Conditions: Gout
Keywords: Dotinurad Febuxostat
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 451
Healthy volunteers: no

Brief summary:
The primary purpose of the study is to confirm the efficacy of dotinurad 4 milligram (mg) to febuxostat 40 mg on the percentage of participants achieving a serum uric acid (SUA) level less than or equal to (\<=) 6.0 milligrams per deciliter (mg/dL) at Week 24 in Chinese participants with gout.

Detailed description:

Arms:
arm 1: Participants will receive one dotinurad 1 mg tablet and one febuxostat 20 mg matched placebo tablet, orally, once daily on Day 1 to Day 28 (up to 4 weeks) in Treatment 1 Phase; and then one dotinurad 2 mg tablet and two febuxostat 20 mg matched placebo tablets, orally, once daily on Day 29 to Day 84 (up to 8 weeks) followed by two dotinurad 2 mg tablets and two febuxostat 20 mg matched placebo tablets, orally, once daily on Day 85 to Day 168 (up to 12 weeks) in Treatment 2 Phase (Treatment 1 Phase=4 weeks; Treatment 2 Phase=20 weeks). arm 2: Participants will receive one febuxostat 20 mg tablet and one dotinurad 1 mg matched placebo tablet, orally, once daily on Day 1 to Day 28 (up to 4 weeks) in Treatment 1 Phase; and then two febuxostat 20 mg tablets and one dotinurad 2 mg matched placebo tablet, orally, once daily on Day 29 to Day 84 (up to 8 weeks) followed by two febuxostat 20 mg tablets and two dotinurad 2 mg matched placebo tablets, orally, once daily on Day 85 to Day 168 (up to 12 weeks) in Treatment 2 Phase (Treatment 1 Phase=4 weeks; Treatment 2 Phase=20 weeks).

Interventions: intervention 1: Dotinurad intervention 2: Febuxostat intervention 3: Dotinurad Matched Placebo intervention 4: Febuxostat Matched Placebo
Intervention descriptions: intervention 1: Dotinurad oral tablets. intervention 2: Febuxostat oral tablets. intervention 3: Dotinurad matched placebo oral tablets. intervention 4: Febuxostat matched placebo oral tablets.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
FYU-981-J086-301
Study Protocol Title:
A Randomized, Multicenter, Double-Blind, Superiority Study 
of Dotinurad (4 mg) and Febuxostat (40 mg) for the Treatment 
of Subjects With Gout
Sponsor:
Eisai Co., Ltd.
4-6-10 Koishikawa, Bunkyo-Ku, Tokyo 112 8088, Japan
Applicant
FUJI YAKUHIN CO., LTD.
4-383 Sakuragi-Cho, Omiya-Ku, Saitama-Shi, Saitama
330 9508, Japan
Sponsor’s 
Investigational Product 
Name:
FYU-981/dotinurad
Indication:
Gout
Phase:
3
Approval Date:
V1.0
23 Dec 2020 (Original Protocol)
V2.0
V3.0
03 Mar 2021 (Amendment 01)
07 Jul 2021 (Amendment 02)
GCP Statement:
This study is to be performed in full compliance with China 
Good Clinical Practice (C-GCP) and all applicable regulations.  
All required study documentation will be archived as required 
by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary 
information of Eisai (the sponsor).  Any viewing or disclosure 
of such information that is not authorized in writing by the 
sponsor is strictly prohibited.  Such information may be used 
solely for the purpose of reviewing or performing this study.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No. FYU-981
Name of Active Ingredient:  Dotinurad
Study Protocol Title
A Randomized, Multicenter, Double-Blind, Superiority Study of Dotinurad (4 mg) and Febuxostat 
(40 mg) for the Treatment of Subjects With Gout
Sites
Approximately 30 sites
Study Period and Phase of Development
Approximately 21 months from first subject enrolled to last subject’s last visit/last assessment.
Phase 3
Objectives
Primary Objective
To confirm the superiority of dotinurad 4 mg to febuxostat 40 mg on the proportion of subjects 
achieving a serum uric acid (SUA) level ≤6.0 mg/dL at Week 24 in Chinese subjects with gout.
Secondary Objectives

To confirm the non-inferiority of dotinurad 2 mg to febuxostat 40 mg on the proportion of 
subjects achieving a SUA level ≤6.0 mg/dL at Week 12 in Chinese subjects with gout

To compare the proportion of subjects achieving a SUA level ≤6.0 mg/dL at each time point 
between treatment groups

To compare the percent reduction in SUA level from baseline at each time point between 
treatment groups

To compare the change in SUA level from baseline at each time point between treatment groups

To compare the SUA level at each time point between treatment groups

To evaluate the safety and tolerability of dotinurad


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Study Design
FYU-981-J086-301 is a multicenter, randomized, double-blind, superiority, parallel-group study 
designed to confirm if the efficacy of dotinurad (4 mg/day) is superior to febuxostat (40 mg/day) in 
Chinese subjects 18 years or older in gout.  Approximately 450 subjects will be randomized to 
treatment groups in a ratio of 1:1 and will receive dotinurad 1 mg/day for the first 4 weeks, 2 mg/day 
for 8 weeks, and 4 mg/day for 12 weeks; or febuxostat 20 mg/day for the first 4 weeks, and 
40 mg/day for 20 weeks.  In addition, the randomization will be stratified by SUA level category (<9; 
9 to <10; 10 to <11; ≥11 mg/dL) and body mass index (BMI) category (<25; ≥25 kg/m2).
The study has 3 phases: Screening Phase (4 to 28 days), Treatment I Phase (4 weeks), and Treatment 
II Phase (20 weeks).
Screening Phase
Screening Phase begins no more than 28 days, and no less than 4 days before the subject is 
randomized.  During this period, informed consent will be obtained, and the subject’s eligibility will 
be assessed.
Treatment I Phase
On Day 0 of the Treatment I Phase, subjects who meet all the inclusion criteria and none of the 
exclusion criteria will be randomized to 1 of 2 treatment groups (dotinurad or febuxostat).
From Day 1 of the Treatment I Phase, subjects will receive dotinurad 1 mg/day or febuxostat 
20 mg/day once daily for 4 weeks.
Treatment II Phase
During the Treatment II Phase, subjects in the dotinurad group will take dotinurad 2 mg/day once 
daily for 8 weeks initially and 4 mg/day once daily for 12 weeks.  Subjects in the febuxostat group 
will take febuxostat 40 mg/day once daily for 20 weeks.
Number of Subjects
Approximately 650 subjects will be screened to provide 450 randomized subjects.
Inclusion Criteria
1.
Gouta patient (with a history of gout attack or concurrent gouty tophi) with SUA level 
>7.0 mg/dL in the Screening Phase (within 14 days prior to randomization)
a:  Met 2015 ACR/EULAR gout classification criteria
2.
Male or female, age ≥18 years at the time of informed consent
3.
Provided written informed consent signed by the subject prior to entering the study or undergoing 
any study procedures, indicating that they understand the purpose and procedures required for the 
study and are willing to participate in the study.


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Exclusion Criteria
1.
Females who are breastfeeding or pregnant at screening (as documented by a positive beta-
human chorionic gonadotropin [β-hCG] test)
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive (Subject must have been on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and must agree to stay on the 
same dose of the oral contraceptive throughout the study and for 28 days after study 
drug discontinuation.)
o
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
It is permissible that if a highly effective method of contraception is not appropriate or acceptable 
to the subject, then the subject must agree to use a medically acceptable method of contraception, 
ie, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or 
cervical/vault cap with spermicide.
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing).
3.
Patient with gouty arthritis that has not resolved within 14 days prior to randomization
4.
Any history of a medical or psychiatric condition that, in the opinion of the investigator, may 
have affected the subject’s safety or interfered with the study assessments
5.
Currently has secondary hyperuricemia:
1) Lesch-Nyhan syndrome
2) Phosphoribosylpyrophosphate synthetase superactivity
3) Congenital myogenic hyperuricemia
4) Hematopoietic neoplasms (acute leukemia, lymphoma malignant, myeloproliferative disorder,
myelodysplastic syndrome, etc)
5) Solid tumors (breast cancer, seminoma, sarcoma, Wilms tumor, small cell lung cancer, etc)
6) Non-neoplastic diseases (psoriasis vulgaris, secondary polycythemia, hemolytic anemia)
7) Rhabdomyolysis
8) Hypothyroidism
9) Polycystic kidney
10) Lead poisoning/lead nephropathy
11) Down’s syndrome
12) Familial juvenile gouty nephropathy
13) Hyperlactacidemia
14) Glycogen storage disease type 1


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6.
A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated 12-lead 
electrocardiogram (ECG)
7.
Prohibited concomitant drugs within 14 days prior to screening and during the study
8.
Changing the dosage and/or administration, or initiating any restricted concomitant drugs within 
14 days prior to screening and during the study
9.
Have been routinely receiving non-steroidal anti-inflammatory drugs (NSAIDs) or 
corticosteroids (not including topical application) for a disease other than gouty arthritis
10. Comorbidities with nephrolithiasis or clinical urinary calculi (eg, haematuria, back pain)
11. Evidence of clinically significant disease (eg, cardiac disease:  heart failure and angina unstable, 
respiratory, gastrointestinal, renal, or neurological disease:  cerebral infarction) that in the 
opinion of the investigator(s) could affect the subject’s safety or interfere with the study 
assessments
12. Relevant history of cardiac (eg, myocardial infarction or angina attacks) or neurologic disease 
(eg, cerebral infarction) within 1 year prior to screening
13. Current presence of active gastrointestinal ulcer disease, or history of active gastrointestinal ulcer 
disease within 1 year prior to screening
14. Evidence of clinical significant hepatic disease:  refer to Grade 2 in the “Seriousness Grading 
Criteria for Adverse Drug Reactions” or AST (GOT) or ALT (GPT) >3× upper limit of normal 
(ULN) in the Screening Phase
15. Estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 in the Screening Phase
16. Systolic blood pressure of ≥180 mmHg or diastolic blood pressure of ≥110 mmHg in the 
Screening Phase
17. HbA1c (NGSP value) of ≥8.4% in the Screening Phase
18. Current presence or history of neoplasm malignant in the 5 years prior to screening
19. Hypersensitivity to the study drugs (dotinurad or febuxostat) or their excipients, or all of urine 
alkalinizer (potassium citrate/sodium citrate hydrate compound preparations, et al)  
20. Any history of or concomitant medical condition that in the opinion of the investigator(s) would 
compromise the subject’s ability to safely complete the study
21. Scheduled for surgery during the study
22. Known to be human immunodeficiency virus (HIV) positive
23. Active viral hepatitis (B or C) as demonstrated by positive serology
24. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive or had a close contact 
with SARS-CoV-2 positive patient in the Screening Phase
25. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active 
treatment, including the use of oxygen
26. Use of illegal recreational drugs
27. History of drug or alcohol dependency or abuse within approximately 2 years prior to screening
28. Currently enrolled in another clinical study or used any investigational drug or device within 
28 days or 5× the half-life, whichever is longer, preceding informed consent


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Study Treatments
Dose Levels
Treatment I Phase
(4 weeks)
Treatment II Phase 
(20 weeks)
Day 1 to Day 28
Day 29 to Day 84 
(8 weeks)
Day 85 to Day 168 
(12 weeks)
Test 
treatment
One dotinurad 1 mg tablet 
and
one febuxostat 20 mg-matched 
placebo tablet
One dotinurad 2 mg tablet 
and 
two febuxostat 20 mg-matched 
placebo tablets
Two dotinurad 2 mg tablets 
and 
two febuxostat 20 mg-matched 
placebo tablets
Comparator 
treatment
One febuxostat 20 mg tablet
and 
one dotinurad 1 mg-matched 
placebo tablet
Two febuxostat 20 mg tablets
and 
one dotinurad 2 mg-matched 
placebo tablet
Two febuxostat 20 mg tablets
and 
two dotinurad 2 mg-matched 
placebo tablets
Formulation
Dotinurad will be supplied as 1 and 2 mg tablets; febuxostat-placebo will be supplied as 20 mg-
matched tablet.
Febuxostat will be supplied as 20 mg tablet; dotinurad-placebo will be supplied as 1 and 2 mg-
matched tablets.
Mode of Administration
The study drug will be administered orally once daily at approximately the same time each day.
Duration of Treatment
Twenty-four weeks:  4 weeks of Treatment I Phase, and 20 weeks of Treatment II Phase.
Concomitant Drug/Therapy
Prohibited Concomitant Drug and Therapy
Following drugs are prohibited within 14 days prior to screening and during the study.
1.
Drugs to treat gout and hyperuricemia
1) Uricosuric drugs (probenecid, bucolome, benzbromarone)
2) Uric acid production-inhibitory drugs (allopurinol, febuxostat [except the investigational 
product])
3) Prophylaxis for gout flare (that includes colchicine, NSAIDs, corticosteroids, et al; and does 
not include topical application)
2.
Drugs that affect the SUA level
1) Salicylic acid-based antipyretics and analgesics (except aspirin taken to control 
thromboembolism formation, and salicylamide)
3.
Drugs that potentially interact with the test drug
1) Mercaptopurine hydrate
2) Azathioprine
3) Vidarabine
4) Hexamine


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If a medication (including in Chinese traditional medicine) is not on the list of prohibited medications 
but in the opinion of the investigator, which also can be used to treat gout/hyperuricemia, it must not 
be used throughout the study.  If a medication is not specified as prohibited but is in the same class as 
a medication that is listed in the protocol, and if the investigator is uncertain, the Medical Monitor 
must be consulted.  If a subject starts any prohibited medication or therapy during the study, he/she 
must discontinue from the study, with the exception that certain prohibited medications must be used 
to particular condition if this is agreed with the Medical Monitor.
Restricted Concomitant Drug and Therapy
Subjects who are on the following treatment are required to be on a stable dose and same mode of 
administration for at least 14 days prior to screening and to keep the stable during the study. Subjects 
are not permitted to initiate these drugs within 14 days prior to screening and during the study.
1.
Dietary and physical therapy for the underlying disease
2.
Drugs or containing compound preparations that potentially affect SUA level
1) Immunosuppressants (mizoribine, cyclosporin, tacrolimus hydrate)
2) Antituberculous drugs (pyrazinamide, ethambutol hydrochloride)
3) Hyperlipidemia drugs (fenofibrate, atorvastatin, rosuvastatin, pitavastatin)
4) Antihypertensives (losartan potassium)
5) Diuretics (thiazide diuretics, loop diuretics)
6) Sodium-dependent glucose transporter (SGLT) 2 inhibitors
7) Niacin formulations (niacin, niacinamide, tocopherol nicotinate)
8) Theophylline
9) Aspirin (for controlling thromboembolism formation)
Assessments
Efficacy Assessment
SUA level.
Pharmacokinetic Assessments
Not applicable.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Not applicable.
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs), and serious 
adverse events (SAEs); withdrawal from treatment; laboratory evaluation for hematology, blood 
chemistry, and urine values; periodic measurement of vital signs and ECGs; and the performance of 
physical examinations.
Other Assessments
Not applicable.
Bioanalytical Methods
Not applicable.


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Statistical Methods
Study Endpoints
Primary Endpoint
Proportion of subjects with ≤6.0 mg/dL in SUA level at Week 24 (LOCF)
Secondary Endpoints

Proportion of subjects with ≤6.0 mg/dL in SUA level at Week 12 (LOCF)

Proportion of subjects with ≤6.0 mg/dL in SUA level at each time point

Mean percent reduction from baseline in SUA level at each time point

Mean change from baseline in SUA level at each time point

Mean SUA level at each time point
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 dose of 
study drug and had at least 1 postdose primary efficacy measurement (ie, SUA level).

The Per Protocol (PP) Analysis Set is the group of subjects who sufficiently complied with the 
protocol.  Details of the evaluability criteria will be determined before database lock and 
treatment unblinding and will be specified in the statistical analysis plan (SAP).
Efficacy Analyses
The FAS will be used as a primary analysis set for the efficacy analyses.
Primary Efficacy Analysis
The analysis for the difference in the proportion of subjects with ≤6.0 mg/dL in SUA level (ie, 
responder rate) at Week 24 (LOCF) between dotinurad 4 mg and febuxostat 40 mg will be conducted 
based on a Cochran–Mantel–Haenszel (CMH) test stratified by baseline SUA level and baseline 
BMI.  The statistical test will be two-sided at the 5% significance level.
The same primary efficacy analysis mentioned above will be repeated based on the PP Analysis Set 
as a sensitivity analysis.
Secondary Efficacy Analyses
For all the secondary efficacy analyses, no multiplicity adjustment will be made.
The difference in the responder rate at Week 12 (LOCF) between dotinurad 2 mg and febuxostat 
40 mg and the 95% confidence interval will be estimated based on Mantel–Haenszel method 
adjusting for the baseline SUA level and baseline BMI.  The prespecified non-inferiority margin will 
be –10% in this analysis, which will be for the reference purpose only.
The proportion of subjects with ≤6.0 mg/dL in SUA level at each time point will be summarized.
The mean percent reduction from baseline in SUA level at each time point will be summarized using 
descriptive summary statistics (eg, n, mean, SD, median, minimum, maximum), estimated based on 
the longitudinal data analysis (LDA) model and presented in figures.  The detail of the LDA model 
will be specified in the SAP.
The mean actual value and the mean change from baseline in SUA level at each time point will be 
summarized using descriptive summary statistics.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Not applicable.


