysis .................................................................................................................. 31 
6.6.1 Plasma Concentrations .............................................................................................. 31 
6.6.2 PK Analysis .............................................................................................................. 31 
6.7 
Safety Data Analysis ..................................................................................................... 31 


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
FibroGen, Inc. 
Confidential and Proprietary 
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00 
Page 7 of 58 
 
 
6.7.1 Adverse Events ......................................................................................................... 32 
6.7.2 Deaths ....................................................................................................................... 33 
6.7.3 Clinical Laboratory Assessments .............................................................................. 33 
6.7.4 Vital Signs ................................................................................................................. 33 
6.7.5 ECG........................................................................................................................... 33 
6.7.6 Physical Examination................................................................................................ 33 
6.7.7 Additional Data Presentations ................................................................................... 33 
6.8 
Interim Analysis ............................................................................................................ 34 
Appendix A Potentially Clinically Significant Values ................................................................ 35 
1 Lab PCS Cutoff Values .......................................................................................................... 35 
2 Vital Signs PCS Cutoff Values .............................................................................................. 38 
3 ECG PCS Cutoff Values ........................................................................................................ 38 
Appendix B General Specifications for Tables, Listings, Figures ............................................... 39 
1 Software Used ........................................................................................................................ 39 
2 General ................................................................................................................................... 39 
3 Table/Listing/Figure Output File Type and Organization ..................................................... 39 
4 Page Layout ........................................................................................................................... 39 
5 Titles and Footnotes ............................................................................................................... 40 
7 Significant Digits of Summary Statistics ............................................................................... 41 
8 Figure Specifications ............................................................................................................ 43 
9 Unit Conversion .................................................................................................................... 43 
10 Definitions and Formulas .................................................................................................... 43 
Appendix C General Specifications for Submission Data ............................................................ 45 
1 Study Data Tabulation Model (SDTM) ................................................................................. 45 
2 Analysis Data Model (ADaM) ............................................................................................... 47 
Appendix D FACT-An (Version 4) .............................................................................................. 49 
FACT-An (Version 4) ............................................................................................................... 51 
FACT-An Scoring Guidelines .................................................................................................. 53 
FACIT-Fatigue Subscale Scoring Guidelines ........................................................................... 58 


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
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No table of figures entries found. 
No table of figures entries found. 
LIST OF TABLES 
LIST OF FIGURES 
LIST OF APPENDICES 
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ABBREVIATIONS 
 
Abbreviation 
Definition 
~ 
Approximately 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BSC 
Best Supportive Care 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CHr 
Reticulocyte Hemoglobin Content 
CI 
Confidence Interval 
CIA 
Chemotherapy Induced Anemia 
CKD 
Chronic Kidney Disease 
Cmax 
Maximum Concentration 
CRF 
Case Report Form 
DD 
Dialysis-dependent 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
ECG/EKG 
Electrocardiogram 
EE 
Efficacy Evaluable 
EOS 
End of Study 
EOT 
End of Treatment 
EPO 
Erythropoietin 
ESA 
Erythropoiesis-stimulating Agent 
ESRD 
End-stage Renal Disease 
FACT-An 
Functional Assessment of Cancer Therapy-Anemia 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 


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FAS 
Full analysis Set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transferase 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
HDL 
High-density lipoprotein (cholesterol) 
HIF 
Hypoxia-inducible Factor 
HIF-PH 
Hypoxia-inducible Factor Prolyl Hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl hydroxylase inhibitor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate or Hazard Ratio 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IU 
International Unit 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LDL 
Low-density lipoprotein (cholesterol) 
LLN 
Lower Limit of Normal 
LFT 
Liver Function Test 
LOCF 
Last Observation Carried Forward 


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MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MDRD 
Modification of Diet in Renal Disease 
MDS 
Myelodysplastic Syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Sample Size 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
PTT/PT 
Prothrombin Time/Partial Thromboplastin Time 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Assessments 
Tbili 
Total Bilirubin 
TEAE 
Treatment-emergent Adverse Event 
TESAE 
Treatment-emergent Serious Adverse Event 
TIA 
Transient ischemic Attack 
TIBC 
Total Iron Binding Capacity 
TIW 
Three Times Weekly 
TSAT 
Transferrin Saturation 
UIBC 
Unsaturated Iron-binding Capacity 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
VLDL 
Very low-density lipoprotein (cholesterol) 
WBC 
White Blood Cell 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) documents planned analyses for Study FGCL-4592- 
092 (Amendment 3): A Phase 2 Open Label Study Investigating the Efficacy and Safety 
of Roxadustat (FG-4592) for Treatment of Anemia in Patients Receiving Chemotherapy 
Treatment for Non-Myeloid Malignancies. 
This SAP includes detailed elaboration of statistical analysis methods, models, 
definitions, and data handling rules. It supersedes the statistical sections in the protocol 
in case of differences. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2 
STUDY OBJECTIVES 
Primary Objective: 
• 
To evaluate the efficacy of roxadustat for the treatment of anemia in patients receiving 
multi-cycle treatments of myelosuppressive chemotherapy. 
Secondary Objectives: 
• 
Evaluate the safety of roxadustat 
• 
Evaluate the impact of roxadustat on RBC transfusion requirements 
• 
Evaluate effect of roxadustat on biological indicators: hemoglobin, hematocrit, 
reticulocytes, hepcidin, serum iron, ferritin, transferrin saturation and total iron binding capacity 


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3 
STUDY DESIGN 
3.1 
Overview 
This is a Phase 2, open label single-arm study. The study will evaluate the efficacy of roxadustat 
for the treatment of anemia in patients receiving multi-cycle treatments of myelosuppressive 
chemotherapy. A total of up to 100 patients will be enrolled in this trial. 
This trial has three study periods: 
Screening (up to 28 days) 
16-week Treatment with roxadustat 
4-week Follow-Up 
Patients undergo 16 weeks of study treatment with roxadustat. Study visits are scheduled every 2 
weeks up to Week 12 and then after 4 weeks at Week 16. Patients’ clinical status and safety will 
be regularly evaluated. Patient reported outcome on Health related Quality of Life (HRQOL) 
assessments via FACIT-F (fatigue) and FACT-An (anemia) at baseline (Day 1), and at various times 
as described in the SOA. If, per investigator, unexpected disease progression (malignancy) occurs 
during the treatment period, patients will be discontinued from study treatment and continue in 
the follow-up period. 
A schematic overview of the study is provided in Figure 1. 
 
Figure 1. 
Study Schema 
 
 
 
3.2 
Study Population 
Patients with anemia caused by myelosuppressive chemotherapy. 
3.3 
Sample Size Determination 
Up to approximately 100 patients will be enrolled into this study. The sample size is determined 
by clinical judgment, not by statistical power analysis. 


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3.4 
Randomization and Treatment Blinding 
This is an open-label single arm study. There is no randomization and study drug is not blinded. 
3.5 
Study Treatment 
Study drug Roxadustat is administered 3 times a week (TIW) for up to 16 weeks. Starting dose is 
2.0 mg/kg before protocol Amendment 3 and 2.5 mg/kg in protocol Amendment 3. Dose titration 
rules are described in the protocol Appendix 2. 
3.6 
Study Assessments 
The schedule of assessments is presented in Appendix 1 of the protocol. 
AEs, concomitant medications, non-drug procedures, and vital signs are collected at all study 
visits. Dosing records are collected at weeks 5, 9, 13 and 16. ECG and physical examination are 
performed before and at the end of treatment, and at post treatment follow up. FACT-An 
questionnaire is administered on Day 1 and weeks 5, 9, 13, and 16 (EOT). Lab test schedule is 
shown below. 
Table 1. Central lab tests and schedule 
 
Lab Category 
Test Name 
Assessment Time Point 
CBC 
Hb and ANC, HCT, MCH, MCHC, MCV, 
RBC, WBC, Neutrophils, Basophils, 
Eosinophils, Lymphocytes, Monocytes, Abs. 
Neutrophils, Abs. Basophils, Abs. Eosinophils, 
Abs. Lymphocytes, Abs. Monocytes, Platelets 
Screening 1 and 2, Day 1, 
weeks 3, 5, 7, 9, 11, 13, 16 
(EOT), and EOS 
Serum chemistry 
Albumin, Bicarbonate, Calcium, Chloride, 
Creatinine Enzymatic, Glucose Serum, 
Magnesium, Phosphorus, Potassium, Sodium, 
UREA (BUN), eGFR by MRD, LDH 
Screening, Day 1, weeks 5, 9, 
13, 16 (EOT), and EOS 
LFTs 
ALT, AST, Alkaline Phosphatase, Total 
Bilirubin 
Screening, Day 1, weeks 5, 9, 
13, 16 (EOT), EOS 
Iron Biomarkers 
Iron, Ferritin, Transferrin, Transferrin 
Saturation, TIBC, UIBC 
Screening, Day 1, weeks 9, 
16 (EOT), and EOS 
Reticulocyte 
count; CHr 
Reticulocyte Count, CHr 
Day 1, weeks 5, 9, 13, 16 
(EOT), EOS 
Hepcidin 
Hepcidin 
Day 1, weeks 5, 9, 13, 16 
(EOT), EOS 
Serum Lipid Panel Cholesterol, HDL Cholesterol, LDL 
Cholesterol Calculated, Triglyceride, VLDL 
Cholesterol Calculated 
Day 1, weeks 9, 16 (EOT), 
and EOS 


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PT, PTT, INR 
PT, APTT, INR 
Day 1, EOT, EOS 
Serum hCG 
pregnancy test 
HCG, Quant 
Screening 1 
C-reactive protein CRP, high sensitivity 
Day 1, EOT 
Exploratory 
biomarkers 
VEGF, Erythropoietin 
Screening 1, week 9, 16 
(EOT) 
B12, Folate 
Vitamin B12, Folate 
Screening 1 
HbsAg, anti-HCV 
AB, HIV 
Hep B Surface Ag, Hep C Ab Screen, HIV-1/- 
2 Ag and Ab Screen 
Screening 1 
 
 
Roxadustat PK Sub-study: 
There is an optional population PK sub-study for roxadustat in this protocol. Patients are not required 
to participate in the sub-study, and this decision will not make them ineligible for the overall study 
protocol. Patients who volunteer to participate sign an additional informed consent form. Samples are 
taken after 4 weeks of treatment at each dose level at 1 or 2 pre-dose sample times and at 1-4 hours 
post-dose (ideally on the same day as the pre-dose sample but not required). In addition, two samples 
may be taken at > 5 hours after dosing (may be at different clinic visits consequent with other 
assessments). 
Paclitaxel PK Sub-study: 
This optional PK sub-study investigates the potential effect of Roxadustat timing of 
administration on the pharmacokinetics of paclitaxel. Participation in this sub-study is voluntary. 
Roxadustat dosing for participants are as follows: 
• Dosing of roxadustat is separated from paclitaxel administration by approximately 
24 hours or 1 day for the initial paclitaxel dose. 
• Dosing of roxadustat is separated from paclitaxel administration by approximately 
48 hours or 2 days for the next paclitaxel dose. 
• Roxadustat and paclitaxel are dosed on the same day. 
 
 
 
3.7 
Protocol Amendments 
 
Version 
Date 
Main Changes 
Original 
02Apr2019 
Amendment 1 
16Jul2019 
1. Added exclusion criteria #2 “Patients who are only 
receiving hormonal products, biological products, 
novel immunosuppressive products (such as PD-1 


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and PD-L1 checkpoint inhibitors) or targeted 
biological or radiation therapy to treat/manage their 
cancer. (Patients receiving concomitant 
myelosuppressive therapy if not intended for cure 
may be allowed to participate)” 
2. Added exclusion criteria #3 “Patients who prefer a 
Red Blood Cell (RBC) transfusion as treatment of 
anemia at time of study entry, over receiving the 
investigational drug Roxadustat” 
3. Updated exclusion #13 to “Current condition 
requiring anticoagulants. Anticoagulant use for non- 
cardiovascular conditions are allowed. CV 
prophylaxis with low-dose aspirin, Plavix may be 
allowed” 
4. Updated exclusion #21 to “History of leukemia 
(current or historical Chronic Lymphocytic Leukemia 
may be allowed)” 
Amendment 2 
30Jan2020 
1. Added Inclusion # 9 “ Estimated life expectancy ≥ 6 
months at enrollment (Day 1)” 
2. Updated exclusion #4 to “Received an RBC 
transfusion or ESA within 4 weeks of enrollment 
(Day 1)” 
3. Removed exclusion #13 
4. Added clarifications in analysis methods 
Amendment 3 
22May2020 
1. Increased starting dose for newly enrolled patients 
from 2.0 mg/kg to 2.5 mg/kg 
2. Reduced interval between roxadustat and paclitaxel 
dosing from 48 hours to 24 hours 
3. Added Paclitaxel PK sub-study to evaluate the effect 
of roxadustat timing of administration on the 
pharmacokinetics of paclitaxel. 
 
 
3.8 
Changes from the Protocol 
1. Definition of ITT population 
Original definition in the protocol: 
Defined as all patients enrolled in the roxadustat treatment period, regardless of whether 
patients received any study drug. 
New definition: 
The ITT population consists of all patients enrolled in the roxadustat treatment period and 
received at least one dose of study medication. 
2. Analysis of Additional Exploratory Biomarkers 


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Descriptive summary of change from baseline to Week 9 in VEGF and erythropoietin is 
added. 
3. An exploratory endpoint, number (%) of patients that require transfusion from Day 1 Week 
16, is added. 
4.  An additional/exploratory endpoint, mean change in hemoglobin level from baseline up to 4 
weeks after the last dose of chemotherapy during the treatment period (without RBC 
transfusion, is added. 
5. An additional/exploratory endpoint, proportion of patients requiring chemotherapy dose 
reduction or dose hold primarily due to anemia (assessed by the investigator) during the 
treatment period, is added 
6. Various Subgroup Analyses (Starting dose groups, baseline hs-CRP, and Age/gender/race) 
are added. 


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4 
STUDY ENDPOINTS AND DEFINITIONS 
4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is maximum change in hemoglobin in 16 weeks from baseline 
without RBC transfusion. 
Baseline Hb is defined as the mean of the assessments from central lab prior to first dose of the 
study treatment, which include up to two latest screening values prior to Day 1 and a value on 
Day 1. All central lab Hb assessments (scheduled and unscheduled) during the treatment period 
(from Day 1 to EOT or ET) are included in evaluation of this endpoint. Hb values within 4 
weeks after an RBC transfusion will be excluded. If all post Day 1 Hb values are found to be 
under influence of transfusion (i.e. within 4 weeks of transfusion), Hb change from baseline for 
that subject will be considered “0”. These rules are applied to all Hb-related endpoints. 
4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this trial are: 
• Mean change in hemoglobin level from baseline to week 16 (without RBC 
transfusion) 
• Change in hemoglobin from baseline through week 8, 12, 16 (without RBC 
transfusion) 
• Proportion of patients who achieved a ≥1 g/dL increase in hemoglobin from baseline 
through week 16 
• Time to achieve a ≥1 g/dL increase in hemoglobin from baseline 
• Proportion of patients who achieved a ≥1.5 g/dL increase in hemoglobin from 
baseline through week 16 
• Proportion of patients who achieved a hematopoietic response at any time in the study 
(defined as an increase in Hb of 1.5 g/dL OR attaining a Hb of 11) 
• Proportion of patients who achieved a ≥2 g/dL increase in hemoglobin from baseline 
through week 16 
• Number (%) of patients who had a RBC transfusion from beginning of Week 5 (Day 
29) to week 16 


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4.3 
Additional Efficacy Endpoints 
• Mean change in hemoglobin level from baseline up to 4 weeks after the last dose of 
chemotherapy during the treatment period (without RBC transfusion) 
• Proportion of patients requiring chemotherapy dose reduction or dose hold primarily 
due to anemia (assessed by the investigator) during the treatment period 
• Proportion of patients who achieved a ≥1 g/dL increase in hemoglobin from baseline 
through week 8 and 12 
• Proportion of patients who achieved a ≥1.5 g/dL increase in hemoglobin from 
baseline through week 8 and 12 
• Number (%) of patients that require transfusion from Day 1 Week 16 
• Number (%) of patients that require transfusion as medical intervention and/or ESA 
(erythropoiesis stimulating agent) as a rescue agent. [Time Frame: 16 weeks] 
• Percentage of Participants by Tumor Type with Improvement in FACIT-F (fatigue) 
and Increase in Hemoglobin ≥ 1 g/dL [Time Frame: baseline to week 16] 
• Change from Baseline in Quality of life as measured by: 
Functional Assessment of Cancer Therapy-Anemia (FACT-An) test 
[Time Frame: baseline to week 8 and 16] 
Questionnaires of FACT-An (Functional Assessment of Cancer Therapy - Anemia, 
version 4) and FACIT - F (Functional Assessment of Chronic Illness Therapy 
Measurement System – Fatigue) are presented in Appendix D. Definitions of the 
domain scores and scoring algorithms are also included. 
4.4 
Exploratory Evaluations 
• Effect on hepcidin and iron metabolism 
Change from baseline to assessment time points in hepcidin and iron parameters 
(iron, ferritin, transferrin, TSAT, TIBC, UIBC) 
• Effect on cholesterol parameters and lipid metabolism 
Change from baseline to assessment time points in cholesterol, HDL, LDL, VLDL, 
and triglyceride 
• Analysis of change from baseline to Week 9 in VEGF and erythropoietin is added 
4.5 
Subgroup Analyses 
• Starting dose groups 
• Tumor Type (breast, lung, ovary, pancreas, stomach-GI tract) 
• Chemotherapy regimen (platinum, paclitaxel, gemcitabine) 
• Baseline hs-C-reactive protein (CRP) <=ULN vs. >ULN 
• Age/Gender/Race 


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4.6 
PK Parameters and Biomarkers 
• Roxadustat PopPK 
• Paclitaxel DDI 
4.7 
Safety Parameters 
Safety parameters include the following: 
• AEs and SAEs 
• Laboratory tests 
• Vital signs 
• 12-lead electrocardiograms (ECGs) 
• Physical examinations 


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5 
GENERAL STATISTICAL CONSIDERATIONS 
5.1 
Statistical Hypothesis Testing 
This is an open-label single arm study. No formal hypothesis testing will be performed. Efficacy 
and safety data will be summarized descriptively with 95% confidence interval (CI) for the key 
statistics. 
5.2 
Analysis Populations 
5.2.1 All Enrolled or Intent-to-Treat (ITT) Population 
The ITT population consists of all patients enrolled in the roxadustat treatment period and 
received at least one dose of study medication. 
5.2.2 Full Analysis Set (FAS) 
Full analysis set (FAS) consists of all enrolled patients who receive at least one dose of 
roxadustat, have a baseline Hb and at least one central lab Hb assessment during the treatment 
period. 
FAS population will be used for all efficacy analysis. 
5.2.3 Efficacy Evaluable (EE) 
Efficacy Evaluable (EE) population consists of all enrolled patients who have at least one Hb 
value after 4 weeks of treatment. 
5.2.4 Safety (SAF) Population 
Safety (SAF) population consists of all patients who took at least one dose of study medication. 
The primary analysis of safety will be based on the Safety population. 
5.2.5 PK Analysis Set (PKS) 
The PK Analysis Set consists of subjects who participated in the PK substudy. 
5.3 
Handling of Dropouts or Missing Data 
All data collected in the study database will be included in the analysis. Missing efficacy and 
safety values will not imputed, with the exception of the cases described below. 
5.3.1 Handling Missing Hb Assessment 
For subjects in the FAS population, if all post Day 1 Hb values are found to be under influence 
of transfusion (i.e. within 4 weeks of post-transfusion), Hb change from baseline for these 
subjects will be considered “0”. No other imputation will be performed. 
5.3.2 Handling Missing/Incomplete AE Onset Date 
If the AE onset date is incomplete or missing, the following rules will be applied to obtain 
imputed AE onset date: 
• If year and month are present, only day is missing, 
a) If AE onset Year/month = Day 1 Year/month, assign onset date = date of Day 1; 
b) If AE onset Year/month ≠ Day 1 Year/month, assign onset Day = 1; 