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Pharmacokinetic Analyses
Not applicable.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Not applicable.
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs, out of 
normal range laboratory safety test variables, abnormal ECG findings, out-of-normal range vital 
signs and weight, along with change from baseline in laboratory safety test variables, ECGs, and vital 
signs and weight measurements, will be summarized by treatment group using descriptive statistics.
Interim Analyses
Not applicable.
Sample Size Rationale
For the responder rate, assuming a rate of 45% for febuxostat 40 mg and 60% for dotinurad 4 mg, a 
sample size of 225 subjects in each group will provide approximately 90% power to detect a 
between-group difference in the proportion of responders based on a two-group Chi-square test with 
a 0.05 two-sided significance level.  The primary efficacy analysis will be based on the FAS.  Hence, 
450 subjects will be the target number of subjects as the FAS.


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TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................10
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................15
5
ETHICS.......................................................................................................................18
5.1
Institutional Review Boards/Independent Ethics Committees.............................18
5.2
Ethical Conduct of the Study..............................................................................18
5.3
Subject Information and Informed Consent ........................................................18
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................20
7
INTRODUCTION.......................................................................................................21
7.1
Compound Overview .........................................................................................21
7.1.1
Gout.........................................................................................................21
7.1.1.1
Current Treatment and Unmet Medical Needs ..................................21
7.1.2
Dotinurad .................................................................................................22
7.2
Clinical Experience............................................................................................22
7.3
Study Rationale..................................................................................................22
7.3.1
Targeting Population ................................................................................22
7.3.2
Primary Endpoint .....................................................................................22
7.3.3
Study Duration .........................................................................................23
7.3.4
Dose of Dotinurad ....................................................................................23
7.3.5
Choice of Comparator Drug......................................................................24
7.3.6
Mode of Administration ...........................................................................24
8
STUDY OBJECTIVES................................................................................................25
8.1
Primary Objective ..............................................................................................25
8.2
Secondary Objectives.........................................................................................25
9
INVESTIGATIONAL PLAN ......................................................................................26
9.1
Overall Study Design and Plan...........................................................................26
9.1.1
Screening Phase .......................................................................................26
9.1.2
Treatment I Phase.....................................................................................27
9.1.3
Treatment II Phase....................................................................................27
9.2
Discussion of Study Design, Including Choice of Control Groups......................27
9.3
Selection of Study Population ............................................................................28
9.3.1
Inclusion Criteria......................................................................................28
9.3.2
Exclusion Criteria.....................................................................................28
9.3.3
Removal of Subjects From Therapy or Assessment ..................................30
9.4
Treatments.........................................................................................................30


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9.4.1
Treatments Administered..........................................................................30
9.4.2
Identity of Investigational Products ..........................................................31
9.4.2.1
Chemical Name of Dotinurad ...........................................................31
9.4.2.2
Comparator Drug..............................................................................32
9.4.2.3
Labeling for Study Drug ...................................................................32
9.4.2.4
Storage Conditions ...........................................................................32
9.4.3
Method of Assigning Subjects to Treatment Groups.................................32
9.4.4
Selection of Doses in the Study ................................................................33
9.4.5
Selection and Timing of Dose for Each Subject........................................33
9.4.6
Blinding ...................................................................................................33
9.4.7
Prior and Concomitant Therapy................................................................33
9.4.7.1
Prohibited Concomitant Drug and Therapy.......................................34
9.4.7.2
Restricted Concomitant Drug and Therapy........................................34
9.4.7.3
Urinary Tract Management...............................................................35
9.4.7.4
Gouty Arthritis Treatment.................................................................35
9.4.8
Treatment Compliance .............................................................................36
9.4.9
General Precautions..................................................................................36
9.4.10
Drug Supplies and Accountability ............................................................37
9.5
Study Assessments.............................................................................................37
9.5.1
Assessments .............................................................................................37
9.5.1.1
Screening Assessments.....................................................................37
9.5.1.1.1
Demography ...............................................................................37
9.5.1.1.2
Medical History ..........................................................................37
9.5.1.1.3
Classification of Hyperuricemia..................................................38
9.5.1.1.4
Estimated Glomerular Filtration Rate (eGFR) .............................39
9.5.1.1.5
Other Characteristics of Gout/Hyperuricemia..............................39
9.5.1.1.6
Alcohol Consumption Status.......................................................39
9.5.1.1.7
Height.........................................................................................39
9.5.1.1.8
Viral Screening ...........................................................................39
9.5.1.2
Efficacy Assessments .......................................................................40
9.5.1.2.1
Serum Uric Acid Level ...............................................................40
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker...............................................................................40
9.5.1.4
Safety Assessments...........................................................................40
9.5.1.4.1
Adverse Events...........................................................................41
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................43
9.5.1.4.3
Study-Specific Adverse Events ...................................................43


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9.5.1.4.4
Laboratory Measurements...........................................................44
9.5.1.4.5
Vital Signs and Weight Measurements........................................45
9.5.1.4.6
Physical Examinations ................................................................45
9.5.1.4.7
Electrocardiograms .....................................................................45
9.5.1.4.8
Other Safety Assessments ...........................................................45
9.5.2
Schedule of Procedures/Assessments........................................................46
9.5.2.1
Schedule of Procedures/Assessments................................................46
9.5.3
Appropriateness of Measurements............................................................50
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................50
9.5.4.1
Reporting of Serious Adverse Events................................................50
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................51
9.5.4.3
Reporting of Events Associated with Special Situations....................51
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................51
9.5.4.3.2
Reporting of Abnormal Hepatic Tests of Clinical Interest ...........52
9.5.4.4
Expedited Reporting .........................................................................52
9.5.4.5
Breaking the Blind............................................................................52
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................53
9.5.5
Completion/Discontinuation of Subjects...................................................53
9.5.6
Abuse or Diversion of Study Drug............................................................54
9.5.7
Confirmation of Medical Care by Another Physician................................54
9.6
Data Quality Assurance......................................................................................55
9.6.1
Data Collection.........................................................................................55
9.6.2
Clinical Data Management .......................................................................55
9.7
Statistical Methods.............................................................................................55
9.7.1
Statistical and Analytical Plans.................................................................55
9.7.1.1
Study Endpoints................................................................................56
9.7.1.1.1
Primary Endpoint........................................................................56
9.7.1.1.2
Secondary Endpoints...................................................................56
9.7.1.2
Definitions of Analysis Sets..............................................................56
9.7.1.3
Subject Disposition...........................................................................56
9.7.1.4
Demographic and Other Baseline Characteristics..............................56
9.7.1.5
Prior and Concomitant Therapy ........................................................57
9.7.1.6
Efficacy Analyses.............................................................................57
9.7.1.6.1
Primary Efficacy Analysis...........................................................57
9.7.1.6.2
Secondary Efficacy Analyses......................................................58


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9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................58
9.7.1.8
Safety Analyses ................................................................................58
9.7.1.8.1
Extent of Exposure......................................................................58
9.7.1.8.2
Adverse Events...........................................................................58
9.7.1.8.3
Laboratory Values.......................................................................59
9.7.1.8.4
Vital Signs and Weight ...............................................................60
9.7.1.8.5
Electrocardiograms .....................................................................60
9.7.1.8.6
Other Safety Analyses.................................................................61
9.7.2
Determination of Sample Size ..................................................................61
9.7.3
Interim Analysis.......................................................................................61
9.7.4
Other Statistical/Analytical Issues ............................................................61
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................61
10
REFERENCE LIST.....................................................................................................62
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......64
11.1
Changes to the Protocol......................................................................................64
11.2
Adherence to the Protocol..................................................................................64
11.3
Monitoring Procedures.......................................................................................64
11.4
Recording of Data..............................................................................................65
11.5
Identification of Source Data..............................................................................65
11.6
Retention of Records..........................................................................................65
11.7
Auditing Procedures and Inspection ...................................................................66
11.8
Handling of Study Drug .....................................................................................66
11.9
Publication of Results ........................................................................................66
11.10 Disclosure and Confidentiality ...........................................................................67
11.11 Discontinuation of Study....................................................................................67
11.12 Subject Insurance and Indemnity........................................................................67
12
APPENDICES.............................................................................................................68
LIST OF IN-TEXT TABLES
Table 1
Treatments Administered........................................................................31
Table 2
Clinical Laboratory Tests........................................................................44
Table 3
Schedule of Procedures/Assessments in Study FYU-981-J086-301.........47
LIST OF IN-TEXT FIGURES
Figure 1
Overview of Study Design......................................................................26


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LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................69
Appendix 2
The ACR/EULAR Gout Classification Criteria (Neogi, et al., 2015).......72


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ACR
American College of Rheumatology
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
AMG
alpha 1-microglobulin
AST
aspartate aminotransferase
BMG
beta 2-microglobulin
BMI
body mass index
BP
blood pressure
C-GCP
China Good Clinical Practice
CHD
coronary heart disease
CHMP
Committee for Medicinal Products for Human Use
CMH
Cochran–Mantel–Haenszel
CRA
clinical research associate/ Chinese Rheumatology Association
CRF
case report form
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CVD
cardiovascular disease
CYP
cytochrome P450
DECT
dual-energy computed tomography
ECG
electrocardiogram
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
early termination
EULAR
European League Against Rheumatology
FAS
Full Analysis Set
FEUA
fractional excretion of urate clearance


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Abbreviation
Term
FT3
free triiodothyronine
FT4
free thyroxine
GCP
Good Clinical Practice
GOT
glutamic oxaloacetic transaminase
GPT
glutamic pyruvic transaminase
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high density lipoprotein
HIV
human immunodeficiency virus
ICF
informed consent form
ID
identification
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IRB
Institutional Review Board
IUS
intrauterine hormone-releasing system
IxRS
interactive voice and web response system
KDIGO
Kidney Disease: Improving Global Outcomes
KOL
key opinion leader
LDA
longitudinal data analysis
LDL
low density lipoprotein
LLN
lower limit of normal
LLT
lower level term
LNH
low/normal/high
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MOA
mode of action
MSU
monosodium urate monohydrate
NAG
N-acetyl-β-D-glucosaminidase


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Abbreviation
Term
NGSP
National Glycohemoglobin Standardization Program
NSAID
non-steroidal anti-inflammatory drug
PP
Per Protocol
PT
preferred term
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
SD
standard deviation
SGLT
sodium-dependent glucose transporter
SI
Système International
SOC
system organ class
SOP
standard operating procedure
SUA
serum uric acid
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory value
TSH
thyroid stimulating hormone
TT3
total triiodothyronine
TT4
total thyroxine
ULN
upper limit of normal
ULT
urate lowering treatment
URAT1
urate transporter 1
UUE
urinary urate excretion
WBC
white blood cell
WHO DD
World Health Organization Drug Dictionary


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with China Good Clinical 
Practice (C-GCP), and any local regulations.  Any protocol amendment or revision to the ICF 
will be resubmitted to the IRB/IEC for review and approval, except for changes involving 
only logistical or administrative aspects of the study (eg, change in clinical research 
associates [CRAs], change of telephone number[s]).  Documentation of IRB/IEC compliance 
with C-GCP and any local regulations regarding constitution and review conduct will be 
provided to the sponsor.
Documented study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee.  If the IRB/IEC decides to suspend or terminate the 
study, the investigator will immediately send the notice of study suspension or termination by 
the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per applicable 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice 
(GCP) guidelines as required by the following:

Principles of the World Medical Association Declaration of Helsinki

C-GCP

Other applicable local regulations
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator (or designee) must 
explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s) or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records as well as contact information 


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(phone number[s] of investigational site and name[s] of contact person).  Each subject must 
be informed that participation in the study is voluntary, that he/she may withdraw from the 
study at any time, and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at screening 
before any study-specific procedures are performed.  No subject can enter the study before 
his/her informed consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with C-
GCP, and all applicable local regulations.  Each subject must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The 
original, signed ICF for each subject will be verified by the sponsor (or designee) and kept 
on file according to local procedures at the site.
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.


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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 investigational sites in China.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organizations (CROs) are listed in the Investigator 
Study File provided to each site.


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7
INTRODUCTION
7.1
Compound Overview
7.1.1
Gout
Gout is caused by hyperuricemia which is defined as a serum uric acid (SUA) concentration 
greater than 7.0 mg/dL.  At SUA levels greater than 7.0 mg/dL, uric acid crystals can 
precipitate out of solution and deposit in joints and other body tissues where they can 
produce an inflammatory response.
In China, there has been a continuing increase in gout patients in the recent years due to 
changing of dietary behavior, the prolongation of life span and the continuous improvement 
of health care. The prevalence of gout in China has been increasing rapidly during the past 
years (Multi-Disciplinary Expert Task Force on Hyperuricemia and Its Related Diseases, 
2017).  From meta analysis, the prevalence of gout is about 1.1% (Liu, et al., 2015).  Gout 
has become the most common arthritis related to rheumatic disease of adult.  Gout is 
generally thought as an independent risk factor for chronic kidney disease, hypertension, 
coronary heart disease (CHD), cardiovascular disease (CVD) and type 2 diabetes; and an 
independent predictor factor for premature death (Bardin and Richett, 2017).  Gout stone can 
cause the joint deformity, gouty nephropathy, disability, even the death.
Management of hyperuricemia at an appropriate level is important for preventing acute gouty 
arthritis, gouty kidney, and urinary calculi.  In addition, it may protect renal function, and 
reduce the risks of cardiovascular disorders (Siu, et al., 2006; Athyros, et al., 2004).  Based 
on the findings above, it is thought that urate lowering treatment (ULT) will become much 
more important in the future.
7.1.1.1
Current Treatment and Unmet Medical Needs
The etiology of hyperuricemia includes excessive production of uric acid, decreased 
excretion of uric acid, and the combined type. Approximately 90% of hyperuricemia is the 
uric acid decreased excretion type and the combined type in China (Chen, 2006).
The basic principle of selecting drug is based on classification of hyperuricemia. The 
xanthine oxidase inhibitor allopurinol has been used as a uric acid production inhibitor for 
many years; febuxostat is marketed later, and has been increasingly prescribed in recent 
years, but hepatic dysfunction, the incidence of cardiovascular death and all-cause mortality 
was reported to be high.  Benzbromarone is the main uricosuric drug, but it can cause serious 
hepatic disorders (Van der Klauw, et al., 1994). It also has a potent inhibitory effect on the 
drug metabolizing enzyme cytochrome P450 (CYP), particularly on CYP2C9 (Kunishima, et 
al., 2003; Locuson, et al., 2003). So a potent, well-tolerated, and selective uricosuric drug 
without causing hepatic impairment, and less drug-drug interaction is needed in clinical 
practice.


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7.1.2
Dotinurad
Fuji Yakuhin Co., Ltd. has conducted an intensive investigation on a novel uricosuric drug, 
and discovered dotinurad, which has a superior uricosuric effect derived from potent 
suppression of uric acid reabsorption.
Dotinurad reduces SUA levels by selectively inhibiting urate transporter 1 (URAT1), which 
is expressed on the proximal renal tubules and is responsible for reabsorption of uric acid.
7.2
Clinical Experience
The efficacy and safety of dotinurad were demonstrated in nonclinical studies and clinical 
studies. A total of 17 clinical studies for dotinurad were conducted in Japan, and dotinurad 
was approved for hyperuricemia and gout in Japan in January 2020.  As for details on the 
results of these clinical studies for dotinurad, refer to the Investigator's Brochure.
7.3
Study Rationale
7.3.1
Targeting Population
For every gout patient, ULT should be considered and discussed.  Appropriate ULT reduces 
the frequency of gout flare and avoids their reoccurrence.  In addition, effective ULT reduces 
the size and number of tophi, therefor improving the quality of life of patients with gout.  
And it may protect renal function, and reduce the risks of cardiovascular disorders.  So, ULT 
is recommended by the guidelines of ACR (American College of Rheumatology), EULAR 
(European League Against Rheumatology) and CRA (Chinese Rheumatology Association).  
Gout patients with SUA >7 mg/dL and a history of gout attack or concurrent gout tophi will 
be enrolled.
7.3.2
Primary Endpoint
The target SUA level of ≤6 mg/dL is appropriate for the most of gout patients from the 
guideline.  It is believed that SUA level ≤6 mg/dL allows dissolution of the crystals of urate, 
and maintain ≤6 mg/dL also can avoid new formation of urate crystals.  European Medicines 
Agency (EMA) paper on guideline on clinical investigation of medicinal products for the 
treatment of gout (EMA/CHMP/774470/2018) suggests: for confirmatory trials, the primary 
endpoint should be defined as sustained SUA levels below a target level of 6 mg/dL, for a 
period of 3 consecutive months, which starts once the treatment is optimized and stable.  And 
guideline for the diagnosis and management of hyperuricemia and gout in China (2019) also 
suggests to modify the dose based on patient’s SUA level for achieving the target of SUA 
≤6 mg/dL (Chinese Society of Endocrinology, Chinese Medical Association, 2020).  
Therefore, the proportion of subjects achieving a SUA level ≤6.0 mg/dL was selected for 
primary endpoint.