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• If year is present, month and day are missing, 
a) If onset year = year of Day 1, assign onset date = date of Day 1; 
b) If onset year ≠ year of Day 1, assign January 1st to onset month and day. 
• If onset date is completely missing, assign onset date = date of Day 1. 
If the AE stop date is complete and the imputed AE onset date is after the stop date, then the AE 
onset date will be re-assigned to be the same as the stop date. 
5.3.3 Handling Missing/Incomplete CM Start/Stop Dates 
The following rules will be used to impute incomplete CM start and end date: 
• Incomplete CM start date: assign 1 to missing Day, January to missing Month. 
• Incomplete CM end date: assign 30 to missing Day, December to missing Month. Impute 
CM end date only if ‘ONGOING’ is not checked. 
If the imputed end date is before the start date (imputed or non-imputed start date), then the 
imputed end date will be replaced with the start date. 
No imputation will be performed for the following cases: 
• CM end date will not be imputed if ‘ONGOING’ is checked. 
• Year of CM start or end is missing. If CM end year is missing, then the CM will be 
assumed to have been used during the study treatment period. 
5.4 
Adjustment for Covariates 
Comparison between starting doses may be performed with adjustment of tumor type, chemo 
type, and other baseline characteristics. 
5.5 
Definition of Baseline 
Baseline Hb is defined in Section 4.1. 
Baseline for the iron parameters (iron, ferritin, transferrin, transferring saturation, TIBC, UIBC) 
is defined as mean of the last screening value and Day 1 value. 
Baseline for other lab tests and vital sign parameters is defined as Day 1 value, or the latest 
screening value if Day 1 value is missing. 
5.6 
Analysis Visit Window 
Scheduled visits are on the following days: -28 days to Day 1 for screening/baseline visits, days 
15, 29, 43, 57, 71, 85, 113 (EOT) for treatment visits, and 141 (EOS) for follow up visit. 
Study assessments are scheduled on the first day of Weeks 3, 5, 7, … to evaluate treatment effect 
up to the week before, such as change from baseline to Weeks 2, 4, 6, … In other words, ‘change 
from baseline to week 3’ based on the timing of data collection and ‘change from baseline to 
week 2’ based on the actual treatment duration are equivalent. 
5.6.1 Hb Analysis Visit Window 
Scheduled Hb assessments are on the following days: -42 to -1 (Screenings 1 and 2), 1 (pre- 
dose), 15, 29, 43, 57, 71, 85, 113 (EOT), and 141 (EOS). 


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Table 3. Hb analysis window 
 
Analysis Visit 
Window 
Baseline 
Prior to first dose on Day 1 
Week 3 - 11 
X = 3, 5, 7, 9, 11 
Target day = 7 * (X – 1) + 1 
Window = [Target day – 7, Target day + 6] 
Week 13 
[78, 98] 
Week 16 
[99, day of EOT/ET record 
EOS 
After EOT/ET record 
5.6.2 CHr, Hepcidin, and PRO Analysis Visit Window 
Scheduled assessments for CHr, hepcidin, and PRO are on the following days: Day 1 (pre-dose), 
29, 57, 85, 113 (EOT), and 141 (EOS). 
Table 4. CHr, Hepcidin, and PRO analysis window 
 
Analysis Visit 
Window 
Baseline 
Prior to first dose on Day 1 
Week 5 - 13 
X = 5, 9, 13 
Target day = 7 * (X – 1) + 1 
Window = [Target day – 14, Target day + 13] 
Week 16 
[99, EOT/ET] 
EOS 
After EOT/ET record 
5.6.3 Iron Marker and Lipid Analysis Visit Window 
Scheduled iron marker assessments are on the following days: Screening 1 (iron markers), Day 1 
(pre-dose), 57, 113 (EOT), and 141 (EOS) 
Table 5. Iron marker and lipid analysis window 
 
Analysis Visit 
Window 
Baseline 
Prior to first dose on Day 1 
Week 9 
X = 9 
Target day = 7 * (X – 1) + 1 
Window = [Target day – 28, Target day + 27] 
Week 16 
[85, EOT/ET] 


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EOS 
After EOT/ET record 
5.6.4 Safety Assessment Analysis Visit Window 
Safety data (lab tests, vital signs, ECG, ECOG, physical exams) are summarized by nominal 
clinic visit. Data collected during the unscheduled visits are not included in the by-visit summary 
tables, but are included in data listings and in evaluations for clinically significant abnormal 
changes. 
5.7 
Pooling Data of Study Sites 
All study sites are pooled in all analyses due to the small number of subjects enrolled at each site. 
5.8 
General Layout 
All study parameters, including baseline characteristics, efficacy, safety, PK and biomarker, will 
be summarized descriptively. Descriptive statistics including the number of subjects (n), mean, 
95% CI of the mean, standard deviation (SD), median, minimum and maximum will be 
presented for continuous variables. For continuous PK parameters, coefficient (CV) and 
geometric mean may also be presented. Number (n) and percentage (%) of subjects in each 
category will be summarized for categorical variables. 95% CI will be presented for response 
rate. Median and other quartiles will be presented for time to response. 
 
5.9 
Data Errata and Hard-Coding 
Data errors identified after database lock are documented in an errata log. Under special 
circumstances, hard-coding in SAS programs is necessary to correct data errors in order to avoid 
obscure study results. Only limited cases deemed necessary and are approved by study team will 
be hard-coded. The changed values as well as approval from the study team will be documented. 


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6 
STATISTICAL ANALYSES 
6.1 
Subject Enrollment and Disposition 
The number of subjects enrolled in each study site will be summarized. 
The number of subjects in each study population (Enrolled/Safety, FAS, EE, and PK) will be 
summarized. The number of subjects who completed or discontinued the study as well as the 
reasons for early discontinuation will be summarized. 
Subject who discontinued the study prematurely and the reasons will be listed. 
6.2 
Protocol Deviations 
Protocol deviations will be categorized as follows: 
• Entry Deviation: Subject entered study, but did not satisfy eligibility criteria. 
• Withdrawal Deviation: Subject met withdrawal criteria during the study but was not 
withdrawn. 
• Dosing Deviation: Subject received the wrong treatment or more than the maximum dose 
allowed (>3.5 mg/kg) or failed to hold dose when Hb >13.0 g/dL 
• Prohibited Medication Deviation: Subject received an excluded concomitant treatment. 
• Operational Deviation: All other deviations; including, but not limited to: informed 
consent form-related deviations other than consent not obtained, IRB/IEC approval 
expired, study drug not stored under protocol-specified conditions, missing laboratory 
report, out-of window visit, etc.; includes missed visits, and subject refusal of a study 
procedure or procedures. 
Important deviations are defined as those that are likely to affect a) the safety or physical or 
mental integrity of the subject, b) the scientific value of the trial. Medical Monitor will 
identify important deviations, following the guidelines, before the database lock. 
Deviations are summarized by subject count and by event count, by study site. All recorded 
protocol deviations are listed. Reported items that are not considered as protocol deviations are 
not included in summary tables and data listings, but remain in the database for reference. 
6.3 
Demographic and Baseline Characteristics 
6.3.1 Demographic and Other Baseline Variables 
Demographic variables will include age in years, gender, race, ethnicity, and country. Age is 
defined as the age on the day of signing informed consent. 
 
6.3.2 Baseline Parameters 
The following demographics and other baseline variables will be summarized descriptively. 
- 
Age (<=64, 65 – 74, >=75) 
- 
Sex 
- 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other) 


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- 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
- 
BMI (<25, 25 -<30, 30 -<35, >=35) 
- 
Weight (<50, 50 -<70, 70 – <100, >=100 kg) 
Lab parameters at baseline 
- 
Baseline Hb level (<8, 8 -<9, >=9 g/dL) 
- 
Baseline CRP (<= ULN, >ULN) 
- 
Baseline ferritin (<100, 100 – 400, >400 ug/L) 
- 
Baseline TSAT (<20%, 20 – 40%, >40%) 
- 
Baseline iron repletion status [(TSAT>=20% and Ferritin>=100ug/L) versus 
(TSAT<20% or Ferritin<100ug/L)] 
- 
Baseline hepcidin (<=ULN, >ULN) 
Weight collected at Day 1 is considered as bassline and used for starting dose calculation and 
dose adjustments. Height collected at Screening, BMI calculated based on height and weight 
collected at Screening are defined as baseline. 
 
6.3.3 Medical History 
Medical conditions captured in the Medical History CRF, including allergies and surgeries, will 
be coded in system organ class (SOC) and preferred term (PT) using MedDRA (version 24.0). 
The coded terms will be tabulated by SOC and PT.  Detail data will be presented in data listing. 
6.3.4 Tumor Type and Disease Burden 
Cancer diagnosis (tumor type) is captured in Medical History CRF and is identified using SOC = 
Neoplasms benign, malignant and unspecified (incl cysts and polyps), or SOC code = 10029104. 
The stage (TNM) of the primary cancer is captured in Disease Burden CRF. 
6.3.5 Prior and Concomitant Medications 
The World Health Organization Drug Dictionary Enhanced version (March 01, 2021) will be 
used to classify concomitant medications by therapeutic class and generic name. 
Prior medications are defined as medications that ended prior to the first dose of the study drug. 
Concomitant medications are defined as medications that are taken on or after the date of first 
dose of the study drug regardless of the start date of the medications. 
Prior and concomitant medications will be summarized and listed. 
Chemotherapies 
Chemo-therapies are captured on the Concomitant CRF. To identify paclitaxel, platinum, and 
gemcitabine the following ATC codes will be used. 
 
Chemotherapy Type 
ATC Code 
Drug Name 
Paclitaxel 
L01CD01 
paclitaxel 
L01CD02 
docetaxel 


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L01CD03 
paclitaxel poliglumex 
L01CD04 
cabazitaxel 
Platinum 
L01XA01 
cisplatin 
L01XA02 
carboplatin 
L01XA03 
oxaliplatin 
L01XA04 
satraplatin 
L01XA05 
polyplatillen 
gemcitabine 
L01BC05 
If Paclitaxel (e.g. Taxol® or Abraxane®) is given as part of a chemotherapy regimen, roxadustat 
dosing should be held for 24 hours before and after treatment (time 0 = start of infusion) with 
this drug. Roxadustat dosing frequency may be adjusted, as needed. 
Other Potential Drug Interactions 
Dose adjustments of strong modulators of CYP2C8 (e.g. gemfibrozil, clopidogrel) and UGT 
enzymes per physician judgment are allowed. 
Phosphate Binders 
Concomitant use of phosphate binders (ATC4 code = A02AB for aluminum compounds and 
ATC4 code = V03AE for treatment of hyperkalemia and hyperphosphatemia) will be 
summarized. 
Statins 
Concomitant use of statins (ATC4 code = C10AA for HMG CoA reductase inhibitors, ATC4 
code = C10BA for HMG CoA reductase inhibitors in combination with other lipid modifying 
agents, and ATC4 code = C10AX for other lipid modifying agents) will be summarized. 
Proportion of patients who used the higher than recommended dose will be tabulated. 
 
Table x. 
Recommended Maximum Daily Dose of Statins 
 
Statins 
Recommended Maximum Dose (mg/day) 
Atorvastatin 
40 
Simvastatin 
5 
Rosuvastatin 
5 
Pravastatin 
40 
Fluvastatin 
20 
Pitavastatin 
2 
Lovastatin 
20 
ESA Use 
ESA (ATC4 code = B03XA) use will be summarized by study period: screening up to Day 1, 
treatment period (defined as from first dose of study drug to Hb assessment at EOT), and post- 
treatment period. 


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Supplemental Iron Use 
Oral iron supplementation (ATC4 code = B03AA) is allowed. IV iron (ATC4 code = B03AC) 
use is prohibited, but may be considered if patient is iron-deficient and unresponsive to oral iron 
supplementation and lacking erythroid response to study medication. Use of oral and IV iron 
will be summarized by study period. 
6.4 
Study Treatment and Other Intervention 
6.4.1 Study Drug Exposure 
Duration of study drug exposure is defined as: 
Days on treatment = Date of EOT/ET Hb assessment - first dose date + 1. 
Total weekly study drug exposure is defined as the total dose (in mg or mg/kg) of study drug 
administered within the week as recorded in the dosing record. 
Duration of exposure, average weekly dose during treatment and weekly dose by week, as well 
as total study drug exposure will be summarized. In addition, cases of roxadustat dose exceeding 
400 mg or 3.5 mg/kg/dose, whichever is lower, will be listed separately. 
Starting dose for initial 20 patients is approximately 2.0 mg/kg (for first 4 weeks), as shown 
below the dose level at different weight ranges: 
 
Body Weight 
45 to < 70 kg 
70 - 100 kg 
> 100 kg 
Dose Level 
100 mg 
150 mg 
200 mg 
Patients enrolled after protocol Amendment 3 receive approximately 2.5 mg/kg (for first 4 weeks) as 
starting dose, as shown below the dose level at different weight ranges. 
 
Body Weight 
45 to < 70 kg 
70 - 100 kg 
> 100 kg 
Dose Level 
150 mg 
200 mg 
250 mg 
Dose adjustment evaluation will be made every 4 weeks, and dose will be titrated to Hb level and 
rate of Hb change according to the titration algorithm in Error! Reference source not found. of 
the protocol. 
6.4.2 Treatment Compliance 
Treatment compliance is defined as the total number of correct doses actually taken by a patient 
divided by the prescribed doses expected to be taken multiplied by 100. 
6.4.3 RBC Transfusions 
RBC transfusion from Week 5 (Day 29) to Week 16/EOT is a secondary efficacy endpoint. 
Planned analysis is described in Section 6.5.3. 


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6.5 
Efficacy Analyses 
The efficacy analyses will be primarily based on the FAS population. Sensitivity analyses will be 
performed based on the EE population for selected key endpoints, including but not limited to 
primary and secondary efficacy endpoints. 
6.5.1 Primary Efficacy Analysis: Maximum Hb Change from Baseline 
The primary efficacy endpoint, maximum change from baseline in Hb without RBC transfusion 
during the treatment period, is defined in Section 4.1. This endpoint will be summarized 
descriptively including mean (SD), median, range, and 95% CI of the mean. 
6.5.2 Secondary Analyses of Hb Change from Baseline 
Mean Hb change from baseline over the treatment period, without RBC transfusion, will be 
computed using the mean area-under-the-curve trapezoid method, from Day 1 to last Hb 
assessment during treatment. Hb change from baseline (without RBC transfusion) by visit is 
defined by the analysis visit window in Section 5.6. These endpoints will be summarized 
descriptively, similar to the primary endpoint. 
Hb treatment response during the treatment period without RBC transfusion is defined by the 
following different criteria: 
• ≥1 g/dL increase 
• ≥1.5 g/dL increase 
• ≥1.5 g/dL increase or attaining a Hb ≥ 11 g/dL 
• ≥2 g/dL increase 
Proportion of responders will be tabulated, along with the 95% CI estimated using the Clopper- 
Pearson method. Proportion of responders will also be tabulated by visit based on observed data 
only. 
Median as well as 25th and 75th percentiles of time to Hb response, will be estimated via Kaplan- 
Meier product limit method. If there is no Hb response during the treatment period, then time to 
response is censored on the date of last Hb assessment that is not under influence of RBC 
transfusion. 
6.5.3 Analysis of Other Secondary Endpoints 
Proportion of subjects who used RBC transfusion (1) from Day 29 (week 5) to date of EOT/ET 
Hb assessment and (2) from Day 1 to date of EOT/ET Hb assessment will be tabulated, along 
with the 95% CI estimated using the Clopper-Pearson method. Total number of RBC 
transfusions and time-adjusted incidence rate will also be summarized. 
Change from baseline in FACT-An domain scores will be summarized descriptively by visit and 
by Hb response. Detailed definitions of domain scores are described in Appendix D. 


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6.5.4 Exploratory Analyses 
6.5.4.1 
Effect on Hepcidin 
Hepcidin levels are measured on Day 1, week 5, week 9, week 13, week 16 (or EOT/ET) and 
follow-up. Measured value and change from baseline will be summarized descriptively by visit. 
6.5.4.2 
Effect on Iron Biomarkers 
 
Iron biomarkers (Transferrin, TIBC, UIBC, TSAT and Ferritin, serum iron) are at screening, Day 
1, week 9, week 16 (or EOT/ET) and follow-up. Measured value and change from baseline in 
iron parameters will be summarized descriptively by visit. 
6.5.4.3 
Effect on Cholesterol and Lipid Metabolism 
 
Lipids panel (non-fasting) parameters include total cholesterol, LDL, HDL, LDL/HDL ratio and 
triglycerides. Serum samples are collected on Day 1, weeks 9, 16 (EOT), and EOS. Measured 
value and change from baseline in iron parameters will be summarized descriptively by visit. 
6.5.4.4 Analysis of Change from Baseline to Week 9 in VEGF and Erythropoietin 
Samples for VEGF and Erythropoietin are collected at screening, week 9, week 16 (or EOT) and 
follow-up. Measured value and change from baseline in iron parameters will be summarized 
descriptively by visit. 
6.5.5 Subgroup Analyses 
The key efficacy endpoints will summarized by the following subgroups: 
• Starting dose groups 
• Tumor type 
• Chemotherapy regimen 
• Baseline hs-C-reactive protein (CRP) <=ULN vs. >ULN 
• Age/Gender/Race 
6.6 
PK Analysis 
6.6.1 Roxadustat Plasma Concentrations 
Optional population PK sub-study to measure roxadustat plasma concentration at various time points, 
before and after roxadustat dosing. 
6.6.2 Paclitaxel PK Analysis 
Optional Paclitaxel PK sub-study to investigate the potential effect of roxadustat timing of 
administration on the pharmacokinetics of paclitaxel. 
6.7 
Safety Data Analysis 
Safety analyses will include summary of adverse events (including treatment emergent AEs, 
treatment emergent serious AEs, AEs leading to treatment discontinuation, and deaths), lab test 