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7.3.3
Study Duration
Treatment I Phase of 4 weeks is selected to prevent the risk of gouty arthritis caused by a 
rapid decrease in the SUA level.  The duration is based on Japan Phase 3 studies.
Eight-week duration of dotinurad 2 mg/day in Treatment II Phase is based on FYU-981-014 
study, which was a Phase 3 study conducted in Japan.  In FYU-981-014 study, the duration 
of 2 mg/day was 8 weeks.  And it is sufficiently long for this duration to assess non-
inferiority of dotinurad 2 mg and febuxostat 40 mg in Chinese patients.  That allows us to 
compare Chinese data and Japanese data as necessary.
Twelve-week duration of dotinurad 4 mg/day in Treatment II Phase is based on EMA paper 
on guideline on clinical investigation of medicinal products for the treatment of gout 
(EMA/CHMP/774470/2018).  According to this guideline, the pivotal trials should be 
sufficiently long to establish a sustained effect of urate lowering for at least 3 months, once 
the treatment is optimized at a stable dose level.  So in this study, 12 weeks of dotinurad 
4 mg/day is established.
EMA paper on guideline on clinical investigation of medicinal products for the treatment of 
gout also suggests that a parallel, randomized, double-blind trial should be performed for a 
minimum of 6 months.  Therefore, subjects in the dotinurad group will be treated for 24 
weeks in total.
7.3.4
Dose of Dotinurad
All antihyperuricemia drugs should be started from the low dose to avoid gout attack.  Even 
though the approved starting dose of dotinurad in Japan is 0.5 mg/day, Chinese key opinion 
leaders (KOLs) suggested that 0.5 mg/day is low in terms of efficacy of dotinurad and half of 
treatment dose (2 mg/day), ie, 1 mg/day would be appropriate for starting dose of dotinurad.  
Study FYU-981-014 showed that 20-mg febuxostat group had a similar reduction rate in 
SUA levels (33.39±9.26%) to 1-mg dotinurad group (30.53±10.16%).  This result suggests 
that the risk of acute gout attack caused by a rapid decrease in the SUA levels with 1 mg/day 
dotinurad is less likely to be exceeded 20 mg/day febuxostat.  The above points suggest that 
the incidence of gout attack at 1 mg/day is acceptable in clinical practice.
The proportion of subjects achieving SUA level ≤6.0 mg/dL at the final visit was 84.8% 
(84/99 subjects) and 88.0% (88/100 subjects) in the 2-mg dotinurad group and 40-mg 
febuxostat group, respectively in Study FYU-981-014.  From the Chinese Phase 3 studies of 
febuxostat, the proportion of subjects achieving SUA level ≤6.0 mg/dL tends to be 
approximately lower than that of Japanese subjects with the same dose of drug, is around 
45%.  Even though the responder rate with dotinurad 2 mg/day was over 80% in Japanese 
subjects, 4 mg/day might be needed to achieve SUA level ≤6.0 mg/dL in Chinese subjects.
The above points suggest it is appropriate that the titration of 1 mg/day (for 4 weeks) to 
2 mg/day (for 8 weeks) of dotinurad; and increase dose to 4 mg/day (for 12 weeks).


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7.3.5
Choice of Comparator Drug
Dotinurad and benzbromarone have the same mode of action (MOA), both belong to 
uricosuric drugs.  However, benzbromarone is launched decades ago, and febuxostat has 
been increasingly prescribed in recent years, and is taking the place of benzbromarone’s 
share in China.  Considering these, comparison data with febuxostat will be more useful for 
the clinical positioning of dotinurad after launched.
Dose of Febuxostat
All ULTs should be started at a low dose and then titrated upwards, to avoid and decrease the 
acute gout attack.  “Guideline for the diagnosis and management of hyperuricemia and gout 
in China (2019)” recommends to start from 20 mg/day for febuxostat (Chinese Society of 
Endocrinology, Chinese Medical Association, 2020), and “Chinese multi-disciplinary 
consensus on the diagnosis and treatment of hyperuricemia and its related diseases” 
recommends the starting dose of 20 to 40 mg/day (Multi-Disciplinary Expert Task Force on 
Hyperuricemia and Its Related Diseases, 2017).  Given the above, febuxostat 20 mg was 
selected as a starting dose.
In Phase 3 studies of febuxostat in China (CTR20150590, CTR20130132 and 
CTR20130048), febuxostat 40 mg was selected to assess non-inferiority compared 
allopurinol 300 mg, which is set as a daily dose in its package insert.  One of those Phase 3 
studies selected only one dose strength, febuxostat 40 mg.  Considering above, febuxostat 
40 mg was selected as a compared dose.
7.3.6
Mode of Administration
As no food effects were shown in FYU-981-016 study, no restriction of food intake was 
imposed to dotinurad in the current study.  Further, Japanese package insert indicated 
dotinurad should be taken once daily without stating specific timing.  Febuxostat, the 
comparator of this study, also has no restriction of food intake.  Considering the above, once 
daily dosing of dotinurad and febuxostat was set at approximately the same time each day.


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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to confirm the superiority of dotinurad 4 mg to 
febuxostat 40 mg on the proportion of subjects achieving a SUA level ≤6.0 mg/dL at Week 
24 in Chinese subjects with gout.
8.2
Secondary Objectives
The secondary objectives of the study are:

To confirm the non-inferiority of dotinurad 2 mg to febuxostat 40 mg on the proportion 
of subjects achieving a SUA level ≤6.0 mg/dL at Week 12 in Chinese subjects with gout

To compare the proportion of subjects achieving a SUA level ≤6.0 mg/dL at each time 
point between treatment groups

To compare the percent reduction in SUA level from baseline at each time point between 
treatment groups

To compare the change in SUA level from baseline at each time point between treatment 
groups

To compare the SUA level at each time point between treatment groups

To evaluate the safety and tolerability of dotinurad


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
FYU-981-J086-301 is a 24-week treatment, multicenter, randomized, double-blind, 
superiority, parallel-group study designed to confirm if the efficacy of dotinurad (4 mg/day) 
is superior to febuxostat (40 mg/day) in Chinese subjects 18 years or older in gout.
The study will consist of the Screening Phase (4 to 28 days), Treatment I Phase (4 weeks), 
and Treatment II Phase (20 weeks).
Approximately 450 subjects will be randomized to treatment groups in a ratio of 1:1 and will 
receive dotinurad 1 mg/day for the first 4 weeks, 2 mg/day for 8 weeks, and 4 mg/day for 
12 weeks; or febuxostat 20 mg/day for the first 4 weeks, and 40 mg/day for 20 weeks.  In 
addition, the randomization will be stratified by SUA level category (<9; 9 to <10; 10 to <11; 
≥11 mg/dL) and body mass index (BMI) category (<25; ≥25 kg/m2).
An overview of the study design is presented in Figure 1.
Figure 1 Overview of Study Design
R = randomization
9.1.1
Screening Phase
Screening Phase begins no more than 28 days, and no less than 4 days before the subject is 
randomized.  Between Day –28 and Day –4, informed consent will be obtained, and the 
subject’s eligibility will be assessed.
1 mg/day
40 mg/day
R
Period:
Starting between 
Day –28 and Day –4
Treatment I
Phase:
Febuxostat
20 mg/day
Day –28
Day 0/
Week 0
Day –4
Week 12
Week 24
Week 4
Day 1
2 mg/day
4 mg/day
Dotinurad
Treatment II
Screening


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In the Screening Phase, medical history, demography (including other characteristics of 
gout/hyperuricemia), prior therapy, classification of hyperuricemia, estimated glomerular 
filtration rate (eGFR), serum beta-human chorionic gonadotropin (β-hCG) (or hCG) test, 12-
lead ECG, abdominal ultrasound and abdominal radiography will be collected. SUA level
will be assessed. Physical examinations, vital signs, safety assessments, blood and urine for 
standard clinical laboratory assessments also will be collected. As for the details, see 
Table 3.
9.1.2
Treatment I Phase
The duration of Treatment I Phase is from Week 0 (Day 0) to Week 4.  On Day 0 of the
Treatment I Phase, subjects who meet all the inclusion criteria and none of the exclusion 
criteria will be randomized to 1 of 2 treatment groups (dotinurad or febuxostat) in a ratio of 
1:1.
From Day 1 of the Treatment I Phase, subjects will receive dotinurad 1 mg/day or febuxostat 
20 mg/day once daily for 4 weeks.
Vital signs, concomitant therapy, safety assessments (including gouty arthritis, urinary
calculi, acute renal failure, liver injury), blood and urine for standard clinical laboratory 
assessments will be collected at Visit 3. And SUA level will be assess at Visit 3.  As for the 
details, see Table 3.
9.1.3
Treatment II Phase
The duration of Treatment II Phase is from the first day after Week 4 to the last day of 
Week 24/Early Termination Visit.  During the Treatment II Phase, subjects in the dotinurad 
group will take dotinurad 2 mg/day once daily for 8 weeks initially and 4 mg/day once daily 
for 12 weeks.  Subjects in the febuxostat group will take febuxostat 40 mg/day once daily for 
20 weeks.
Vital signs, concomitant therapy, safety assessments (including gouty arthritis, urinary
calculi, acute renal failure, liver injury), blood and urine for standard clinical laboratory 
assessments will be collected at each visit of Treatment II Phase. Physical examination and 
12 lead ECG will be collected at Visit 5 and Visit 8.  Serum β-hCG (or hCG) test, abdominal 
ultrasound and abdominal radiography will be collected at Visit 8. And SUA level will be 
assess at each visit.  As for the details, see Table 3.
If a subject has any symptoms, signs, or findings about urinary calculi, acute renal failure, 
and severe liver injury during the whole Treatment Phase, the subject needs to have an 
unscheduled visit to assess the related situation. 
9.2
Discussion of Study Design, Including Choice of Control Groups
Details on the rationale for the study design including the choice of comparator drug are 
provided in Section 7.3.


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9.3
Selection of Study Population
Approximately 450 subjects will be randomized at approximately 30 sites in China.  Subjects 
who do not meet all of the inclusion criteria or who meet any of the exclusion criteria will not 
be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Gouta patient (with a history of gout attack or concurrent gouty tophi) with SUA level 
>7.0 mg/dL in the Screening Phase (within 14 days prior to randomization)
a:  Met 2015 ACR/EULAR gout classification criteria
2. Male or female, age ≥18 years at the time of informed consent
3. Provided written informed consent signed by the subject prior to entering the study or 
undergoing any study procedures, indicating that they understand the purpose and 
procedures required for the study and are willing to participate in the study.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Females who are breastfeeding or pregnant at screening (as documented by a positive β-
hCG test)
2. Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive (Subject must have been on a stable dose of the same 
oral contraceptive product for at least 28 days before dosing and must agree to 
stay on the same dose of the oral contraceptive throughout the study and for 
28 days after study drug discontinuation.)
o
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
It is permissible that if a highly effective method of contraception is not appropriate or 
acceptable to the subject, then the subject must agree to use a medically acceptable 
method of contraception, ie, double-barrier methods of contraception such as latex or 
synthetic condom plus diaphragm or cervical/vault cap with spermicide.
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 


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bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing).
3. Patient with gouty arthritis that has not resolved within 14 days prior to randomization
4. Any history of a medical or psychiatric condition that, in the opinion of the investigator, 
may have affected the subject’s safety or interfered with the study assessments
5. Currently has secondary hyperuricemia:
1) Lesch-Nyhan syndrome
2) Phosphoribosylpyrophosphate synthetase superactivity
3) Congenital myogenic hyperuricemia
4) Hematopoietic neoplasms (acute leukemia, lymphoma malignant, myeloproliferative 
disorder, myelodysplastic syndrome, etc)
5) Solid tumors (breast cancer, seminoma, sarcoma, Wilms tumor, small cell lung cancer, 
etc)
6) Non-neoplastic diseases (psoriasis vulgaris, secondary polycythemia, hemolytic 
anemia)
7) Rhabdomyolysis
8) Hypothyroidism
9) Polycystic kidney
10) Lead poisoning/lead nephropathy
11) Down’s syndrome
12) Familial juvenile gouty nephropathy
13) Hyperlactacidemia
14) Glycogen storage disease type 1
6. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated 12-lead 
electrocardiogram (ECG)
7. Prohibited concomitant drugs within 14 days prior to screening and during the study
8. Changing the dosage and/or administration, or initiating any restricted concomitant drugs 
within 14 days prior to screening and during the study
9. Have been routinely receiving non-steroidal anti-inflammatory drugs (NSAIDs) or 
corticosteroids (not including topical application) for a disease other than gouty arthritis
10. Comorbidities with nephrolithiasis or clinical urinary calculi (eg, haematuria, back pain)
11. Evidence of clinically significant disease (eg, cardiac disease:  heart failure and angina 
unstable, respiratory, gastrointestinal, renal, or neurological disease:  cerebral infarction) 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with 
the study assessments
12. Relevant history of cardiac (eg, myocardial infarction or angina attacks) or neurologic 
disease (eg, cerebral infarction) within 1 year prior to screening
13. Current presence of active gastrointestinal ulcer disease, or history of active 
gastrointestinal ulcer disease within 1 year prior to screening


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14. Evidence of clinical significant hepatic disease:  refer to Grade 2 in the “Seriousness 
Grading Criteria for Adverse Drug Reactions” or AST (GOT) or ALT (GPT) >3× upper 
limit of normal (ULN) in the Screening Phase
15. eGFR of <30 mL/min/1.73 m2 in the Screening Phase
16. Systolic blood pressure of ≥180 mmHg or diastolic blood pressure of ≥110 mmHg in the 
Screening Phase
17. HbA1c (NGSP value) of ≥8.4% in the Screening Phase
18. Current presence or history of neoplasm malignant in the 5 years prior to screening
19. Hypersensitivity to the study drugs (dotinurad or febuxostat) or their excipients, or all of 
urine alkalinizer (potassium citrate/sodium citrate hydrate compound preparations, et al)
20. Any history of or concomitant medical condition that in the opinion of the investigator(s) 
would compromise the subject’s ability to safely complete the study
21. Scheduled for surgery during the study
22. Known to be human immunodeficiency virus (HIV) positive
23. Active viral hepatitis (B or C) as demonstrated by positive serology
24. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive or had a close 
contact with SARS-CoV-2 positive patient in the Screening Phase
25. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring 
active treatment, including the use of oxygen
26. Use of illegal recreational drugs
27. History of drug or alcohol dependency or abuse within approximately 2 years prior to 
screening
28. Currently enrolled in another clinical study or used any investigational drug or device
within 28 days or 5× the half-life, whichever is longer, preceding informed consent
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason (see Section 9.5.5 on the discontinuation criteria for individual subjects).
9.4
Treatments
9.4.1
Treatments Administered
The day of the first dose of study drug is defined as Day 1, ie, the first day after Visit 2 
(Day 0) at which the randomization will be performed.
The following treatments will be administered to subjects in this study (Table 1).


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Table 1
Treatments Administered
Treatment I Phase
(4 weeks)
Treatment II Phase 
(20 weeks)
Day 1 to Day 28
Day 29 to Day 84 
(8 weeks)
Day 85 to Day 168 
(12 weeks)
Test 
treatment
Dotinurad 1 mg
One dotinurad 1 mg tablet 
and 
one febuxostat 20 mg-matched 
placebo tablet
(Except Day 0)
Dotinurad 2 mg
One dotinurad 2 mg tablet 
and 
two febuxostat 20 mg-matched 
placebo tablets
Dotinurad 4 mg
Two dotinurad 2 mg tablets 
and 
two febuxostat 20 mg-matched 
placebo tablets
Comparator 
treatment
Febuxostat 20 mg
One febuxostat 20 mg tablet
and 
one dotinurad 1 mg-matched 
placebo tablet
(Except Day 0)
Febuxostat 40 mg
Two febuxostat 20 mg tablets
and 
one dotinurad 2 mg-matched 
placebo tablet
Febuxostat 40 mg
Two febuxostat 20 mg tablets
and 
two dotinurad 2 mg-matched 
placebo tablets
The study drug will be administered orally once daily at approximately the same time each 
day.
9.4.2
Identity of Investigational Products
Investigational products, ie, test drug and active control, will be supplied by the sponsor.
Dotinurad will be supplied as 1 and 2 mg tablets; febuxostat-placebo will be supplied as
20 mg-matched tablet.
Febuxostat will be supplied as 20 mg tablet; dotinurad-placebo will be supplied as 1 and 
2 mg-matched tablets.
9.4.2.1
Chemical Name of Dotinurad

Test drug code:  FYU-981

Generic name:  Dotinurad

Chemical name:  (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ6-1,3-
benzothiazol-3-yl)methanone

Molecular formula:  C14H9Cl2NO4S

Molecular weight:  358.20

Dosage form and content:  1 mg tablet and 2 mg tablet

Drug Packaging:  Dotinurad is packaged in blister card and paper box.