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results, vital signs, ECGs, and physical exams. In general, safety data will only be summarized 
descriptively based on the Safety population and no rigorous inferential statistical procedures 
will be applied. 
6.7.1 Adverse Events 
AEs and SAEs are collected on the AE CRFs. SAEs are special cases of AEs. The definitions of 
AEs, SAEs, severity, and relationship to study medication are described in Section 9 of the 
protocol. Adverse events are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA: version 24.0) for system organ class (SOC) and preferred term (PT). 
Due to various reasons, some patients were unable to return the dosing diary. So the date of last 
dose was not captured in some patients. In this study, all AEs occurred on or after the date of the 
first study drug (Day 1) are considered treatment emergent adverse events (TEAEs). 
All reported AEs are presented in listings. The number and percent of subjects experiencing 
TEAEs will be tabulated by SOC and PT and will be sorted alphabetically by SOC and by 
decreasing order of frequency of PT within each SOC. The decreasing order of frequency of 
preferred terms will be based on the overall population. A subject with multiple adverse events 
within a SOC is only counted once in this SOC. Similarly, a subject with multiple adverse events 
within a PT is only counted once in this PT. 
TEAE will also be tabulated by severity grade. In the case of multiple events within the same 
preferred term, the event with the highest severity grade is included. Missing data in the severity 
grade will not be imputed and is ranked the lowest severity grade in the case of multiple events. 
The following summaries will be presented: 
● 
Overview of the AE Profile 
● 
Summary of AEs by SOC and PT 
● 
Summary of most common AEs (≥5% incidence rate) by PT 
● 
Summary of SAEs by SOC and PT 
● 
Summary AEs that led to treatment discontinuation by SOC and PT 
● 
Summary Fatal AEs by SOC and PT 
● 
Summary AEs with severity Grade >=3 by SOC and PT 
● 
Summary Related (including possibly and probably) AEs by SOC and PT 
● 
Summary Related (including possibly and probably) SAEs by SOC and PT 
● 
Summary AEs of special interest (eg, deep vein thrombosis, pulmonary embolism, 
seizures, infection, sepsis requiring hospitalization, MI, and stroke) 
The following events are presented in data listings. 
- 
All reported AEs 
- 
SAEs 
- 
Fatal AEs 
- 
AEs leading to treatment or study discontinuation 


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- 
AEs of special interest 
All reported adverse events (regardless of treatment emergent or not) will be presented in data 
listings. 
 
6.7.2 Deaths 
Deaths and cause of death captured on the Death CRF will be listed. 
6.7.3 Clinical Laboratory Assessments 
Change from baseline in laboratory tests listed in Section 3.6 will be summarized descriptively 
by visit. Incidence of treatment emergent potentially clinically significant (PCS) changes from 
baseline during the study will also be summarized. Patients whose baseline value is in the PCS 
range will be excluded from the corresponding summary of treatment emergent PCS change. 
PCS cutoff values are presented in Appendix A. Only scheduled assessments are included in the 
by-visit summaries; however, all scheduled and unscheduled assessments are included in 
evaluation of PCS change. 
The following scatter plots for evaluation of drug induce severe hepatotoxicity (eDISH plots) 
will be presented 
• 
Scatter plot of peak total bilirubin vs. peak ALT 
• 
Scatter plot of peak total bilirubin vs. peak AST 
The peak values in the above eDISH plots may not be from the same sample. Listing of patients 
who met the criteria of moderate or severe liver abnormality (3x ULN in AST and 2x ULN in 
total bilirubin, or 3x ULN in ALT and 2xULN in total bilirubin) from the same sample will be 
presented. 
6.7.4 Vital Signs 
Change from baseline in vital sign parameters [systolic blood pressure (SBP), diastolic blood 
pressure (DBP), and heart rate (HR)] will be summarized descriptively by visit. Incidence of 
treatment emergent potentially clinically significant (PCS) changes from baseline during the 
study will also be summarized. PCS cutoff values are presented in Appendix A. 
6.7.5 ECG 
Change from baseline in vital sign parameters [heart rate, QRS interval, QT interval, QT interval 
– Bazett correction (QTCB), QT interval – Fridericia correction (QTCF), RR interval and PR 
interval] will be summarized descriptively by visit. Incidence of treatment emergent potentially 
clinically significant (PCS) changes from baseline during the study will also be summarized. 
PCS cutoff values are presented in Appendix A. 
6.7.6 Physical Examination 
Physical examination findings will be listed by subject, visit, and body system. 
6.7.7 Additional Data Presentations 
Data listings, using all available data collected, will be provided. 


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6.8 
Interim Analysis 
Informal interim analyses will be conducted to evaluate the initial dose and response as well as 
safety and tolerability. 


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APPENDIX A POTENTIALLY CLINICALLY SIGNIFICANT VALUES 
1 Lab PCS Cutoff Values 
 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Alanine Aminotransferase 
(ALT) 
U/L 
≥3 * ULN 
Alkaline Phosphatase (ALP) 
U/L 
≥3 * ULN 
Aspartate Aminotransferase 
(AST) 
U/L 
≥3 * ULN 
Gamma-Glutamyl Transferase 
(GGT) 
U/L 
≥3 * ULN 
Calcium 
mmol/L 
<0.8*LLN 
>1.2 * ULN 
Creatine Phosphokinase(CPK) 
U/L 
>10 * ULN 
Creatinine 
µmol/L 
> 1.5 x Baseline Value 
Potassium 
µmol/L 
<0.75*LLN 
>1.2 * ULN 
Sodium 
mmol/L 
<0.9*LLN 
>1.1 * ULN 
Total Bilirubin 
µmol/L 
>2 * ULN 
Total Protein 
µmol/L 
<0.9 * LLN 
>1.1 * ULN 
Urea (BUN) 
mmol/L 
>1.5x Baseline Value 
HEMATOLOGY 
Neutrophils 
109/L 
≤1 
Platelet Count 
109/L 
≤ 100 
≥700 
White Blood Cell Count 
109/L 
≤2.5 
≥15 
LLN: Lower limit of normal, value provided by the laboratory 
ULN: Upper limit of normal, value provided by the laboratory 


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CTCAE TOXICITY GRADING FOR LABORATORY TESTS 
The following table is extracted from NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03 (June 14, 2010) 
Chemistry 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin 
Decreased 
3 g/dL – LLN 
2 - <3 g/dL 
<2 g/dL 
Alkaline 
phosphatase (ALP) 
ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
> 20.0 x ULN 
ALT 
ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
AST 
ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Total bilirubin 
ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
Calcium (Corrected) Decreased 
8.0 mg/dL – LLN 
7.0 - <8.0 mg/dL 
6.0 - <7.0 mg/dL 
<6.0 mg/dL 
ULN – 11.5 mg/dL 
>11.5 – 12.5 mg/dL 
>12.5 – 13.5 mg/dL >13.5 mg/dL 
GGT 
ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
> 20.0 x ULN 
Glucose (Random) 
Decreased 
55 mg/dL – LLN 
40 - <55 mg/dL 
30 - <40 mg/dL 
<30 mg/dL 
Glucose (Fasting) 
ULN – 160 mg/dL 
>160 – 250 mg/dL 
>250 – 500 mg/dL 
> 500 mg/dL 
Phosphorous 
Decreased 
2.5 -<LLN mg/dL 
2.0 -<2.5 mg/dL 
1.0 - <2.0 mg/dL 
<1.0 mg/dL 
Potassium 
Decreased 
3.0 mmol/L – LLN 
3.0 mmol/L – LLN[1] 
2.5 - <3.0 mmol/L 
<2.5 mmol/L 
ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Sodium 
Decreased 
130 mmol/L – LLN 
None 
120 - <130 mmol/L 
<120 mmol/L 
ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L >160 mmol/L 
Magnesium 
Decreased 
1.2 mg/dL – LLN 
0.9 - <1.2 mg/dL 
0.7 - <0.9 mg/dL 
<0.7 mg/dL 
ULN – 3.0 mg/dL 
None 
>3.0 – 8.0 mg/dL 
>8.0 mg/dL 


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Serum Hematology 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Uric acid 
ULN – 10 mg/dL[2] 
None 
ULN – 10 mg/dL[3] 
>10 mg/dL 
Creatinine 
Enzymatic 
>1 – 1.5 x baseline[4] 
ULN – 1.5 x ULN 
>1.5 – 3.0 x baseline[4] 
>1.5 – 3.0 x ULN 
>3.0 x baseline[4] 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Triglycerides 
150 – 300 mg/dL 
>300 – 500 mg/dL 
>500 – 1,000 mg/dL 
>1,000 mg/dL 
Hgb 
Decreased 
10.0 g/dL – LLN 
8.0 - <10.0 g/dL 
<8.0 g/dL 
>0 – 2 g/dL 
(+ ULN/Baseline)[5] 
>2 – 4 g/dL 
(+ ULN/Baseline)[5] 
>4 g/dL 
(+ ULN/Baseline)[5] 
Platelet 
Decreased 
75,000 /mm3 – LLN 
50,000 – <75,000 
/mm3 
25,000 - <50,000 
/mm3 
<25,000 /mm3 
WBC 
Decreased 
3,000 /mm3 – LLN 
2,000 - <3,000 /mm3 
1,000 - <2,000 /mm3 
<1,000 /mm3 
None 
None 
>100,000 /mm3 
aPTT 
ULN – 1.5 x ULN 
>1.5 – 2.5 x ULN 
>2.5 x ULN 
Lymphocytes 
Decreased 
800 /mm3 – LLN 
500 - <800 /mm3 
200 - <500 /mm3 
<200 /mm3 
None 
>4,000 – 20,000 /mm3 >20,000 /mm3 
Neutrophils 
Decreased 
1,500 /mm3 – LLN 
1,000 - <1,500 /mm3 
500 - <1,000 /mm3 
<500 /mm3 
Decreased: below LLN; Otherwise, above ULN; 
[1] Symptomatic, Intervention indicated 
[2] without physiologic consequences 
[3] with physiologic consequences 
[4] Baseline is used if it is above ULN 
[5] Increase from ULN/baseline: if baseline is above ULN, the increase should be above the 
baseline; otherwise, the increase should be above ULN. 


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2 Vital Signs PCS Cutoff Values 
 
 
Vital Sign Parameter 
Flag 
Criteria 
Observed Value 
Change from Baseline 
Systolic Blood 
Pressure (mmHg) 
High 
≥ 170 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Diastolic Blood 
Pressure (mmHg) 
High 
≥ 110 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Pulse Rate 
(bpm) 
High 
≥ 120 
Increase of ≥ 20 
Low 
≤ 50 
Decrease of ≥ 20 
 
 
 
3 ECG PCS Cutoff Values 
 
 
ECG 
Unit 
Higher Limit 
QRS interval 
msec 
≥ 150 
PR interval 
msec 
≥ 250 
QTc interval 
msec 
> 500; 
Change from baseline > 30 and > 60 


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APPENDIX B GENERAL SPECIFICATIONS FOR TABLES, LISTINGS, FIGURES 
1 Software Used 
All programming of tables, listings and figures (TLFs) will be performed using the statistical 
software package SAS version 9.4 or greater. 
2 General 
All TLFs are based on SDTM and/or ADaM datasets. By default, data listings reflect the actual 
values captured in SDTM and ADaM datasets, including date/time variables and missing values. 
Except for concatenation of some variables for compact display purpose, data are presented 
directly with minimum manipulation. In general, the character standard result variables, such as 
–STRESC, are presented in data listings. Date are presented in listings in format yyyy-mm-dd. 
For incomplete date, CDISC presentation convension is followed. 
 
For continuous variables that are recorded as “<X” or “>X”, the value of “X” will be used in the 
calculation of summary statistics. The value “X” is also captured in the numeric variable in the 
SDTM datasets as well as in the ADaM datasets for consistency, although SDTMIG recommends 
capturing missing values in the numeric variables. 
 
In general, reported verbatim, such as terms of AE, medical history, medication names, specifications 
to the ‘Other’ fields, findings, etc., are presented in upper case. However, when reported fields are 
long, such as comments and protocol deviation descriptions, listing in lower case enhances 
readability. 
 
3 Table/Listing/Figure Output File Type and Organization 
In general, the final set of TLFs will include both PDF and RTF files. Outputs are combined in 
several large PDF files, eg, all tables, all listings, and all figures, in the order as in the planned TLF in 
Section 12. A table of content should be included with hyperlinking to individual outputs. True RTF 
files (in-text format) will be created for tables and listings. SAS outputs for statistical procedures 
used in analysis of primary, secondary, and exploratory efficacy endpoints will also be included. 
 
4 Page Layout 
All column headers (consisting of one or several words) will start with uppercase and thereafter 
only lowercase characters, except for acronyms and abbreviations. In case values from the 
database will be displayed in column headers, they may be displayed as in the database. Pages 
will be numbered as ‘Page x of y’, where ‘y’ is the total number of pages of the corresponding 
table or listing. The page specifications are presented in Table A. 
 
Table A. 
Specifications for Page Layout 


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Paper Size 
Letter 
Orientation 
Landscape 
Alignment 
Center 
Font size 
9 
Font type 
Courier New (default) 
Margins 
Top 
0.75” 
Bottom 
0.38” 
Left 
0.75” 
Right 
0.38” 
The margin sizes and font size for listings may be flexible to provide sufficient information on a 
single page to facilitate review and comparison. 
When created using SAS, tables and listings will be created using ODS, and output files will be 
produced in RTF. When RTF files are produced, titles and footnotes will appear as document 
headers/footers. 
5 Titles and Footnotes 
All tables and listings will have a header showing “FibroGen, Inc.”, the protocol number, 
database cutoff date or ‘Final Database’, and Page x of y. A footer will show the program file 
path/name, output file path/name, run date and time. 
 
All titles are written in title format, with uppercase at the beginning of each word; articles, 
prepositions, and conjunctions, which are of three characters length or less will start with 
lowercase letters (Mixed Case). Footnotes are in regular text format. 
 
Titles 
In total there are up to 10 titles available, defined as following: 
 
first title 
“FibroGen, Inc.” (left aligned) and “Database extraction date: 
ddMMMyyy” or “Final Locked Database” (right aligned) 
second title 
protocol number + “Clinical Study Report” (left aligned) and “Page x of 
y” (right aligned) 
third title 
blank 
fourth title: 
table/listing/figure number 
fifth title: 
table/listing/figure title 


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sixth title: 
population names if provided in SAP, or brief definition of specific 
analysis set 
Footnotes 
Up to 10 footnote lines are available for tables, listings and figures. Footnotes 1, 9 and 10 are 
standard. Footnotes 2 to 8 (left aligned) might be used as needed. They are to be specified in the 
Shell. 
 
first footnote 
is a separating horizontal line. 
second – eighth 
are free text which can be used for explanations. Footnotes will be 
referenced using numbers in square brackets, starting with [1], 
followed by 
[2] etc. 
ninth footnote 
left blank; in case needed may also be used as for explanations. 
tenth footnote 
the program name (left aligned); the date and time in the format 
ddMMMyyyy hh:mm when the output was created; the version 
(e.g. draft or final); and the word “Confidential”. 
Footnotes are denoted by [1], [2], and so on. 
If footnotes take more than 30% of the space of a long listing, they may be presented only on a 
standalone first page. 
TLF numbers and titles should be inputted from an external file that can be directly copy-and- 
pasted from the SAP planned TLFs, rather than including in the body of the program. This is to 
ensure consistency between the SAP and the actual outputs. 
Footnotes may be inputted from an external file as well for ease of managing changes. 
For summary tables, the corresponding listings with the parameters being summarized should be 
footnoted as reference. For figures, the corresponding summary table should be footnoted as 
reference. 
7 Significant Digits of Summary Statistics 
- 
All percentages will be rounded to one decimal place and aligned by the decimal place. 
- 
If the count is zero, the percentage will be suppressed and only ‘0’ will be presented. 
- 
Any p-values will be rounded to four decimal places and will be presented as ‘<.0001’ if 
they are less than 0.0001 after rounding. 
- 
For variables of direct measurements, summary statistics are displayed with the following 
specifications of decimal places in Table B. 
 
Table B. 
Significant Digits of Summary Statistics 


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Description 
Characteristic Number of decimal places 
Count 
N 
0 
Mean 
Mean 
As in source + 1 
Standard 
deviation 
Std 
As in source + 1 
Standard error of 
the mean 
SEM 
As in source + 2 
Confidence 
Interval 
CI 
As in source + 1 
Minimum 
Min 
As in source 
Median 
Median 
As in source 
Maximum 
Max 
As in source 
Q1 / Q3 
Q1/Q3 
As in source 
10% / 90% 
10%/90% 
As in source 
Percentage 
% 
All percentages will be rounded to one decimal place and 
lined up by the decimal place. The percentage will be 
suppressed when the count is zero 
Coefficient of 
variation 
CV (%) 
1 
p-value 
p-value 
p-values will be rounded to four decimal places and will 
be presented as ‘<.0001’ if they are less than 0.0001 after 
rounding 
N=number; Std=Standard deviation; CI=Confidence Interval; Min=minimum; Max=maximum; 
CV=Coefficient of variation 
 
As a general guideline for derived parameters, 3 significant digits may be displayed for a 
parameter with an overall mean less than 100; otherwise, 1 decimal place may be used. If a 
derived parameter is in the same scale as some related measured parameters, such as MAP, QTc, 
the same display format may be used as the measured parameters. 
Summary Statistics are to be displayed in the following order: Count, Mean, Standard Deviation, 
<Coefficient of Variation, Standard Error of the Mean, Confidence Interval>, Minimum, <10%>, 
<Q1>, Median, <Q3>, <90%>, Maximum. 


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For categorical variables the categories will be displayed in the TLFs in the same order they 
appear in the CRF. 
 
8 Figure Specifications 
- 
In general, figures should include annotation of key summary statistics: n, mean, SD or 
SE, median for continuous variables; n and percent for categorical variables; number of 
subjects at risk and cumulative number of events as well as median and 95% CI for time- 
to-event data. Other statistics such as quartiles, ranges may be included depending on 
need and space. 
 
- 
P-values should be presented if comparisons are of interest. 
 
- 
For scatter plots, linear or non-linear trend lines should be included if the association of 
the two variables is of interest. Correlation coefficient or regression coefficients as well 
as corresponding p-values should be presented. 
 
- 
For box plots, ‘BOXSTYLE=SCHEMATIC’ should be used. The whiskers are drawn to 
the most extreme points in the group that lie within the fences. The upper fence is defined 
as the third quartile (represented by the upper edge of the box) plus 1.5 times the 
interquartile range. The lower fence is defined as the first quartile (represented by the 
lower edge of the box) minus 1.5 times the interquartile range. Observations outside the 
fences are identified with a special symbol. 
 
9 Unit Conversion 
 
Units Presented in 
TLFs 
Units Reported or 
Derived from CRF 
Conversion Formula 
Kilogram (kg) 
Pound (lb) 
kg = lb/2.2 
Centimeter (cm) 
Inch (in) 
cm = 2.54 * in 
Celsius C° 
Fahrenheit (F°) 
C° = (5/9) * (F° – 32) 
Year 
Day 
1 year = 365.25 days 
Months 
Day 
1 month = 30.4375 days 
10 Definitions and Formulas 
(1) Age is calculated as of date that the informed consent form was signed. 
age = INTCK( ‘YEAR’, Birth Date, Date of Informed Consent, ‘C’) 
(2) Duration of treatment (days) is calculated as: date of EOT/ET Hb assessment – first dose 
date +1 
(3) BMI = Weight (kg) / (Height (m))2 


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(4) eGFR will be calculated using the following Modification of Diet in Renal Disease 
(MDRD) equation: 
eGFR (in mL/min per 1.73m2) = 186 x (SCr in mg/dL)-1.154 x (Age in years)-0.203 
x (0.742 if female) x (1.210 if African American) 
where SCr = serum creatinine concentration 
(5) Mean Arterial Pressure (MAP) will be derived using the following equation: 
MAP = (2/3) * DBP + (1/3) SBP 