Manufacturer:  FUJI YAKUHIN CO., LTD.


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9.4.2.2
Comparator Drug

Generic name:  Febuxostat

Chemical name:  2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-
carboxylic acid

Molecular formula:  C16H16N2O3S

Molecular weight:  316.37

Dosage form and content: 20 mg tablet

Drug packaging:  Febuxostat is packaged in blister card and paper box.

Manufacturer:  TEIJIN PHARMA LIMITED for febuxostat 20 mg; and 
Eisai Co., Ltd. for febuxostat 20 mg-matched placebo
9.4.2.3
Labeling for Study Drug
The following information has to be provided but not limited to:

For clinical study use only

Name of the sponsor

Chemical name/drug identifier

Lot number/batch number

Storage conditions, expiration date if necessary

Blank space for subject ID

Blank space for site ID
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
On Day 0 of the Treatment I Phase, subjects who meet all the inclusion criteria and none of 
the exclusion criteria will be randomized to 1 of 2 treatment groups (dotinurad or febuxostat) 
in a ratio of 1:1.  In addition, the randomization will be stratified by SUA level category (<9; 
9 to <10; 10 to <11; ≥11 mg/dL) and BMI category (<25; ≥25 kg/m2).
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent statistician.  The 


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randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
Randomization will be performed centrally by an interactive voice and web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized blister card 
identification numbers.  At enrollment (and after successful completion of Visit 1), the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 2 [Day 0]), the IxRS will assign each subject a unique randomization 
number.
9.4.4
Selection of Doses in the Study
Details on the doses selected for this study are provided in Section 7.3.
9.4.5
Selection and Timing of Dose for Each Subject
As stated in Section 9.4.1, the day of the first dose of study drug is defined as Day 1, ie, the 
first day after Visit 2 (Day 0) at which the randomization will be performed.
The study drug will be administered orally once daily at approximately the same time each 
day.
9.4.6
Blinding
During the Treatment I and Treatment II Phases, subjects and all personnel involved with the 
conduct and the interpretation of the study, including the investigators, investigational site 
personnel, and sponsor staff, will be blinded to the treatment codes in order to reduce 
potential bias during data collection and evaluation of endpoints.  Randomization data will be 
kept strictly confidential, filed securely by an appropriate group at the sponsor or CRO, and 
accessible only to authorized persons per SOPs until the time of unblinding.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor and the IxRS vendor.  In the 
event that emergency conditions require knowledge of the study treatment given, the blind 
may be broken via the code breaker facility within the IxRS.  Emergency procedures for 
revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, the 
investigator should consult with the sponsor to ascertain the necessity of breaking the code.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent) will be recorded on the 
case report form (CRF).  The AE or medical condition for which the concomitant medication 
or therapy was administered will be recorded.


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9.4.7.1
Prohibited Concomitant Drug and Therapy
Following drugs are prohibited within 14 days prior to screening and during the study.
1. Drugs to treat gout and hyperuricemia
1) Uricosuric drugs (probenecid, bucolome, benzbromarone)
2) Uric acid production-inhibitory drugs (allopurinol, febuxostat [except the 
investigational product])
3) Prophylaxis for gout flare (that includes colchicine, NSAIDs, corticosteroids, et al; and 
does not include topical application)
2. Drugs that affect the SUA level
1) Salicylic acid-based antipyretics and analgesics (except aspirin taken to control 
thromboembolism formation, and salicylamide)
3. Drugs that potentially interact with the test drug
1) Mercaptopurine hydrate
2) Azathioprine
3) Vidarabine
4) Hexamine
If a medication (including in Chinese traditional medicine) is not on the list of prohibited 
medications but in the opinion of the investigator, which also can be used to treat 
gout/hyperuricemia, it must not be used throughout the study.  If a medication is not 
specified as prohibited but is in the same class as a medication that is listed in the protocol, 
and if the investigator is uncertain, the Medical Monitor must be consulted.  If a subject starts 
any prohibited medication or therapy during the study, he/she must discontinue from the 
study, with the exception that certain prohibited medications must be used to particular 
condition if this is agreed with the Medical Monitor.
9.4.7.2
Restricted Concomitant Drug and Therapy
Subjects who are on the following treatment are required to be on a stable dose and same 
mode of administration for at least 14 days prior to screening and to keep the stable during 
the study.  Subjects are not permitted to initiate these drugs within 14 days prior to screening
and during the study.
1. Dietary and physical therapy for the underlying disease
2. Drugs or containing compound preparations that potentially affect SUA level
1) Immunosuppressants (mizoribine, cyclosporin, tacrolimus hydrate)
2) Antituberculous drugs (pyrazinamide, ethambutol hydrochloride)
3) Hyperlipidemia drugs (fenofibrate, atorvastatin, rosuvastatin, pitavastatin)
4) Antihypertensives (losartan potassium)
5) Diuretics (thiazide diuretics, loop diuretics)


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6) Sodium-dependent glucose transporter (SGLT) 2 inhibitors
7) Niacin formulations (niacin, niacinamide, tocopherol nicotinate)
8) Theophylline
9) Aspirin (for controlling thromboembolism formation)
9.4.7.3
Urinary Tract Management
If a subject meets any of the criteria described below, according to Guideline for the 
diagnosis and management of hyperuricemia and gout in China (2019): urine alkalinizer 
(citrate preparations, et al) must be coadministered, and keep the morning urine pH between 
6.2 and 6.9. Dosage is decided on urinary pH value, generally 9 – 10 g/d for potassium 
sodium hydrogen citrate, and lasts for 2 – 3 months. For the specific treatment regimen
(treatment targeting, drug, dosage and duration), it needs to be adjusted according to the 
investigator’s clinical judgment based on the subject’s medical situation. Even if a subject 
meets none of the criteria, urine alkalinizer (citrate preparations, et al) is to be coadministered 
as needed.
1. A history of urinary calculi
2. A urine pH of <6.0 on clinical examination after obtaining consent
9.4.7.4
Gouty Arthritis Treatment
The diagnosis of gouty arthritis can refer to Chinese version-2015 ACR/EULAR gout 
classification criteria, which is shown in Appendix 4 of Chinese multi-disciplinary consensus 
on the diagnosis and treatment of hyperuricemia and its related disease (Multi-Disciplinary 
Expert Task Force on Hyperuricemia and Its Related Diseases, 2017).
Subjects who have developed acute gouty arthritis attack during the study participation 
period are to receive pharmacologic therapy as early as possible (generally should be 
initiated within 24 hour of acute gout attack onset), including NSAIDs (excluding salicylic 
acid-based antipyretics and analgesics), colchicine, and corticosteroids.  The choice of drug 
should be based on the presence of contraindications, the subject’s previous experience with 
treatments, time of initiation after acute attack and the number and type of joint involved.  
According to Guideline for the diagnosis and management of gout in China (2016),
recommended first option for acute attack is NSAIDs to relieve the symptom (1B), and then 
recommend to monotherapy of low dose colchicine for subjects with the contraindication of 
NSAIDs (2B), recommend to monotherapy of corticosteroids for the short term (2B).  And 
from the treatment for acute gout arthritis attack, need to be adjusted according to the 
investigator’s clinical judgment based on subjects medical situation. If a subject has 
developed gouty arthritis after the start of study treatment, the investigational product 
administration to him/her is to be continued, in principle.
At Week 0/Day 0
Subjects who have developed gouty arthritis attack after the randomization day and before 
taking the first study drug are not to receive the study drug, and the subjects are to be 
discontinued from the study.


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At Week 4/Day 28
Subjects who have developed gouty arthritis that has not disappeared by Week 4, are to 
continue to take the current investigational product without increasing dose for up to 1 week 
after the specified visit date (ie, up to Day 35) until the event disappears, and following the 
resolution of event, the study drug with increasing dose is to be dispensed at an Unscheduled 
Visit (ie, before or on Day 35) to the recovered subject.  If the gouty arthritis does not 
disappear by 1 week or shorter after the specified visit day (ie, within Day 35), the subject is 
to be discontinued from the study treatment.
At Week 12/Day 84
Subjects who have developed gouty arthritis that has not disappeared by Week 12, are to 
continue to take the current investigational product without increasing dose for up to 1 week 
after the specified visit date (ie, up to Day 91) until the event disappears, and following the 
resolution of event, the study drug with increasing dose is to be dispensed at an Unscheduled 
Visit (ie, before or on Day 91) to the recovered subject.  If the gouty arthritis does not 
disappear by 1 week or shorter after the specified visit day (ie, within Day 91), the subject is 
to be discontinued from the study treatment.
At Week 24/Day 168
Subjects who have developed gouty arthritis that has not disappeared by Week 24, are to 
continue to take the investigational product for up to 1 week after the specified visit date (ie, 
up to Day 175) until the event disappears.  After then, regardless of outcome of the gouty 
arthritis, the subjects are to undergo all procedures/assessments scheduled at Week 24.
9.4.8
Treatment Compliance
Compliance will be assessed for each study drug by examination of blister cards returned to 
the investigator and tablets counting at each visit and unscheduled visit.  Tablets will be 
counted separately for tablets for dotinurad and febuxostat.
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study.
9.4.9
General Precautions
The investigator will instruct subjects to be careful regarding the points listed below:
1. Subjects should avoid excessive eating and drinking during the study participation period.
2. Subjects should have sufficient water intake during the study participation period.
3. Subjects should avoid alcohol intake from the day before the study visit to the end of the 
study visit.
4. Subjects should avoid excessive exercise from the day before the study visit to the end of 
the study visit.
5. On the day of study visit, subjects should return to the investigational site without having 
breakfast if the visit is scheduled in the morning.  If the visit is scheduled in the 
afternoon, subjects should visit to the investigational site without having lunch.


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6. Subjects should not start other drugs during the study wherever possible.  If subjects plan 
to use over-the-counter medications (eg, cold remedies, headache medications), they 
should contact the investigator before using these medications. If subjects have used 
these medications, they should contact the investigator on the day of study visit.
7. When subjects are planning to receive medical care by another physician, they should 
inform the personnel in the other site that they are receiving study treatment in this study.
See also Section 9.5.7 Confirmation of Medical Care by Another Physician.
8. For females of childbearing potential, contraception by methods that are considered 
medically appropriate must be used during the study participation period (see Section
9.3.2 Exclusion Criteria 2).
9.4.10
Drug Supplies and Accountability
The investigator will maintain accurate records of the receipt of all study medication.
In
addition, accurate records will be kept regarding when and how many study medications are
dispensed and used by each subject in the study. Reasons for deviation from the expected
dispensing regimen must also be recorded. Throughout the duration of the study, study
medication will be reconciled on a periodic basis by the CRAs. The investigator agrees to 
provide sufficient access to study medication as required for the reconciliation process to be 
completed in a timely fashion.
At completion of the study, all study medication will be reconciled by the CRO monitor and
then returned at the direction of CRO to either CRO or a third party contractor to be retained
or destroyed according to applicable local regulations. Prior to any action being taken with
study medication after the study is completed, the investigator will contact CRO for approval
of such action.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Screening Assessments
9.5.1.1.1
DEMOGRAPHY
Subject demography information will be collected at the Screening Visit and recorded in the 
CRF. Demography information includes age at informed consent, sex, race/ethnicity.
9.5.1.1.2
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All medical and surgical history within 5 years must be noted in the Medical History 
and Current Medical Conditions CRF.


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9.5.1.1.3
CLASSIFICATION OF HYPERURICEMIA
The disease type of hyperuricemia will be classified according to the following methods. 
Height, weight, SUA level, urinary uric acid level, serum creatinine level, urinary creatinine 
level, and 60-minute urine volume will be measured between 14 days and 4 days before the 
randomization day.  Urinary urate excretion (UUE; rounding off the second decimal place 
and displaying 1 decimal place) and fractional excretion of urate clearance (FEUA; rounding 
off the third decimal place and displaying 2 decimal places) will be calculated and the 
disease type of hyperuricemia will be classified.
The measurements/calculations of height, weight, SUA level, urinary uric acid level, serum 
creatinine level, urinary creatinine level, 60-minute urine volume, and classification of 
hyperuricemia (disease type of hyperuricemia) will be recorded in the CRF.  FEUA and UUE 
will be automatically calculated and output to the CRF by the electronic data capture (EDC) 
system.  If any parameter is considered to be reference data or unmeasurable data by the 
laboratory test facility or the investigator for reasons such as nonmeasurement or 
hemolyzed/chylous/coagulated samples, the classification of hyperuricemia is regarded as 
“not determination”.
1. Method
a:  Blood collection for SUA level and serum creatinine level measurements 
b:  Urine collection for urinary uric acid level, urinary creatinine level, and 60-minute urine volume 
measurements
2. Formulas
UUE (mg/hr/1.73 m2):
[urinary uric acid level (mg/dL) × 60-minute urine volume (mL/hr) /100] × 
[1.73/body surface area (m2) a]
a:  Body surface area (m2) = weight0.425(kg) × height0.725(cm) ×0.007184
FEUA (%):
100 × [urinary uric acid level (mg/dL) × serum creatinine level (mg/dL)] /
[SUA level (mg/dL) × urinary creatinine level (mg/dL)]
–30 minutes
0 minute
30 minutes
60 minutes
Height/ Weight
measurement
Water loading
300 mL
Urination
Blood
collection a
Urine
collection b


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3. Determination of Classification of Hyperuricemia
Disease type
UUE (mg/hr/1.73 m2)
FEUA (%)
Overproduction type
>25
and
≥5.5
Underexcretion type
≤25
and
<5.5
Combined type
>25
and
<5.5
9.5.1.1.4
ESTIMATED GLOMERULAR FILTRATION RATE (eGFR)
In the Screening Phase, eGFR will be calculated at a central laboratory, and the eGFR value 
will be recorded in the CRF.
9.5.1.1.5
OTHER CHARACTERISTICS OF GOUT/HYPERURICEMIA
The following items on the characteristics of gout/hyperuricemia and the prior medications 
for gout/hyperuricemia will be surveyed at the Screening Visit and recorded in the CRF:  
previous urinary calculi (presence/absence), family history (presence/absence), date for the 
diagnosis of gout, date for the diagnosis of asymptomatic hyperuricemia, all medications 
used in the past for gout/hyperuricemia (none; benzbromarone; allopurinol; febuxostat; 
others), the last medication for gout/hyperuricemia (none; benzbromarone; allopurinol; 
febuxostat; others), duration of treatment for gout/hyperuricemia (none; <1; 1 to <10; 
≥10 years), previous gouty arthritis (presence/absence), and previous gouty tophi 
(presence/absence).
9.5.1.1.6
ALCOHOL CONSUMPTION STATUS
Presence or absence of alcohol consumption will be surveyed at the Screening Visit and 
recorded in the CRF (when drinking frequency is at least 3 days per week and the daily 
regular alcohol consumption is at least 500 mL of beer, or 60 mL of whiskey, or 50 mL of 
low-alcohol liquor it will be taken as “presence”).
9.5.1.1.7
HEIGHT
Height without shoes will be measured at the Screening Visit and recorded in the CRF.
9.5.1.1.8
VIRAL SCREENING
Viral screening for hepatitis B (HBsAg), hepatitis C (HCV antibody IgG), and HIV will be
conducted at the Screening Visit.  The results will be recorded in the medical records of the 
site.


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9.5.1.2
Efficacy Assessments
9.5.1.2.1
SERUM URIC ACID LEVEL
Efficacy assessment consists of SUA level.  SUA level is considered a measure for the 
efficacy assessment and is not to be used in the safety assessment because there is expected 
to be variation in SUA level due to the pharmacological effects of dotinurad and febuxostat.
The measurement of SUA level during the study will be performed by a central laboratory.  
All blood samples will be collected at approximately the same time each visit, and sent to the 
central laboratory on the day of collection unless otherwise instructed.  Laboratory 
certification as available will be included in the final clinical study report for this study.
Screening Phase
A blood sampling for the assessment of SUA level will be conducted between 14 days and 
4 days before the randomization day.  The SUA level in the Screening Phase will be recorded 
in the CRF (See Section 9.5.1.1.3).
The baseline is to be selected between 14 days and 4 days before, whichever is closer to the 
randomization day.
Treatment I and II Phases
Blood samplings for the assessment of SUA level will be conducted at approximately the 
same time at Weeks 4, 8, 12, 16, 20, and 24, or Early Termination Visit.  The sampling date 
and time at each blood sampling point will be recorded in the CRF.
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Not applicable.
9.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, and serious adverse 
events (SAEs);  withdrawal from treatment; laboratory evaluation for hematology, blood 
chemistry, and urine values; periodic measurement of vital signs and ECGs; and the 
performance of physical examinations.


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9.5.1.4.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drugs are 
dotinurad and febuxostat.
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded on the 
CRF beginning from the time the subject signs the study ICF through the last visit and for 7 
days after the subject’s last dose. Refer to Section 9.5.4.1 for the time period after the end of 
treatment for SAE collection.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF.
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.


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Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.4.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.


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9.5.1.4.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.4.3
STUDY-SPECIFIC ADVERSE EVENTS
The study-specific events, gouty arthritis, urinary calculi, acute renal failure, liver injury, 
should always be considered adverse events and reported on the Adverse Event CRF.  As for 
the diagnosis of gouty arthritis, refer to Section 9.4.7.4.  In addition, site(s) of onset of gouty 
arthritis should be collected as additional information and included in the AE term.


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9.5.1.4.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 2.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 3) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count,
WBC count with differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Calcium, chloride, potassium, sodium
Liver function tests
Alkaline phosphatase, ALT, AST, gamma glutamyl transpeptidase,
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function tests
TT3a, FT3a, TT4a, FT4a, TSHa
Other
Albumin, creatine kinase, globulin, glucose,
HbA1c (NGSP value)a, HDL-cholesterol, lactate dehydrogenase, 
LDL-cholesterol, phosphorus, serum amylase, total protein, 
triglycerides
Urinalysis
Qualitative (protein, glucose, urobilinogen, occult blood, ketones), 
pH, specific gravity, urinary sediments (microscopy), NAGb,
AMGb, BMGb, osmolality, microalbuminb
ALT = alanine aminotransferase, AMG = alpha 1-microglobulin, AST = aspartate aminotransferase,
BMG = beta 2-microglobulin, FT3 = free triiodothyronine, FT4 = free thyroxine, HbA1c = hemoglobin A1c, 
HDL = high density lipoprotein, LDL = low density lipoprotein, NAG = N-acetyl-β-D-glucosaminidase,
NGSP = National Glycohemoglobin Standardization Program, RBC = red blood cell, 
TSH = thyroid stimulating hormone, TT3 = total triiodothyronine, TT4 = total thyroxine, 
WBC = white blood cell.
a:  Measure only in the Screening Phase.
b:  Calculate with corrected urinary creatinine.
Clinical laboratory tests during the study will be performed by a central laboratory.  All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  Laboratory certification as available will be included 
in the final clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.4.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event CRF.


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9.5.1.4.5
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute] and temperature [°C]), and weight (kg) will be obtained at the visits designated 
in the Schedule of Procedures/Assessments (Table 3) by a validated method, and the results 
will be recorded in the CRF.
Blood pressure and pulse will be measured after the subject has been sitting for 
approximately 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.
When vital signs are to be obtained concurrently with blood samples, the vital sign 
measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.4.6
PHYSICAL EXAMINATIONS
Physical examinations will only be performed at the Screening Visit, Week 12, and 
Week 24/Early Termination Visit (Table 3).  For all other visits during the study, the physical 
examinations will only be performed when there is a complaint from the subject.  
Documentation of the physical examination will be included in the source documentation at 
the site.  Clinically significant abnormal findings that meet the definition of an AE from the 
physical examinations will be reported on the Adverse Events CRF.
9.5.1.4.7
ELECTROCARDIOGRAMS
Twelve-lead ECG will be obtained as designated in the Schedule of Procedures/Assessments 
(Table 3).
ECG interpretation (categorized as normal; abnormal, not clinically significant; and 
abnormal, clinically significant) and parameters (QTcF, QT, PR, QRS, RR and heart rate) 
will be recorded on the CRF.  If subject has a normal ECG baseline reading, but during any 
visit thereafter the QTcF is measured as >450 ms, 3 consecutive ECGs, including the initial 
ECG with QTcF >450 ms, separated by at least 5 minutes will be performed to confirm the 
abnormality, and the mean of the 3 QTcF values will be recorded on the CRF.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.4.1).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the Adverse Events CRF.
9.5.1.4.8
OTHER SAFETY ASSESSMENTS
Pregnancy Test
A serum β-hCG (or hCG) test will be performed at the Screening Visit and Week 24/Early 
Termination Visit (Table 3) for premenopausal women and postmenopausal women who 


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have been amenorrheic for less than 12 consecutive months.  The results will be recorded in 
the medical records of the site.
Abdominal Ultrasound/Abdominal Radiography
Abdominal ultrasound and plain abdominal radiography will be performed at the Screening 
Visit and Week 24/Early Termination Visit (Table 3), and the presence or absence of urinary
calculi or clinically significant urinary calculi will be observed. Documentation of the 
abdominal ultrasound and plain abdominal radiography will be included in the source 
documentation at the site.  Clinically significant abnormal findings that meet the definition of 
an AE from the abdominal ultrasound and plain abdominal radiography will be reported on 
the Adverse Events CRF.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the schedule of procedures/assessments.


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Table 3
Schedule of Procedures/Assessments in Study FYU-981-J086-301
Phase
Screening
Treatment I
Treatment II
Visit
1
2
3
4
5
6
7
8
ETa
Unscheduled o
Week
–4
0b
4c
8
12d
16
20
24e
Day
–28
0
28
56
84
112
140
168
Possible Study Day(s) Given Window
–28 to –4
0
23 to 33
51 to 61
77 to 91
105 to 119 133 to 147 161 to 175
Procedures/Assessments
Demography
X
Informed consent/assent
X
Inclusion/exclusion criteria
Medical history
X
Alcohol consumption status
X
Prior and concomitant medication(s)
X
X
Urinary tract managementf
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
Gouty arthritis
X
X
Randomization
X
Study drug
Day 1
Study drug compliance
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
Retrieve unused study drug
X
X
X
X
X
X
X
X
Physical examinationg
X
X
X
X
X
Vital signsh and weight
X
X
X
X
X
X
X
X
X
X
Heighti
X


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Table 3
Schedule of Procedures/Assessments in Study FYU-981-J086-301
Phase
Screening
Treatment I
Treatment II
Visit
1
2
3
4
5
6
7
8
ETa
Unscheduled o
Week
–4
0b
4c
8
12d
16
20
24e
Day
–28
0
28
56
84
112
140
168
Possible Study Day(s) Given Window
–28 to –4
0
23 to 33
51 to 61
77 to 91
105 to 119 133 to 147 161 to 175
Procedures/Assessments
Clinical laboratory testsj
X
X
X
X
X
X
X
X
X
Viral screeningk
X
Serum uric acid levell
X
X
X
X
X
X
X
X
X
Serum β-hCG (or hCG) testm
X
X
X
Classification of hyperuricemiap
X
eGFR
X
12-lead ECGn
X
X
X
X
X
Abdominal ultrasound
/abdominal radiography
X
X
X


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X:  required done.
β-hCG = beta-human chorionic gonadotropin (or hCG = human chorionic gonadotropin); CRF = case report form; ECG = electrocardiogram;
eGFR = estimated glomerular filtration rate; ET = early termination; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; SUA = serum uric acid.
a:
These assessments will be conducted for subjects who discontinued the study early for any reason after Visit 2.
b:
Subjects who have developed gouty arthritis attack after the randomization day and before taking the first study drug are not to receive the study drug, and 
the subjects are to be discontinued from the study.
c:
Subjects who have developed gouty arthritis that has not disappeared by Week 4, are to continue to take the current investigational product without 
increasing dose for up to 1 week after the specified visit date (ie, up to Day 35) until the event disappears, and following the resolution of event, the study 
drug with increasing dose is to be dispensed at an Unscheduled Visit (ie, before or on Day 35) to the recovered subject.  If the gouty arthritis does not 
disappear by 1 week or shorter after the specified visit day (ie, within Day 35), the subject is to be discontinued from the study treatment.
d:
Subjects who have developed gouty arthritis that has not disappeared by Week 12, are to continue to take the current investigational product without 
increasing dose for up to 1 week after the specified visit date (ie, up to Day 91) until the event disappears, and following the resolution of event, the study 
drug with increasing dose is to be dispensed at an Unscheduled Visit (ie, before or on Day 91) to the recovered subject.  If the gouty arthritis does not 
disappear by 1 week or shorter after the specified visit day (ie, within Day 91), the subject is to be discontinued from the study treatment.
e:
Subjects who have developed gouty arthritis that has not disappeared by Week 24, are to continue to take the investigational product for up to 1 week after 
the specified visit date (ie, up to Day 175) until the event disappears.  After then, regardless of outcome of the gouty arthritis, the subjects are to undergo all 
procedures/assessments scheduled at Week 24.
f:
If a subject meets any of the criteria: 1) a history of urinary calculi; 2) a urine pH of <6.0 on clinical examination after obtaining consent, urine alkalinizer 
(citrate preparations, et al) must be coadministered. Even if a subject meets none of the criteria, urine alkalinizer (citrate preparations, et al) is to be 
coadministered as needed.
g:
Physical examinations will only be performed at Visit 1, Visit 5, Visit 8, and at Early Termination Visit.  For all other visits during the study, the physical 
examinations will only be performed when there is a complaint from the subject.  Clinically significant abnormal findings from the physical examinations 
will be reported as adverse events.
h:
Vital signs include systolic and diastolic blood pressure, pulse, and temperature.
i:
Height without shoes will be measured.
j:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
k:
Viral screening for hepatitis B (HBsAg), hepatitis C (HCV antibody IgG), and HIV will be conducted.
l:
The baseline is to be selected between 14 days and 4 day before, whichever is closer to the randomization day.
m:
Female subjects only.
n:
If subject has a normal ECG baseline reading, but during any visit thereafter the QTcF is measured as >450 ms, 3 consecutive ECGs, including the initial 
ECG with QTcF >450 ms, separated by at least 5 minutes will be performed to confirm the abnormality.  ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) and parameters (QTcF, QT, PR, QRS, RR and heart rate) will be recorded on the 
CRF.
o:
At the unscheduled visit, as for the 2 safety assessments (ie, lab tests and ECG) and SUA assessment, they will be performed only if the investigator(s) 
judges as necessary based on the subject’s condition.
p:
Height, weight, SUA level, urinary uric acid level, serum creatinine level, urinary creatinine level, and 60-minute urine volume will be measured.


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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of gout.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, radiologic studies, and assessment of AEs, are standard 
evaluations to ensure subject safety.
As stated in Section 9.5.1.2.1, SUA level is considered a measure for the efficacy assessment 
and is not to be used in the safety assessment because there is expected to be variation in 
SUA level due to the pharmacological effects of dotinurad and febuxostat.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported to the designated CRO on a completed SAE form by email or fax as 
soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the event.
Serious adverse events, regardless of causality assessment, must be collected beginning from 
the time the subject signs the study ICF through the last visit and for 28 days after the 
subject’s last dose.  All SAEs must be followed to resolution or, if resolution is unlikely, to 
stabilization.  Any SAE judged by the investigator to be related to the study treatment or any 
protocol-required procedure should be reported to the sponsor regardless of the length of 
time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.


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Reporting of AEs to regulatory authorities are provided in Section 9.5.4.6.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be 
reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus are considered to be an SAE 
and should be reported in the same time frame and in the same format as all other SAEs (see 
Reporting of Serious Adverse Events [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows: 
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects


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Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject.
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
and Intentional Overdose, even if asymptomatic, are always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal laboratory tests*, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing and whether nonserious or 
serious, should be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1).  If the event does not meet 
serious criteria, the seriousness criteria on the SAE form should be indicated as “nonserious.”

Elevated AST or ALT lab value that is greater than or equal to 3× ULN
AND

Elevated total bilirubin lab value that is greater than or equal to 2× ULN
AND AT THE SAME TIME

Alkaline phosphatase lab value that is less than 2× ULN
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology.  In addition to reporting the abnormal hepatic 
laboratory tests on an SAE form, the site should also consult the medical monitor for 
guidance on assessment and follow-up.  At a minimum, laboratory testing should be repeated 
at least once weekly until improvement or identification of a cause unrelated to study drug 
use that is unlikely to improve.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 


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will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
For this study, the Reference Safety Information which the Sponsor will use to assess 
expectedness is the Investigator Brochure of dotinurad/the approved China Package Insert of 
febuxostat.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  Wherever possible, 
all subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 3).
Subjects who meet any of the following criteria will be discontinued from the study:
1.
Subjects who withdrew consent
2.
Subject choice (eg, change in residence)
3.
Subjects who had AEs leading to discontinuation from the study
4.
Subjects who were considered impossible to continue the study due to progression of 
gout or inadequate therapeutic effect of the study drug by the investigator
5.
Subjects who take prohibited concomitant drugs during the study, and the use is 
considered to interfere with the efficacy assessments and affect the subject’s safety by 
the investigator, following consultation with the sponsor
6.
Subjects who change the dosage and/or administration, or initiate any restricted 
concomitant drugs during the study, and the change or initiation is considered to 
interfere with the efficacy assessments and affect the subject’s safety by the investigator, 
following consultation with the sponsor
7.
Subjects who begin to routinely receive NSAIDs or corticosteroids (not including topical 
application) for a disease other than gouty arthritis
8.
Subjects who developed gouty arthritis attack after the randomization day and before 
taking the first study drug
9.
Subjects who developed gouty arthritis at Week 4 or 12, and the gouty arthritis did not 
disappear within 1 week after the specified visit date of Week 4 or 12
10. Subjects who developed nephrolithiasis (including clinical urinary calculi) after the first 
study treatment (excluding at the final visit)


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11. Subjects who developed acute kidney injury (AKI) after the first study treatment
(excluding at the final visit)
AKI is defined as any of the following (Kidney Disease: Improving Global Outcomes 
[KDIGO] 2012):
- Increase in serum creatinine (SCr) by ≥0.3 mg/dL (≥26.5 mol/L) within 48 hours; or
- Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred 
within the prior 7 days; or
- Urine volume <0.5 mL/kg/h for 6 hours
12. Subjects with SUA level of ≤2.0 mg/dL for 2 consecutive visits (excluding at the final 
visit)
13. Subjects with AST or ALT level of 5× ULN (excluding at the final visit)
14. Subjects with serum creatinine level of ≥3.0 mg/dL (excluding at the final visit)
15. Subjects who became pregnant after the first study treatment
16. Subjects who were considered inappropriate to continue the study due to any other 
reason by the investigator
Subjects who discontinue early from the study will be discontinued for 1 primary reason of 
the above reasons.  In addition to the primary reason, the subject may indicate 1 or more 
secondary reason(s) for discontinuation.  Study disposition information will be collected on 
the Subject Disposition CRF.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
A subject removed from the study for any reason may not be replaced. In some 
circumstances, a subject who fails in the Screening Phase may be rescreened once following 
consultation with Medical Monitor of the Sponsor. Any such subject will be assigned a new 
subject identification number.
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.


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9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by C-
GCP, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee must sign the completed CRF 
to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, SUA levels, laboratory data), will be entered into a 
clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding. Statistical analyses will be 
performed using SAS software or other validated statistical software as required.  Details of 
the statistical analyses will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.


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9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is the proportion of subjects with ≤6.0 mg/dL in SUA level at Week 24 
(LOCF).
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints are:

Proportion of subjects with ≤6.0 mg/dL in SUA level at Week 12 (LOCF)

Proportion of subjects with ≤6.0 mg/dL in SUA level at each time point

Mean percent reduction from baseline in SUA level at each time point

Mean change from baseline in SUA level at each time point

Mean SUA level at each time point
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment.
The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 dose 
of study drug and had at least 1 postdose primary efficacy measurement (ie, SUA level).
The Per Protocol (PP) Analysis Set is the group of subjects who sufficiently complied with 
the protocol.  Details of the evaluability criteria will be determined before database lock and 
treatment unblinding and will be specified in the SAP.
9.7.1.3
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized.  The number of subjects randomized along with the number of 
subjects in each of the study populations will also be presented.
The number of subjects completing the study will be presented.  Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for 
study termination.  Other reasons for study terminations will also be summarized.  These 
tabulations will be produced for all randomized subjects by treatment group.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics in the Safety Analysis Set, FAS, and PP will 
be summarized for each treatment group using descriptive statistics (eg, n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables).  Continuous variables include age, height, weight, BMI; categorical variables 


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include sex, age group (<45; 45 to <55; 55 to <65; ≥65 years old), BMI group (<25; 
≥25 kg/m2), race, and ethnicity.
Characteristics of gout/hyperuricemia and the prior medications for gout/hyperuricemia for 
the Safety Analysis Set, FAS, and PP will be summarized for each treatment group using 
descriptive statistics. Continuous variables include SUA level and eGFR; categorical 
variables include all medications used in the past for gout/hyperuricemia (none; 
benzbromarone; allopurinol; febuxostat; others), the last medication for gout/hyperuricemia 
(none; benzbromarone; allopurinol; febuxostat; others), SUA level category (<9; 9 to <10; 10 
to <11; ≥11 mg/dL), eGFR category (≥30 to <60; 60 to <90; ≥90 mL/min/1.73 m2), and 
classification of hyperuricemia (overproduction type, underexcretion type; combined 
type/normal type).
Details of the statistical analyses for the demographic and other characteristics will be 
indicated in the SAP.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).
Prior medications will be defined as medications that stopped before the first dose of study 
drug.  Concomitant medications will be defined as medications that (1) started before the first 
dose of study drug and were continuing at the time of the first dose of study drug, or (2) 
started on or after the date of the first dose of study drug.  In addition, prior and concomitant 
nonpharmacological procedures will be defined similarly to prior and concomitant 
medications.
All medications and nonpharmacological procedures will be presented in subject data 
listings.
9.7.1.6
Efficacy Analyses
The FAS will be used as a primary analysis set for the efficacy analyses.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The analysis for the difference in the proportion of subjects with ≤6.0 mg/dL in SUA level 
(ie, responder rate) at Week 24 (LOCF) between dotinurad 4 mg and febuxostat 40 mg will 
be conducted based on a Cochran–Mantel–Haenszel (CMH) test stratified by baseline SUA 
level and baseline BMI.  The statistical test will be two-sided at the 5% significance level.
The same primary efficacy analysis mentioned above will be repeated based on the PP 
Analysis Set as a sensitivity analysis.
Subgroup analyses will be performed as appropriate.