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APPENDIX C GENERAL SPECIFICATIONS FOR SUBMISSION DATA 
1 Study Data Tabulation Model (SDTM) 
Raw datasets will be mapped to SDTM datasets following variable names and attributes 
specified in the SDTM Implementation Guide (version 3.3 and subsequent update). Data coding 
is also mapped to the SDTM controlled terminology. Pinnacle 21 will be used to check 
compliance to the SDTM guidelines. Deviations from the guidelines will be documented. 
Detailed mapping specifications are documented in Define.xml and annotation CRFs. 
Table A contains a list of SDTM datasets to be created for the study. The corresponding 
supplemental datasets are not included. This set of SDTM datasets includes only data for the 
Randomized Treatment Period as described in Section 1. 
Table A. 
Study Data Tabulation Model Datasets (SDTM) 
 
SDTM 
Domain 
SDTM 
Domain 
Description 
SDTM Domain 
Structure 
General 
Observat 
ion Class 
Source 
Data Used 
Key Variables 
AE 
Adverse 
Events 
One record per adverse 
event per subject 
Events 
AE 
STUDYID, USUBJID, 
AESTDTC, AEDECOD, 
AESPID 
CM 
Concomitant 
Medications 
One record per recorded 
medication occurrence 
per subject 
Interventi 
ons 
CM, CMIPF 
STUDYID, USUBJID, 
CMCAT, CMSPID, 
CMTRT, CMSTDTC 
DD 
Death Details 
One record per subject 
Findings 
DTH 
STUDYID, USUBJID, 
DDTESTCD 
DM 
Demographics 
One record per subject 
Special 
Purpose 
Domains 
DM, EX, 
ICF, DTH, 
SITE_INV 
STUDYID, USUBJID 
DS 
Disposition 
One record per 
disposition status or 
protocol milestone per 
subject 
Events 
DS, ICF, 
DTH, EX 
STUDYID, USUBJID, 
DSSTDTC, DSDECOD, 
DSSPID, EPOCH 
DV 
Protocol 
Deviations 
One record per protocol 
deviations per subject 
Events 
DV 
STUDYID, USUBJID, 
DVTERM 
EC 
Exposure as 
Collected 
One record per protocol- 
specified study treatment 
per collected-dosing 
interval per subject 
Interventi 
ons 
EX 
STUDYID, USUBJID, 
ECTRT, ECSTDTC, 
ECGRPID 
EG 
ECG Test 
Results 
One record per ECG 
observation per visit per 
subject 
Findings 
EG 
STUDYID, USUBJID, 
EGTESTCD, VISITNUM 


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EX 
Exposure 
One record per constant 
dosing interval per 
subject 
Interventi 
ons 
EX 
STUDYID, USUBJID, 
EXTRT, EXSTDTC 
IE 
Inclusion/Excl 
usion Criteria 
Not Met 
One record per 
inclusion/exclusion 
criterion not met per 
subject 
Findings 
IE 
STUDYID, USUBJID, 
IETESTCD 
LB 
Laboratory 
Test Results 
One record per lab test 
per specimen per method 
per LOINC code per 
reason not done per visit 
per subject 
Findings 
eDT LB, 
RAND, 
LBC, 
LBPREG 
STUDYID, USUBJID, 
LBCAT, LBTESTCD, 
VISITNUM, LBMETHOD, 
LBREASND, 
LBLOINC 
MH 
Medical 
History 
One record per medical 
history event per time 
interval per subject 
Events 
MH 
STUDYID, USUBJID, 
MHSPID, MHDECOD, 
MHSTDTC, MHENDTC 
PC 
Pharmacokine 
tic 
Concentration 
s 
One record per time-point 
concentration or sample 
characteristic per analyte 
per subject 
Findings 
Source 
documents, 
PKC 
STUDYID, USUBJID, 
PCTESTCD, VISITNUM, 
PCTPTNUM 
PE 
Physical 
Examination 
One record per body 
system or abnormality 
per visit per subject 
Findings 
PE 
STUDYID, USUBJID, 
PETESTCD, VISITNUM 
PP 
Pharmacokine 
tic Parameters 
One record per PK 
parameter per time- 
concentration profile per 
modeling method per 
subject 
Findings 
Source 
documents 
STUDYID, USUBJID, 
PPTESTCD, PPCAT, 
VISITNUM, PPTPTREF 
PR 
Procedures 
One record per recorded 
procedure per occurrence 
per subject 
Interventi 
ons 
NDT, OU 
STUDYID, USUBJID, 
PRCAT, PRTRT, PRSPID 
QS 
Questionnaire 
s 
One record per question 
per questionnaire per visit 
per subject 
Findings 
SGRQ, 
UCSD 
STUDYID, USUBJID, 
QSTESTCD, VISITNUM 
SC 
Subject 
Characteristics 
One record per 
characteristic per subject 
Findings 
DM 
STUDYID, USUBJID, 
SCTESTCD 
SE 
Subject 
Elements 
One record per actual 
Element per subject 
Special 
Purpose 
Domains 
SDTM.DM, 
SDTM.EX, 
SDTM.DS, 
SDTM.SV 
STUDYID, USUBJID, 
TAETORD, SESTDTC 
SU 
Substance Use 
One record per substance 
type per subject 
Interventi 
on 
SUTOB 
STUDYID, USUBJID, 
SUTRT 


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SV 
Subject Visits 
One record per actual 
visit per subject 
Special 
Purpose 
Domains 
All datasets 
including 
visits 
STUDYID, USUBJID, 
VISITNUM 
TA 
Trial Arms 
One record per planned 
Element per Arm 
Trial 
Design 
N/A 
STUDYID, ARMCD, 
TAETORD 
TE 
Trial Elements 
One record per planned 
Element 
Trial 
Design 
N/A 
STUDYID, ETCD 
TI 
Trial 
Inclusion/Excl 
usion Criteria 
One record per I/E 
criterion per protocol 
criteria version 
Trial 
Design 
N/A 
STUDYID, TIVERS, 
IETESTCD 
TS 
Trial 
Summary 
One record per Trial 
Summary parameter per 
occurrence 
Trial 
Design 
N/A 
STUDYID, TSPARMCD, 
TSSEQ 
TV 
Trial Visits 
One record per planned 
Visit per Arm 
Trial 
Design 
N/A 
STUDYID, VISITNUM, 
ARMCD 
VS 
Vital Signs 
One record per vital sign 
measurement per time 
point per visit per subject 
Findings 
VS, SC 
STUDYID, USUBJID, 
VSTESTCD, VISITNUM, 
VSDTC 
 
 
2 Analysis Data Model (ADaM) 
The ADaM datasets are created based on the SDTM datasets following the ADaM 
Implementation Guide (version 1.0 and subsequent update). They include derived parameters 
and flags that are needed to generate tables/listings/figures. ADSL and ADAE are created using 
the specifications provided in the ADaMIG. Study endpoints are included in analysis files in 
ADaM Basic Data Structure (BDS). Horizontal analysis files are created for analyses on 
relationship of multiple endpoints. Variable names and labels of the horizontal files are from 
PARAMCD and PARAM of the corresponding BDS files. Detail derivations of each variable in 
the ADaM datasets are documented in the Metadata. 
Table B. 
Analysis Data Model (ADaM) 
 
Dataset 
Description 
Structure 
Keys 
ADSL 
Subject-Level Analysis 
Dataset 
One record per subject 
STUDYID SUBJID 
ADAE 
Analysis Dataset 
Adverse Events 
One record per subject per 
adverse event 
STUDYID SUBJID 
AESTDTC 
AETERM 
ADCM 
Analysis Dataset 
Concomitant 
Medications 
One record per subject per 
recorded medication 
STUDYID SUBJID 
CMCAT APERIOD 


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occurrence per start date of 
medication occurrence 
CMTRT CMSTDTC 
CMENDTC 
ADDD 
Analysis Dataset Death One record per subject per 
paramter 
STUDYID SUBJID 
PARAMCD 
ADEG 
Analysis Dataset for 
ECG Test Results 
One record per subject per 
visit 
STUDYID SUBJID 
AVISITN ADT 
ADEX 
Analysis Dataset 
Exposure 
One record per subject per 
parameter per visit 
STUDYID SUBJID 
PARAMCD 
AVISITN ASTDTM 
ADLB 
Analysis Dataset 
Laboratory Test 
Results 
One record per subject per 
parameter per visit 
STUDYID SUBJID 
PARAMCD 
AVISITN 
ADMH 
Analysis Dataset 
Medical History 
One record per subject per 
medical history per start 
date of medical history 
STUDYID SUBJID 
MHTERM 
MHSTDTC 
MHENDTC 
ADPC 
Analysis Dataset PK 
Concentrations 
One record per subject per 
visit per time point per 
parameter 
STUDYID SUBJID 
AVISITN ATPTN 
PARAMCD 
ADPE 
Analysis Dataset 
Physical Examination 
One record per subject per 
category per parameter per 
visit 
STUDYID SUBJID 
PARCAT1 
PARAMN AVISITN 
ADPP 
Analysis Dataset 
Pharmacokinetic 
Parameters 
One record per subject per 
parameter 
STUDYID SUBJID 
AVISITN 
PARAMCD 
ADQS 
Analysis Dataset for 
Questionnaire 
One record per subject per 
category per parameter per 
visit 
STUDYID SUBJID 
PARCAT1N 
PARAMCD 
AVISITN ADT 
ADTTE 
Analysis Dataset Time- 
to-Event 
One record per subject per 
period per parameter 
STUDYID SUBJID 
APERIOD AVAL 
PARAMCD 
ADVS 
Analysis Dataset Vital 
Signs 
One record per subject per 
parameter per visit per 
timepoint 
STUDYID SUBJID 
PARAMCD DTYPE 
VSSEQ AVISITN 
ATPTN 