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9.7.1.6.2
SECONDARY EFFICACY ANALYSES
For all the secondary efficacy analyses, no multiplicity adjustment will be made.
The difference in the responder rate at Week 12 (LOCF) between dotinurad 2 mg and 
febuxostat 40 mg and the 95% confidence interval will be estimated based on Mantel–
Haenszel method adjusting for the baseline SUA level and baseline BMI.  The prespecified 
non-inferiority margin will be –10% in this analysis, which will be for the reference purpose 
only.
The proportion of subjects with ≤6.0 mg/dL in SUA level at each time point will be 
summarized.
The mean percent reduction from baseline in SUA level at each time point will be 
summarized using descriptive summary statistics (eg, n, mean, SD, median, minimum, 
maximum), estimated based on the longitudinal data analysis (LDA) model and presented in 
figures.  The detail of the LDA model will be specified in the SAP.
The mean actual value and the mean change from baseline in SUA level at each time point 
will be summarized using descriptive summary statistics.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses
Not applicable.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics.  
Safety variables include treatment-emergent adverse events (TEAEs), clinical laboratory 
parameters, vital signs, weight, 12-lead ECG results.
9.7.1.8.1
EXTENT OF EXPOSURE
The duration of exposure to study drug will be summarized descriptively.  The number 
(percentage) of subjects will also be summarized by duration of exposure.
Compliance will be assessed for each study drug by examination of blister cards returned to 
the investigator and tablets counting at each visit and unscheduled visit. Tablets will be 
counted separately for tablets for dotinurad and febuxostat (see Section 9.4.8).  Summaries 
will provide descriptive summary statistics and number (percentage) of subjects (<80%; 80% 
to 100%; >100% to 120%; >120%).
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 


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(MedDRA).  Adverse events will be coded to the MedDRA lower level term (LLT) closest to 
the verbatim term.  The linked MedDRA preferred term (PT) and primary system organ class 
(SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during time 
from the first dose of study drug to 28 days after the subject’s last dose, having been absent 
at pretreatment or 

Reemerges during treatment, having been present at pretreatment but stopped before 
treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1 
TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will 
also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
Subgroup analyses for TEAEs will be performed as appropriate.
A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
SOC and PT for each treatment group.  A subject data listing of all SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by SOC and PT for each treatment group.  A subject data listing of all 
AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.4.4, the actual value and the change 
from baseline to each postbaseline visit will be summarized by visit and treatment group 
using descriptive statistics.  Qualitative parameters listed in Section 9.5.1.4.4 will be 
summarized using frequencies (number and percentage of subjects), and changes from 
baseline to each postbaseline visit will be reported using shift tables.  Percentages will be 
based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.


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Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit.  Similar shift tables will also compare the baseline 
LNH classification to the LNH classification for the highest and lowest value.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable.
9.7.1.8.4
VITAL SIGNS AND WEIGHT
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse and 
temperature) and weight, and changes from baseline will be presented by visit and treatment 
group.
The number (percentage) of subjects with at least 1 postbaseline clinically notable values in 
vital signs and weight will be summarized.  Clinically notable values will be defined in the 
SAP.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters (QTcF, QT, PR, QRS, RR and heart rate) and 
changes from baseline will be presented by visit and treatment group.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) by visit and 
treatment group.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF will be summarized.  Clinically abnormal ECG results in QTcF will be 
categorized as follows:
Absolute QTcF interval prolongation:

QTcF interval >450 ms

QTcF interval >480 ms

QTcF interval >500 ms
Change from baseline in QTcF interval:

QTcF interval increases from baseline >30 ms

QTcF interval increases from baseline >60 ms


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9.7.1.8.6
OTHER SAFETY ANALYSES
No analyses are planned for pregnancy tests, and abdominal ultrasound and plain abdominal 
radiography specified in Section 9.5.1.4.8 Other Safety Assessments.
9.7.2
Determination of Sample Size
For the responder rate, assuming a rate of 45% for febuxostat 40 mg and 60% for dotinurad 
4 mg, a sample size of 225 subjects in each group will provide approximately 90% power to 
detect a between-group difference in the proportion of responders based on a two-group Chi-
square test with a 0.05 two-sided significance level.  The primary efficacy analysis will be 
based on the FAS.  Hence, 450 subjects will be the target number of subjects as the FAS.
9.7.3
Interim Analysis
Not applicable.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.


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10 REFERENCE LIST
Athyros VG, Elisaf M, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, 
et al.  Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients 
with coronary heart disease:  a subgroup analysis of the Greek atorvastatin and coronary-
heart-disease evaluation (GREACE) study.  Am J Kidney Dis.  2004;43(4):589–99.
Bardin T and Richett P.  Impact of comorbidities on gout and hyperuricemia:  an update on 
prevalence and treatment options.  BMC Med.  2017;15(1):123.
Chen Haozhu.  Practice of internal medicine.  Beijing:  People's Medical Publishing House.  
2006;2605.
Chinese Society of Endocrinology, Chinese Medical Association.  Guideline for the 
diagnosis and management of hyperuricemia and gout in China (2019).  Chin Endocrinol 
Metab.  2020;36(1):1–13.
European Medicines Agency.  Guideline on clinical investigation of medicinal products for 
the treatment of gout.  EMA/CHMP/774470/2018; 2019.
Hosoya T, Sano T, Sasaki T, Fushimi M, Ohashi T.  Dotinurad versus benzbromarone in 
Japanese hyperuricemic patient with or without gout: a randomized, double-blind, 
parallel-group, phase 3 study.  Clinical and Experimental Nephrology.  2020;24 
(Suppl 1):S62–S70.
Kunishima C, Inoue I, Oikawa T, Katayama S.  The metabolism, toxicity and 
pharmacological studies of benzbromarone (Urinorm®). (in Japanese)  J Saitama Med 
School.  2003;30(4):187–94.
Liu R, Han C, Wu D, Xia X, Gu J, Guan H, et al.  Prevalence of hyperuricemia and gout in 
mainland China from 2000 to 2014: a systematic review and meta-analysis.  Biomed Res Int.  
2015;2015:762820.
Locuson II CW, Wahlstrom JL, Rock DA, Rock DA, Jones JP.  A new class of CYP2C9 
inhibitors:  probing 2C9 specificity with high-affinity benzbromarone derivatives.  Drug 
Metab Dispos.  2003;31(7):967–71.
Multi-Disciplinary Expert Task Force on Hyperuricemia and Its Related Diseases.  Chinese 
multi-disciplinary consensus on the diagnosis and treatment of hyperuricemia and its related 
diseases.  Zhonghua Nei Ke Za Zhi.  2017;56(3): 235–48.
Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al.  2015 Gout 
classification criteria: an American College of Rheumatology/European League Against 
Rheumatism collaborative initiative.  Ann Rheum Dis. 2015;74(10):1789–98.


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Siu YP, Leung KT, Tong MKH, Kwan TH.  Use of allopurinol in slowing the progression of 
renal disease through its ability to lower serum uric acid level.  Am J Kidney Dis.  
2006;47(1):51–9.
Van der Klauw MM, Houtman PM, Stricker BHC, Spoelstra P.  Hepatic injury caused by 
benzbromarone.  J Hepatol.  1994;20(3):376–9.


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor (or appropriate 
study team member) and the IRB/IEC for the site must be notified immediately.  The sponsor 
must notify the health or regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol.
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site and remote 
monitoring will be conducted by the assigned CRA as described in the monitoring plan.  The 
investigator will allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to 
assure compliance with C-GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB/IEC review.
Source documents include, but are not limited to the following:

Clinic, office, or hospital charts

Copies or transcribed health care provider notes which have been certified for accuracy 
after production


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
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, ECGs) regardless of how these images are stored, including microfiche and 
photographic negatives

Medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as source document.  Any correction to entries made 
on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  The 
data recorded directly on the CRF are to be considered as source data.
The investigator is to agree to allow direct access to source documents and study facilities to 
sponsor representative(s), monitor(s) and auditor(s), and is to agree to inspection by 
regulatory authorities or IRB/IEC representative.
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, ICFs, and IRB/IEC correspondence).  The site should plan to retain study 
documents, as directed by the sponsor, for at least 15 years following the completion of the 
study.


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It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of C-GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor (or designated contractor).  Drug supplies must be kept in an appropriate secure 
area (eg, locked cabinet) and stored according to the conditions specified on the drug labels.  
The investigator (or a designated pharmacist) must maintain an accurate record of the 
shipment and dispensing of the study drug in a drug accountability ledger, a copy of which 
must be given to the sponsor at the end of the study.  An accurate record of the date and 
amount of study drug dispensed to each subject must be available for inspection at any time.  
The CRA will visit the site and review these documents along with all other study conduct 
documents at appropriate intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.


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11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.


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12 APPENDICES


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Appendix 1
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
Life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
Life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 2.5ULN if 
baseline was normal; 
2.0 – 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was
abnormal
ALT
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
>3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
AST
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
>3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN if 
baseline was normal; 
1.0 – 1.5baseline if 
baseline was abnormal
>1.5 – 3.0ULN if 
baseline was normal; 
>1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 10.0ULN if 
baseline was normal; 
>3.0 – 10.0baseline if 
baseline was abnormal
>10.0ULN if 
baseline was normal; 
>10.0baseline if 
baseline was 
abnormal
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
Ionized calcium <LLN 
- 1.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
Ionized calcium <1.0 -
0.9 mmol/L; 
symptomatic
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
Ionized calcium <0.9 -
0.8 mmol/L; 
hospitalization indicated
<6.0 mg/dL
<1.5 mmol/L
Ionized calcium <0.8 
mmol/L; life-
threatening 
consequences


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Grade 1
Grade 2
Grade 3
Grade 4
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
Ionized calcium >ULN 
- 1.5 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
Ionized calcium >1.5 -
1.6 mmol/L; 
symptomatic
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
Ionized calcium >1.6 -
1.8 mmol/L; 
hospitalization indicated
>13.5 mg/dL
>3.4 mmol/L
Ionized calcium >1.8 
mmol/L; life-
threatening 
consequences
Creatinine
>ULN – 1.5ULN
>1.5 - 3.0baseline;
>1.5 – 3.0ULN
>3.0baseline;
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 2.5ULN if 
baseline was normal; 
2.0 - 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 - 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 - 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
Glucose, serum-high (hyperglycemia)
Abnormal glucose 
above baseline with no 
medical intervention
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes
Insulin therapy initiated; 
hospitalization indicated
Life-threatening 
consequences; urgent 
intervention indicated
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
Life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
Laboratory finding only 
and intervention not 
indicated
Oral replacement 
therapy indicated
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated
Life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
Life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
Life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L; 
intervention initiated
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
Life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125-129 mmol/L and 
asymptomatic
125 – 129 mmol/L 
symptomatic; 120-124 
mmol/L regardless of 
symptoms
<120 mmol/L
Life-threatening 
consequences


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Grade 1
Grade 2
Grade 3
Grade 4
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
Life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.


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Appendix 2
The ACR/EULAR Gout Classification Criteria
(Neogi, et al., 2015)
Categories
Score
Step 1:  Entry criterion (only apply criteria below to those 
meeting this entry criterion)
At least 1 episode of swelling, pain, or tenderness in a peripheral 
joint or bursa
Step 2:  Sufficient criterion (if met, can classify as gout without 
applying criteria below)
Presence of MSU crystals in a symptomatic joint or bursa (ie, in 
synovial fluid) or tophus
Step 3:  Criteria (to be used if sufficient criterion not met)
Clinical
Pattern of joint/bursa involvement during symptomatic 
episode(s) ever a
Ankle or midfoot (as part of monoarticular or oligoarticular 
episode without involvement of the first metatarsophalangeal 
joint
1
Involvement of the first metatarsophalangeal joint (as part of 
monoarticular or oligoarticular episode)
2
Characteristics of symptomatic episode(s) ever
• Erythema overlying affected joint (patient-reported or 
physician-observed)
• Can’t bear touch or pressure to affected joint
• Great difficulty with walking or inability to use affected 
joint
One characteristic
Two characteristics
Three characteristics
1
2
3
Time course of episode(s) ever
Presence (ever) of ≥2, irrespective of antiinflammatory 
treatment:
• Time to maximal pain <24 hours
• Resolution of symptoms in ≤14 days
• Complete resolution (to baseline level) between 
symptomatic episodes
One typical episode
Recurrent typical episodes
1
2
Clinical evidence of tophus
Draining or chalk-like subcutaneous nodule under 
transparent skin, often with overlying vascularity, located in 
typical locations:  joints, ears, olecranon bursae, finger pads, 
tendons (eg, Achilles)
Present
4
Laboratory
Serum urate: Measured by uricase method.
Ideally should be scored at a time when the patient was not 
receiving urate-lowering treatment and it was >4 weeks from 
the start of an episode (ie, during intercritical period); if
practicable, retest under those conditions.
The highest value irrespective of timing should be scored.
<4 mg/dL (<0.24 mmoles/liter) b
6 – <8 mg/dL (0.36 – <0.48 mmoles/liter)
8 – <10 mg/dL (0.48 – <0.60 mmoles/liter)
≥10 mg/dL (≥0.60 mmoles/liter)
–4
2
3
4
Synovial fluid analysis of a symptomatic (ever) joint or bursa 
(should be assessed by a trained observer) c
MSU negative
–2


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Categories
Score
Imaging d
Imaging evidence of urate deposition in symptomatic (ever) 
joint or bursa:
ultrasound evidence of double-contour sign e
or DECT demonstrating urate deposition f
Present (either modality)
4
Imaging evidence of gout-related joint damage: 
conventional radiography of the hands and/or feet 
demonstrates at least 1 erosion g
Present
4
A web-based calculator can be accessed at: http://goutclassificationcalculator.auckland.ac.nz, and through the American College of 
Rheumatology (ACR) and European League Against Rheumatism (EULAR) web sites.
a:  Symptomatic episodes are periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral joint or bursa.
b:  If serum urate level is <4 mg/dL (<0.24 mmoles/liter), subtract 4 points; if serum urate level is ≥4 – <6 mg/dL 
(≥0.24 – <0.36 mmoles/liter), score this item as 0.
c:  If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to show monosodium 
urate monohydrate (MSU) crystals, subtract 2 points.  If synovial fluid was not assessed, score this item as 0.
d:  If imaging is not available, score these items as 0.
e:  Hyperechoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation angle of the 
ultrasound beam (note: false-positive double-contour sign [artifact] may appear at the cartilage surface but should disappear with a 
change in the insonation angle of the probe).
f:  Presence of color-coded urate at articular or periarticular sites.  Images should be acquired using a dual-energy computed tomography 
(DECT) scanner, with data acquired at 80 kV and 140 kV and analyzed using gout-specific software with a 2-material decomposition 
algorithm that color-codes urate.  A positive scan is defined as the presence of color-coded urate at articular or periarticular sites.  
Nailbed, submillimeter, skin, motion, beam hardening, and vascular artifacts should not be interpreted as DECT evidence of urate 
deposition.
g:  Erosion is defined as a cortical break with sclerotic margin and overhanging edge, excluding distal interphalangeal joints and gull wing 
appearance.
A threshold score of 8 classifies an individual as having gout.


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
FYU-981-J086-301
Study Protocol Title:
A Randomized, Multicenter, Double-Blind, Superiority Study 
of Dotinurad (4 mg) and Febuxostat (40 mg) for the Treatment 
of Subjects With Gout
Investigational Product 
Name:
FYU-981/dotinurad
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with China Good Clinical Practice (C-GCP), including the 
Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
Statistical Analysis Plan
FYU-981-J086-301
Eisai
Version 2
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Page 1 of 25
STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
FYU-981-J086-301
Study Protocol 
Title:
A Randomized, Multicenter, Double-Blind, Superiority Study of 
Dotinurad (4 mg) and Febuxostat (40 mg) for the Treatment of 
Subjects With Gout
Date:
25th Aug 2023
Version:
Version 2.0


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REVISION HISTORY
Revision to Version 2.0
Changes
Rationale 
Section
Added wording on the 
definition of Per Protocol 
Analysis set
For clarification purposes.
Section 4.2.1
Updated subgroup 
classification of HUA.
For clarification purposes.
Section 4.2.4, Section  4.3.4, 
Section  4.4.1, Section 4.6.2
Updated the sponsor’s 
grading of laboratory 
values.
To clarify the grading rule 
for the analysis of 
TEMAV.
Appendix 1
Editorial comments are 
made to correct typos.
For clarification purposes.
Throughout the document


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TABLE OF CONTENTS
REVISION HISTORY..........................................................................................................2
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................5
2
INTRODUCTION.........................................................................................................6
2.1
Study Objectives..................................................................................................6
2.1.1
Primary Objective ......................................................................................6
2.1.2
Secondary Objectives .................................................................................6
2.2
Overall Study Design and Plan.............................................................................6
3
DETERMINATION OF SAMPLE SIZE.......................................................................7
4
STATISTICAL METHODS..........................................................................................7
4.1
Study Endpoints...................................................................................................8
4.1.1
Primary Endpoint .......................................................................................8
4.1.2
Secondary Endpoints..................................................................................8
4.2
Study Subjects .....................................................................................................8
4.2.1
Definitions of Analysis Sets........................................................................8
4.2.2
Subject Disposition.....................................................................................8
4.2.3
Protocol Deviations ....................................................................................9
4.2.4
Demographic and Other Baseline Characteristics........................................9
4.2.5
Prior and Concomitant Therapy................................................................10
4.2.6
Treatment Compliance .............................................................................11
4.3
Data Analysis General Considerations................................................................11
4.3.1
Pooling of Centers....................................................................................11
4.3.2
Adjustments for Covariates ......................................................................11
4.3.3
Multiple Comparisons/Multiplicity...........................................................11
4.3.4
Examination of Subgroups........................................................................12
4.3.5
Handling of Missing Data, Dropouts, and Outliers....................................12
4.3.6
Other Considerations................................................................................12
4.4
Efficacy Analyses ..............................................................................................12
4.4.1
Primary Efficacy Analyses .......................................................................12
4.4.2
Secondary Efficacy Analyses ...................................................................13
4.4.3
Other Efficacy Analyses...........................................................................14
4.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................14
4.5.1
Pharmacokinetic Analyses........................................................................14
4.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses....14
4.6
Safety Analyses..................................................................................................14
4.6.1
Extent of Exposure...................................................................................14


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4.6.2
Adverse Events.........................................................................................15
4.6.3
Laboratory Values ....................................................................................16
4.6.4
Vital Signs................................................................................................17
4.6.5
Electrocardiograms...................................................................................18
4.6.6
Other Safety Analyses ..............................................................................18
4.7
Other Analyses...................................................................................................18
4.8
Exploratory Analyses.........................................................................................18
5
INTERIM ANALYSES...............................................................................................19
6
CHANGES IN THE PLANNED ANALYSES ............................................................19
7
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................19
8
PROGRAMMING SPECIFICATIONS .......................................................................21
9
STATISTICAL SOFTWARE......................................................................................21
10
MOCK TABLES, LISTINGS, AND GRAPHS............................................................21
LIST OF IN-TEXT TABLES
Table 1
Vital Sign Criteria .................................................................................17
Table 2
Windowing Rules..................................................................................19
LIST OF IN-TEXT FIGURES
Figure 1
Study Design...........................................................................................7
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................22


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1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ATC
anatomical therapeutic class
BMI
body mass index
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSR
clinical study report
CV
coefficient of variation
DMC
data monitoring committee
DSMB
data safety monitoring board
FAS
full analysis set
LOCF
last observation carried forward
LS
least squares
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects Models for Repeated Measures
NI
noninferiority
PD
pharmacodynamic
PK
pharmacokinetic
QTcF
QT interval corrected for heart rate by Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SD
Standard deviation
SE
standard error 
SI
Système International
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
WHO
World Health Organization


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2
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol FYU-981-
J086-301. The planned analyses will be included in the clinical study report, regulatory 
submissions and/or future manuscripts.  Additional exploratory or post-hoc analyses not 
identified in this SAP may be performed to facilitate interpretation of study results and 
documented in the clinical study report.
This SAP is to be reviewed and approved prior to study database lock.  If any updates are 
made upon blinded review of study data or for any other reasons in the course of the study, 
such modifications and rationale are likewise to be documented and approved prior to 
unblinding of study database. 
2.1
Study Objectives
2.1.1
Primary Objective
To confirm the superiority of dotinurad 4 mg to febuxostat 40 mg on the proportion of 
subjects achieving a serum uric acid (SUA) level ≤6.0 mg/dL at Week 24 in Chinese subjects 
with gout.
2.1.2
Secondary Objectives
•
To confirm the non-inferiority of dotinurad 2 mg to febuxostat 40 mg on the proportion 
of subjects achieving a SUA level ≤6.0 mg/dL at Week 12 in Chinese subjects with gout
•
To compare the proportion of subjects achieving a SUA level ≤6.0 mg/dL at each time 
point between treatment groups
•
To compare the percent reduction in SUA level from baseline at each time point between 
treatment groups
•
To compare the change in SUA level from baseline at each time point between treatment 
groups
•
To compare the SUA level at each time point between treatment groups
•
To evaluate the safety and tolerability of dotinurad
2.2
Overall Study Design and Plan
FYU-981-J086-301 is a 24-week treatment, multicenter, randomized, double-blind, 
superiority, parallel-group study designed to confirm if the efficacy of dotinurad (4 mg/day) 
was superior to febuxostat (40 mg/day) in Chinese subjects 18 years or older in gout.
The study consists of the Screening Phase (4 to 28 days), Treatment I Phase (4 weeks), and 
Treatment II Phase (20 weeks).


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Approximately 450 subjects will be randomized to treatment groups in a ratio of 1:1 and 
received dotinurad 1 mg/day for the first 4 weeks, 2 mg/day for 8 weeks, and 4 mg/day for 12 
weeks; or febuxostat 20 mg/day for the first 4 weeks, and 40 mg/day for 20 weeks.  In 
addition, the randomization will be stratified by SUA level category (<9; 9 to <10; 10 to <11; 
≥11 mg/dL) and body mass index (BMI) category (<25; ≥25 kg/m2).
The study design was shown in Figure 1.
Figure 1
Study Design
R: Randomization
3
DETERMINATION OF SAMPLE SIZE
For the responder rate, assuming a rate of 45% for febuxostat 40 mg and 60% for dotinurad 4 
mg, a sample size of 225 subjects in each group provides approximately 90% power to detect 
a between-group difference in the proportion of responders based on a two-group Chi-square 
test with a 0.05 two-sided significance level.  The primary efficacy analysis is based on the 
FAS.  Hence, 450 is the target number of subjects as the FAS.
4
STATISTICAL METHODS
All final statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects.
1 mg/day
40 mg/day
R
Period:
Starting between 
Day –28 and Day –4
Treatment I
Phase:
Febuxostat
20 mg/day
Day –28
Day 0/
Week 0
Day –4
Week 12
Week 24
Week 4
Day 1
2 mg/day
4 mg/day
Dotinurad
Treatment II
Screening


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4.1
Study Endpoints
4.1.1
Primary Endpoint
Proportion of subjects with ≤6.0 mg/dL in SUA level at Week 24 (LOCF)
4.1.2
Secondary Endpoints
•
Proportion of subjects with ≤6.0 mg/dL in SUA level at Week 12 (LOCF)
•
Proportion of subjects with ≤6.0 mg/dL in SUA level at each time point
•
Mean percent reduction from baseline in SUA level at each time point
•
Mean change from baseline in SUA level at each time point
•
Mean SUA level at each time point
4.2
Study Subjects
4.2.1
Definitions of Analysis Sets
Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 postdose safety assessment.
Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 dose of 
study drug and had at least 1 postdose primary efficacy measurement (ie, SUA level).
Per Protocol (PP) Analysis Set is the subset of subjects in the Full Analysis Set, who had no 
major protocol deviation(s) that may include but not limited to: lower study drug compliance 
less than 80%, administration of prohibited drug.  The criteria for exclusion in this analysis set 
will be made and documented on a case-by-case basis from the viewpoint of reasonable clinical 
judgment prior to treatment unblinding.
The number (percentage) of randomized subjects in each analysis set will be summarized by 
treatment groups. The summaries for FAS will be based on subjects “as randomized”. The 
summary for Safety Analysis Set will be based on subjects “as treated”. Subject data listing 
for adoption of each analysis set will be listed.
4.2.2
Subject Disposition
The number of subjects screened, the number and percentage of screen failures, and their 
primary reason for screen failure will be summarized. Screen failure data will be listed.
The number and percentage of randomized subjects will be summarized by sites for each 
treatment group.  
The number of subjects who received study drug and completed the study will be presented.  
Subjects who prematurely terminated their participation in the study will be summarized by 


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their primary reason for study termination.  Other reasons for study drug and study 
termination will also be summarized.  These tabulations will be produced for all randomized 
subjects by treatment group. Subject-disposition data will be listed.
4.2.3
Protocol Deviations
Protocol deviations will be identified, reviewed and documented by the clinical team prior to 
database lock/treatment unblinding. All protocol deviations will be categorized according to 
major/minor and standard classifications including but not limited to the following:
•
Violations of inclusion/exclusion criteria
•
Noncompliance with or incorrect implementation of protocol procedures
•
Noncompliance of randomized study drug and dosage
•
Use of prohibited concomitant medication
Major protocol deviations will be listed.
4.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics in the Safety Analysis Set, FAS, and PP 
Analysis Set will be summarized for each treatment group using descriptive statistics (eg, n, 
mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for 
categorical variables).  
Continuous variables include age, height, weight, BMI; categorical variables include sex, age 
category (<45; 45 to <55; 55 to <65; ≥65 years old), BMI category (<25; ≥25 kg/m2), race, 
and ethnicity. In addition, the randomization strata will also be summarized by treatment 
group.
MEDICAL HISTORY
Characteristics of gout/hyperuricemia and the prior medications for gout/hyperuricemia for 
the Safety Analysis Set, FAS, and PP Analysis Set will be summarized for each treatment 
group using descriptive statistics.
Continuous variables include:
•
SUA level (mg/dL) and eGFR (mL/min/1.73 m2) measured at the screening
•
Time (year) since diagnosis of gout
•
Time (year) since diagnosis of asymptomatic hyperuricemia, if subjects are applicable
Categorical variables include:
•
Previous urinary calculi (presence, absence) 


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•
Asymptomatic hyperuricemia (presence, absence)
•
Family history (presence, absence) 
•
Previous gouty arthritis (presence, absence)
•
Previous gouty tophi (presence, absence)
•
All medications used in the past for gout/hyperuricemia (none; benzbromarone; 
allopurinol; febuxostat; others)
•
The last medication for gout/hyperuricemia (none; benzbromarone; allopurinol; 
febuxostat; others)
•
Duration of last medication for gout/hyperuricemia (less than 1yr, over 1yr to less than 10 
yrs, over 10yrs, none)
•
SUA level category (<9; 9 to <10; 10 to <11; ≥11 mg/dL)
•
eGFR category (≥30 to <60; 60 to <90; ≥90 mL/min/1.73 m2)
•
Classification of hyperuricemia (overproduction type, underexcretion type, combined 
type, other type).
All medical histories including all current medical conditions as documented by the Medical 
History eCRF will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).
The number and percent of subjects with medical history will be summarized by System 
Organ Class (SOC), preferred term for each treatment group based on Safety Analysis Set.  
The number and percent of subjects with current medical conditions will be summarized by 
System Organ Class (SOC), preferred term for each treatment group based on Safety 
Analysis Set.
A subject data listing of medical history will be provided.
4.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).
Prior medications will be defined as medications that stopped before the first dose of study 
drug.  Concomitant medications will be defined as medications that (1) started before the first 
dose of study drug and were continuing at the time of the first dose of study drug, or (2) 
started on or after the date of the first dose of study drug.  In addition, prior and concomitant 
nonpharmacological procedures will be defined similarly to prior and concomitant 
medications.


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The number (percentage) of subjects who take prior and concomitant medications will be 
summarized on the Safety Analysis Set by treatment group, Anatomical Therapeutic 
Chemical class (ATC), and World Health Organization Drug Dictionary-preferred term (PT).
The number (percentage) of subjects with prior/ concomitant nonpharmacological procedures 
will be summarized on the Safety Analysis Set by treatment group.
If the Safety Analysis Set and FAS differ, then the summaries will be repeated on the FAS. 
All medications and nonpharmacological procedures will be presented in subject data 
listings.
4.2.6
Treatment Compliance
Compliance for each study drug during the entire study duration will be calculated on the 
basis of number of tablets dispensed, lost and returned, separately for each type of tablet, for 
Safety Analysis Set.
Compliance =
 	
   	   	
   
	  

      	   
 
	  

× 100 (%)
Treatment compliance will be summarized using descriptive summary statistics and number 
(percentage) of subjects using the categories <80%, ≥ 80% to ≤100%, >100% to ≤ 120%, and 
> 120% for each treatment group.  
4.3
Data Analysis General Considerations
4.3.1
Pooling of Centers 
This study is a multicenter study.  Due to expected small number of subjects from some centers, 
subjects from all centers will be pooled for all primary analyses.
4.3.2
Adjustments for Covariates
Randomization stratification factors, BMI category (<25; ≥25 kg/m2) and SUA level category 
(<9; 9 to <10; 10 to <11; ≥11 mg/dL) based on CRF data, will be used in stratified analysis 
for the primary and secondary efficacy analysis. These factors will be adjusted as covariates 
in statistical model.
4.3.3
Multiple Comparisons/Multiplicity
Treatment group comparison for the primary efficacy endpoint will be conducted at α = 0.05 
(2-sided). No multiplicity adjustments will be performed for other efficacy analyses 
including sensitivity analysis based on non-responder imputation and supplemental analysis 
based on PPS.