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APPENDIX D FACT-AN (VERSION 4) 
The Functional Assessment of Cancer Therapy – General (FACT-G; version 4) contains 27 
items that cover four dimensions of well-being: physical (PWB) – 7 items, functional (FWB) 
– 7 items, social/family (SWB) – 7 items, and emotional (EWB) – 6 items. 
The ‘additional concerns’ section contains 20 items: 13 fatigue specific items plus 7 
additional items related to anemia were developed for use in conjunction with the FACT-G 
(Cella 1997). The 13 fatigue items plus the seven additional items related to anemia comprise 
the Anemia Subscale (AnS). Administration of the FACT-G plus the Anemia Subscale (AnS) 
is referred to as the FACT-An. The FACT-An has a recall period of the ‘past seven days’. 
Respondents are asked to provide responses, (i.e., ‘Not at all’, ‘A little bit’, ‘Somewhat’, 
‘Quite a bit’ and ‘Very much’), to a list of statements which are either positively or 
negatively phrased. A final higher score indicates better QoL. 
Each individual item is scored from 0 (Not at all) to 4 (Very much), and then the total score 
is obtained by summation of the resulted scores. 
If there are missing items, subscale scores can be standardized. This is done by multiplying 
the sum of the subscale by the number of items in the subscale, then dividing by the number 
of items actually answered. This can be done on the scoring guide or by using the formula 
below: 
Prorated subscale score = [Sum of item scores] x [N of items in subscale] / [N of items 
answered] 
When there are missing data, standardizing by subscale in this way is acceptable (Webster 
2003) as long as more than 50% of the items were answered (e.g., a minimum of 4 of 7 items, 
4 of 6 items, etc.). The total score is then calculated as the sum of the un-weighted subscale 
scores. The FACT scale is considered to be an acceptable indicator of a subject’s quality of 
life as long as overall item response rate is greater than 80% (e.g., at least 22 of 27 FACT-G 
items completed). This is not to be confused with individual subscale item response rate, 
which allows a subscale score to be prorated for missing items if greater than 50% of items 
are answered. In addition, a total score should only be calculated if ALL of the component 
subscales have available scores. 


FGCLV-e4e5v9a2-D09o2cument Number: FG-CLPLN-0032 
Version: 1.0 
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FG-CLPLN-0032 
 
 


FGCLV-e4e5v9a2-D09o2cument Number: FG-CLPLN-0032 
Version: 1.0 
Status: ApproveSdtatiAstipcpalroAvneadlyDsiastPel(aGnMT-8:00): 14 Jul 2021 
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FG-CLPLN-0032 
 
FACT-An (Version 4) 
 
 


FGCLV-e4e5v9a2-D09o2cument Number: FG-CLPLN-0032 
Version: 1.0 
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FG-CLPLN-0032 
 
FACT-An (Version 4) 
 
 


FGCLV-e4e5v9a2-D09o2cument Number: FG-CLPLN-0032 
Version: 1.0 
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FG-CLPLN-0032 
 
FACT-An Scoring Guidelines 
Instructions:* 1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a 
score. 
3. Multiply the sum of the item scores by the number of items in the 
subscale, then divide by the number of items answered. This 
produces the subscale score. 
4. Add subscale scores to derive total scores (TOI, FACT-G & FACT- 
An). 
5. The higher the score, the better the QOL. 
 
Subscale 
Item Code 
Reverse item? 
Item response 
Item Score 
 
 
PHYSICAL 
GP1 
4 
- 
  
 
=  
 
WELL-BEING 
GP2 
4 
- 
  
 
=  
 
(PWB) 
GP3 
4 
- 
  
 
=  
 
GP4 
4 
- 
  
 
=  
 
GP5 
4 
- 
  
 
=  
 
Score range: 0-28 
GP6 
4 
- 
  
 
=  
 
GP7 
4 
- 
  
 
=  
 
 
Sum individual item scores:   
 
Multiply by 7:   
 
Divide by number of items answered:   
 
=PWB subscale score 
 
 
SOCIAL/FAMILY 
GS1 
0 
+ 
  
 
=  
 
WELL-BEING 
GS2 
0 
+ 
  
 
=  
 
(SWB) 
GS3 
0 
+ 
  
 
=  
 
GS4 
0 
+ 
  
 
=  
 
GS5 
0 
+ 
  
 
=  
 
Score range: 0-28 
GS6 
0 
+ 
  
 
=  
 
GS7 
0 
+ 
  
 
=  
 
 
Sum individual item scores:   
 
Multiply by 7:   
 
Divide by number of items answered:   
 
=SWB subscale score 
 
 
EMOTIONAL 
GE1 
4 
- 
  
 
=  
 
WELL-BEING 
GE2 
0 
+ 
  
 
=  
 
(EWB) 
GE3 
4 
- 
  
 
=  
 
Score range: 0-24 
GE5 
GE4 
4 
4 
- 
- 
  
 
  
 
=  
 
=  
 
GE6 
4 
- 
  
 
=  
 


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Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
 
Sum individual item scores:   
 
Multiply by 6:   
 
Divide by number of items answered:   
 
=EWB subscale score 


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FG-CLPLN-0032 
FGCLV-e4e5v9a2-D09o2cument Number: FG-CLPLN-0032 
Version: 1.0 
Status: ApproveSdtatiAstipcpalroAvneadlyDsiastPel(aGnMT-8:00): 14 Jul 2021 
 
 
 
 
 
FUNCTIONAL 
GF1 
0 
+ 
= 
WELL-BEING 
GF2 
0 
+ 
 
=  
(FWB) 
GF3 
0 
+ 
= 
GF4 
0 
+ 
= 
GF5 
0 
+ 
= 
Score range: 0-28 
GF6 
0 
+ 
= 
 
GF7 
0 
+ 
 
= 
 
Sum individual item scores: 
Multiply by 7: 
Divide by number of items answered:   
 
=FWB subscale score 
 
 
 
Subscale 
Item Code 
Reverse item? 
Item response 
Item Score 
 
 
ANEMIA 
HI7 
4 
- 
= 
SUBSCALE 
HI12 
4 
- 
= 
(AnS) 
An1 
4 
- 
= 
An2 
4 
- 
= 
An3 
4 
- 
= 
Score range: 0-80 
An4 
4 
- 
 
= 
An5 
0 
+ 
 
= 
An6 
4 
- 
 
= 
An7 
0 
+ 
= 
An8 
4 
- 
= 
An9 
4 
- 
 
= 
An10 
4 
- 
 
= 
B1 
4 
- 
 
= 
An11 
4 
- 
= 
An12 
4 
- 
= 
BL4 
0 
+ 
= 
An13 
0 
+ 
= 
An14 
4 
- 
= 
An15 
4 
- 
 
= 
An16 
4 
- 
 
= 
 
Sum individual item scores:  
 
Multiply by 20: 
Divide by number of items answered:   
 
=An Subscale score 


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Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
FGCL-4592-092 
Statistical Analysis Plan 
 
 
To derive a FACT-An Trial Outcome Index (TOI): 
Score range: 0-136 
  
+ 
+ 
= 
=FACT-An TOI 
(PWB score) (FWB score) (AnS score) 
 
 
 
To Derive a FACT-G total score: 
Score range: 0-108 
  
+ 
+ 
+ 
= 
=FACT-G Total score 
(PWB score) (SWB score) (EWB score) (FWB score) 


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FG-CLPLN-0032 
FGCLV-e4e5v9a2-D09o2cument Number: FG-CLPLN-0032 
Version: 1.0 
Status: ApproveSdtatiAstipcpalroAvneadlyDsiastPel(aGnMT-8:00): 14 Jul 2021 
 
 
 
 
To Derive a FACT-An total score: 
Score range: 0-188 
  
+ 
+ 
+ 
+ 
= 
=FACT-An Total 
score 
(PWB score) (SWB score) (EWB score) (FWB score) (AnS score) 
 
 
*For guidelines on handling missing data and scoring options, please refer to the 
Administration and Scoring Guidelines in the manual or on-line at www.facit.org. 


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
 
 
 
 
FACIT-Fatigue Subscale Scoring Guidelines 
Instructions:* 1. Record answers in "item response" column. If missing, 
mark with an X 
2. Perform reversals as indicated, and sum individual items to 
obtain a score. 
3. Multiply the sum of the item scores by the number of items 
in the subscale, then divide by the number of items 
answered. This produces the subscale score. 
4. The higher the score, the better the QOL. 
 
Subscale 
Item Code 
Reverse item? 
Item 
response 
Item Score 
 
 
 
 
FATIGUE 
HI7 
4 
- 
  
 
= 
SUBSCALE 
HI12 
4 
- 
  
 
= 
An1 
4 
- 
  
 
= 
An2 
4 
- 
  
 
= 
Score range: 0-52 
An3 
4 
- 
  
 
= 
An4 
4 
- 
  
 
= 
An5 
0 
+ 
  
 
= 
An7 
0 
+ 
  
 
= 
An8 
4 
- 
  
 
= 
An12 
4 
- 
  
 
= 
An14 
4 
- 
  
 
= 
An15 
4 
- 
  
 
= 
An16 
4 
- 
  
 
= 
 
 
 
Sum individual item scores:  
 
Multiply by 
13:   
 
Divide by number of items 
answered:   
 
=Fatigue Subscale score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
English (Universal) 
Copyright 1987, 1997 
Confirm Current Version After Print Date: 14 Jul 2021 03:18PM GMT-07:00 
 
 
16 November 2007 


Veeva Document Number: FG-CLPLN-0032 
Version: 1.0 
Status: Approved Approved Date(GMT-8:00): 14 Jul 2021 
FG-CLPLN-0032 
 
14-Jul-2021 16:54:32 GMT+0000 
Approval Task 
Verdict: Approve 
14-Jul-2021 17:46:16 GMT+0000 
Approval Task 
Verdict: Approve 
Approval Task 
Verdict: Approve 
14-Jul-2021 21:42:32 GMT+0000 
Approval Task 
Verdict: Approve 
 
 
 
 
 
 
Document Approvals 
Approved Date(GMT-08:00): 14 Jul 2021 
 
 
Approval Task 
Verdict: Approve 
14-Jul-2021 17:02:52 GMT+0000 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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