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4.3.4
Examination of Subgroups
Various subgroup analyses are planned and pre-specified as described in each analysis 
section in this SAP.  No hypothesis testing will be performed in the subgroup analyses.
The subgroups include: BMI category (<25; ≥25 kg/m2), SUA level category (<9; 9 to <10; 
10 to <11; ≥11 mg/dL), and classification of hyperuricemia (overproduction type, 
underexcretion type, combined type, other type).
BMI and SUA category are those assessed at the baseline. Classification of hyperuricemia 
group is defined as entered on the study CRF.
4.3.5
Handling of Missing Data, Dropouts, and Outliers
Specific methods for handling missing values in analyzing the primary and secondary 
endpoints are detailed in each section.  In general, missing values due to subject 
discontinuation, missed or unusable assessments will not be imputed unless otherwise 
specified.
4.3.6
Other Considerations
Not applicable.
4.4
Efficacy Analyses
The FAS will be used as the primary population for all efficacy analyses. The unit of SUA 
will be based on mg/dL for all efficacy analyses.
4.4.1
Primary Efficacy Analyses
The analysis for the difference in the proportion of subjects with ≤ 6.0 mg/dL in SUA level 
(i.e., responder rate) at Week 24 (LOCF) (see section 7) between dotinurad 4 mg and 
febuxostat 40 mg will be conducted based on a Cochran–Mantel–Haenszel (CMH) test 
stratified by baseline SUA level and baseline BMI.  The difference in responder rate between 
dotinurad 4 mg and febuxostat 40 mg and the stratified 95% confidence interval based on 
Mantel-Haenszel method adjusting for the baseline SUA level and baseline BMI will be 
estimated.  Also, the number (percentage) of responder and the asymptotic 95% confidence 
interval will be presented by treatment group.  The same primary efficacy analysis mentioned 
above will be repeated supplementally based on the PP Analysis Set.  
For the primary efficacy endpoint, non-responder imputation method on FAS will also be 
implemented as a sensitivity analysis, which will handle the missing data of SUA at Week 24 
as non-responder (see section 7).
The following subgroup will be investigated for the responder rate at Week 24 (LOCF):
•
SUA level category (<9; 9 to <10; 10 to <11; ≥11 mg/dL)


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•
BMI category (<25; ≥25 kg/m2)
•
Classification of hyperuricemia (overproduction type, underexcretion type, combined 
type, other type)
For the subgroup analyses, the number (percentage) of responder and the 95% confidence 
interval will be presented by treatment group. Furthermore, the difference in responder rate
and unstratified 95% confidence interval will also be presented.
4.4.2
Secondary Efficacy Analyses
For all the secondary efficacy analyses, no multiplicity adjustment will be made.
•
Proportion of subjects with ≤6.0 mg/dL in SUA level at Week 12 (LOCF)
The difference in responder rate at Week 12 (LOCF) between dotinurad 2 mg and febuxostat 
40 mg and the stratified 95% confidence interval will be estimated based on Mantel–
Haenszel method adjusting for the baseline SUA level and baseline BMI.  The prespecified 
non-inferiority margin will be –10% in this analysis, which will be for the reference purpose 
only.  The number (percentage) of responder and the asymptotic 95% confidence interval at 
Week 12 (LOCF) (see section 7) will be presented by treatment group.  
The same analysis mentioned above will be repeated supplementally based on the PP 
Analysis Set.
•
Proportion of subjects with ≤6.0 mg/dL in SUA level at each time point
The number (percentage) of responder at each visit (Week 4, Week 8, Week 12, Week 16, 
Week 20, Week 24) will be presented by treatment group.
Responder rate for each treatment group at each visit (Week 4, Week 8, Week 12, Week 12 
(LOCF), Week 16, Week 20, Week 24, Week 24 (LOCF)) will be presented by bar chart.
•
Mean percent reduction from baseline in SUA level at each time point
The mean percent reduction from baseline in SUA level at each visit (Week 4, Week 8, Week 
12, Week 12 (LOCF), Week 16, Week 20, Week 24, Week 24 (LOCF)) will be summarized 
by treatment group using descriptive summary statistics.  In addition, box-plot will be used 
for graphical presentation.
The following subgroup analysis will be repeated:
•
SUA level category (<9; 9 to <10; 10 to <11; ≥11 mg/dL)
•
BMI category (<25; ≥25 kg/m2)
•
Classification of hyperuricemia (overproduction type, underexcretion type, combined 
type, other type)
In addition, the mean percent reduction and difference in least squares (LS) means between 
dotinurad and febuxostat, and corresponding 95% confidence interval will be estimated based 


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on the mixed-effects models for repeated measures (MMRM).  The model will be adjusted 
for the baseline SUA value, baseline SUA level category (<9; 9 to <10; 10 to <11; ≥11 
mg/dL) and baseline BMI category (<25; ≥25 kg/m2), treatment, time (Week 4, Week 8, 
Week 12, Week 16, Week 20, Week 24) and the interaction of treatment by time.  The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom.  
The unstructured covariance matrix (UN) will be used in the analysis. In the case of 
nonconvergence of UN, the toeplitz covariance matrix (TOEP) will be used. In the case of 
nonconvergence with TOEP, the autoregressive covariance matrix [AR (1)] will be used in 
the model.  The use of MMRM will be based on the assumption of missing at random 
(MAR), which means no imputation for missing values will be conducted.
•
Mean SUA level and mean change from baseline in SUA level at each time point
The mean actual value and the mean change from baseline in SUA level at each time point 
(Baseline, Week 4, Week 8, Week 12, Week 12 (LOCF), Week 16, Week 20, Week 24, 
Week 24 (LOCF)) will be summarized by treatment group using descriptive summary 
statistics and presented by box-plot.
4.4.3
Other Efficacy Analyses
No other efficacy analyses are planned for this study.
4.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
Not applicable 
4.5.1
Pharmacokinetic Analyses
Not applicable 
4.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Not applicable 
4.6
Safety Analyses
All safety analyses will be performed based on observed data using the Safety Analysis Set.  
Safety data will be summarized on an “as treated” basis using descriptive statistics or 
frequency count only.  No hypothesis testing will be performed for safety analyses.  Study 
Day 1 for all safety analyses is defined as the date of the first dose of study drug.
4.6.1
Extent of Exposure
The extent of exposure (duration of exposure) to study drug will be summarized using 
descriptive statistics by treatment group.  Duration of exposure of study drug will be defined 
as the number of days between the date the subject received the first dose of study drug and 
the date the subject received the last dose of study drug, inclusive. 


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4.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 24.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during time 
from the first dose of study drug to 28 days after the subject’s last dose, having been absent 
at pretreatment or 
•
Reemerges during treatment, having been present at pretreatment but stopped before 
treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
An overview table of TEAE, including number of subjects with TEAEs, treatment-related 
TEAEs, severe TEAEs, SAEs (deaths and other SAEs), TEAEs leading to study drug 
adjustment (withdrawal, reduced, interrupted) will be provided by treatment group.
In addition, the following summaries will be produced for the TEAEs by treatment group:
•
Incidence of TEAEs by PT in descending order 
•
Incidence of TEAEs by SOC and PT 
•
Incidence of treatment-related TEAEs by SOC and PT
•
Incidence of TEAEs by SOC, PT, and severity
•
Incidence of treatment-related TEAEs by SOC, PT, and severity
•
Incidence of TEAEs leading to study drug withdrawal by SOC and PT
•
Incidence of serious TEAEs by SOC and PT
•
Incidence of non-serious TEAEs by SOC and PT
•
Incidence of TEAE by PT and time of onset (every 4 weeks)
•
Incidence of treatment-related TEAE by PT and time of onset (every 4 weeks)
If a subject experiences more than one TEAE within a preferred term, the subject will be 
counted only once in the calculation of incidence of TEAE within that preferred term.  
Similarly, if a subject experiences more than one TEAE within a SOC, the subject will be 
counted only once in the calculation of incidence of TEAE within that SOC.  If a subject 
experiences more than one TEAE within a preferred term (or SOC), the occurrence with the 


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highest severity will be used in the calculation of the incidence of TEAE within that 
preferred term (SOC) by severity.  If a subject experiences more than one TEAE within a 
preferred term (or SOC), the occurrence considered most closely related to study drug will be 
used in the calculation of the incidence of TEAE with that preferred term (SOC) by 
relationship (given by investigator).
In addition, the following TEAEs of interest will be summarized by PT and treatment group.
•
Urinary calculi defined by MedDRA HLGT “Urolithiases”
•
Liver injury defined by MedDRA SMQ “Hepatic disorders”
•
Acute renal failure defined by MedDRA SMQ “Acute renal failure”
TEAEs for the following subgroups will be summarized by SOC, PT and treatment group:
•
SUA level category (<9; 9 to <10; 10 to <11; ≥11 mg/dL)
•
BMI category (<25; ≥25 kg/m2)
•
Classification of hyperuricemia (overproduction type, underexcretion type, combined 
type, other type)
A subject data listing of all AEs, all AEs leading to death, all SAEs and all AEs leading to 
discontinuation from study drug will be provided.
4.6.3
Laboratory Values
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in protocol Section 9.5.1.4.4, the actual value and the 
change from baseline to each postbaseline visit will be summarized by visit and treatment 
group using descriptive statistics.  Qualitative parameters listed in protocol Section 9.5.1.4.4 
will be summarized using frequencies (number and percentage of subjects), and changes 
from baseline to each postbaseline visit will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit.  Similar shift tables will also compare the baseline 
LNH classification to the LNH classification for the highest and lowest value.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  A TEMAV is defined as a postbaseline value with an increase from baseline to 
a grade of 2 or higher.  When displaying the incidence of TEMAVs, each subject may be 
counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.


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The number (percentage) of subjects with TEMAV (markedly abnormal high/low) will be 
summarized by treatment group.
The number (percentage) of subjects who met the following criteria for the hepatic test at the 
same time will be summarized by treatment group.  If a subject met the criteria more than 
once for available laboratory data, the subject will be counted only once in the calculation of 
the incidence.  
•
Elevated AST or ALT lab value that is greater than or equal to 3× ULN
•
Elevated total bilirubin lab value that is greater than or equal to 2× ULN
•
Alkaline phosphatase lab value that is less than 2× ULN
A subject data listing of laboratory values will be provided.
4.6.4
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse and 
temperature) and weight, and changes from baseline will be presented by visit and treatment 
group.  Analysis of changes from baseline will be based on the number of subjects with both 
nonmissing baseline and relevant postbaseline results.
The number (percentage) of subjects with at least 1 postbaseline clinically notable values in 
vital signs and weight will be summarized by treatment group.  Clinically notable values will 
be defined in the Table 1.   A subject data listing of vital signs and weight will be provided.
Table 1
Vital Sign Criteria
Variable
Criterion valuea
Change relative to 
baselinea
Clinically notable range
Pulse
> 120 bpm
Increase of ≥15 bpm
H
< 50 bpm
Decrease of ≥15 bpm
L
Systolic BP
> 180 mmHg
Increase of ≥20 mmHg
H
< 90 mmHg
Decrease of ≥20 mmHg
L
Diastolic BP
> 105 mmHg
Increase of ≥15 mmHg
H
< 50 mmHg
Decrease of ≥15 mmHg
L
Weight
--
Increase of ≥7% 
H
--
Decrease of ≥7%
L
BP = blood pressure, H = high, L = low.
a
Clinically notable means that a value must meet the criterion value and must attain the specified 
magnitude of change relative to baseline.


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4.6.5
Electrocardiograms
Descriptive statistics for ECG parameters (QTcF, QT, PR, QRS, RR and heart rate) and 
changes from baseline will be presented by visit and treatment group.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) by visit and 
treatment group.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF will be summarized.  Clinically abnormal ECG results in QTcF will be 
categorized as follows:
Absolute QTcF interval prolongation:
•
QTcF interval >450 ms
•
QTcF interval >480 ms
•
QTcF interval >500 ms
Change from baseline in QTcF interval:
•
QTcF interval increases from baseline >30 ms
•
QTcF interval increases from baseline >60 ms
A subject data listing of ECG results will be provided.
4.6.6
Other Safety Analyses
No analyses are planned for pregnancy tests, and abdominal ultrasound and plain abdominal 
radiography.
A subject data listing of urinary calculi on abdominal ultrasound/abdominal radiography will 
be provided.
4.7
Other Analyses
Not applicable.
4.8
Exploratory Analyses
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are 
performed will be appropriate titled and labeled as exploratory and will be clearly 
distinguished from planned analyses when results are reported in the Clinical Study Report.


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5
INTERIM ANALYSES
Not applicable.
6
CHANGES IN THE PLANNED ANALYSES
Major changes of planned analysis from SAP version 1.0 are listed in the revision history. 
7
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
The data will be handled as follows. The sponsor will determine how to handle all data prior 
to data base lock.
Baseline Assessment
Unless otherwise specified, the baseline measurement is the last observed measurement 
among all available measurements, including from unscheduled assessments, prior to the first 
dose of randomized study drug for a given assessment.
Change from Baseline, Percent Change from Baseline
Change from baseline will be defined as: Post-baseline value - Baseline value
% change from baseline will be defined as: (Change from baseline / Baseline value) * 100
For efficacy analysis, % reduction from baseline will be calculated as: {(Baseline value –
post-baseline value) / Baseline value} *100.
Visit Window
The protocol specified visits/weeks and corresponding time windows used for visit-wise 
analyses are presented in Table 2 in terms of days relative to the date of first dose (i.e., Day 
1).
Table 2
Windowing Rules
Week
Target Visit Date (Study day)
Visit Window (Study day)
Baseline a
1
–
Week 4
28
2 – 42
Week 8
56
43 – 70
Week 12
84
71 – 98
Week 12 (LOCF) b d
–
–
Week 16
112
99 – 126
Week 20
140
127 – 154
Week 24
168
155 – 182


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Table 2
Windowing Rules
Week
Target Visit Date (Study day)
Visit Window (Study day)
Week 24 (LOCF) c d
–
–
End of Treatment e
–
–
a
The last non-missing values including unscheduled assessments on or prior to the date of first dose.
b
The last non-missing values including unscheduled assessments up to Day 98 (inclusive) will be carried 
forward as the data for the efficacy analysis, which is known as Week 12 (LOCF).
c
The last non-missing values including unscheduled assessments up to Day 182 (inclusive) will be carried 
forward as the data for the efficacy analysis, which is known as Week 24 (LOCF).
d
For subjects who discontinued the study, the last non-missing values up to 14 days after the date of last 
dose will be carried forward as the data for the efficacy analysis.
e
The last non-missing values including unscheduled assessments during the study will be used for the 
safety analysis only.
In case of multiple assessments within the same visit window, the assessment closest to the 
target visit day will be used in data analyses; in the event of two assessments being equally 
close to the scheduled visit day, the latest assessment in time will be used. In the event of two 
assessments being equally close to the scheduled visit day, the data will be considered in an 
individual case.
Missing data handling
•
Non-responder imputation for responder analysis of SUA (as binary variable)
Missing values will be considered as non-responders. This handling will be applied to the 
sensitivity analysis of the primary efficacy analysis.
•
Longitudinal data analysis of SUA using MMRM (as continuous variable)
SUA will be analyzed using MMRM based on the assumption of missing at random (i.e., 
MAR).  This analysis assumes subjects with missing values behave the same as the observed 
data within that treatment group, i.e., the missingness is independent of unobserved data after 
accounting for the observed data in the model.
•
AE severity and AE relationship to study drug
For the purpose of summarizing maximum severity, if the severity of an AE is missing for a
subject, then, if this subject has another AE with the same preferred term that has “severe”
severity, the maximum severity of the AE will be noted as “severe’; otherwise the maximum
severity will be noted as missing. Similarly, for the purpose of summarizing treatment-related 
TEAE, if the relationship of an AE to study drug is missing, the AE will be noted to be
related.
•
Determination of TEMAVs for laboratory values
For determining TEMAVs of laboratory values, a missing baseline laboratory value will be 
assumed to be of grade 0.


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Handling of below lower quantification values in laboratory tests
In the cases where laboratory result contains below lower quantification (BLQ) value, it will 
be replaced to the lower limit value of quantification (LLOQ) for summary tables.
Handling of hemolysis or lipemia in laboratory specimen
If the hemolysis or lipemia occurs, those data will not be used in the analysis of laboratory 
test results and efficacy analysis (i.e., SUA).
8
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
9
STATISTICAL SOFTWARE
Statistical analyses will be performed using SAS version 9.4 (or later versions).  In the event 
that certain features graphical analyses cannot be implemented by SAS, other validated 
statistical software can be employed.  
10 MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.


Statistical Analysis Plan
FYU-981-J086-301
Eisai
Version 2
Confidential
Page 22 of 25
Appendix 1
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
Alkaline phosphatase 
>ULN – 2.5ULN if 
baseline was normal; 
2.0 – 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
ALT
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
>3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
AST
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
>3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN if 
baseline was normal; 
1.0 – 1.5baseline if 
baseline was abnormal
>1.5 – 3.0ULN if 
baseline was normal; 
>1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 10.0ULN if 
baseline was normal; 
>3.0 – 10.0baseline if 
baseline was abnormal
>10.0ULN if 
baseline was normal; 
>10.0baseline if 
baseline was 
abnormal
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
Ionized calcium <LLN 
- 1.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
Ionized calcium <1.0 -
0.9 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
Ionized calcium <0.9 -
0.8 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Ionized calcium <0.8 
mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
Ionized calcium >ULN 
- 1.5 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
Ionized calcium >1.5 -
1.6 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
Ionized calcium >1.6 -
1.8 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Ionized calcium >1.8 
mmol/L
Creatinine
>ULN – 1.5ULN
>1.5 - 3.0baseline;
>1.5 – 3.0ULN
>3.0baseline;
>3.0 – 6.0ULN
>6.0ULN


Statistical Analysis Plan
FYU-981-J086-301
Eisai
Version 2
Confidential
Page 23 of 25
Grade 1
Grade 2
Grade 3
Grade 4
GGT (γ-glutamyl transpeptidase) 
>ULN – 2.5ULN if 
baseline was normal; 
2.0 - 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 - 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 - 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
>7.0 mmol/L
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<3.0 – 2.5 mmol/L
<2.5 mmol/L
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
>160 mmol/L
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125-129 mmol/L
120-124 mmol/L
<120 mmol/L


Statistical Analysis Plan
FYU-981-J086-301
Eisai
Version 2
Confidential
Page 24 of 25
Grade 1
Grade 2
Grade 3
Grade 4
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.


Statistical Analysis Plan
FYU-981-J086-301
Eisai
Version 2
Confidential
Page 25 of 25
SIGNATURE PAGE
Author:
[electronic signature in eDMS]
Date
Japan/Asia Clinical Data Science Department, CEG 
fulfillment, DHBL
Eisai Co., Ltd.
Approval:
[electronic signature in eDMS]
Head of Biostatistics
Biostatistics Group, Japan/Asia Clinical Data Science 
Department, CEG fulfillment, DHBL
Eisai Co., Ltd. 
Date
[electronic signature in eDMS]
Study Director
Clinical Development Department
Eisai China Inc.
Date
PPD
PPD
PPD