Clinical trial NCT03226899
Conditions: Gout Chronic Kidney Disease (CKD)
Sponsor: Ironwood Pharmaceuticals, Inc.
Start date: 2017-07-19; Completion date: 2019-02-25
Enrollment: 242 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the safety and efficacy of lesinurad administered with an XOI versus a placebo plus an XOI in gout participants who have moderate renal impairment and who are not at target level of serum urate (sUA).

Detailed description:
This postmarketing study is a randomized, double-blind, placebo-controlled study to evaluate safety (with particular focus on renal and cardiovascular events) and efficacy of lesinurad 200 mg once daily (QD) in combination with an XOI for up to 24 months compared with XOI monotherapy, in participants with gout and moderate renal impairment who have not reached target sUA levels (\<6.0 mg/dL) on an XOI alone.

Arms: arm 1: lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI arm 2: placebo tablet QD plus a stable, medically appropriate dose of an XOI
Interventions: intervention 1: Lesinurad intervention 2: XOI intervention 3: Placebo intervention 4: colchicine intervention 5: corticosteroids
Intervention descriptions: intervention 1: 200 mg oral tablet intervention 2: All participants must be on a stable, medically appropriate dose of XOI as their sole urate-lowering therapy (ULT) indicated for the treatment of gout for at least 4 weeks prior to Screening and throughout the Screening Period. This stable dose of XOI will be maintained throughout the study period. intervention 3: matching placebo oral tablet intervention 4: Gout flare prophylaxis: commercially available colchicine is provided through the Month 6 study visit. Actual colchicine dose (0.5 or 0.6 mg qd) and frequency were adjusted based on the local label, subject medical history, and clinical judgement. intervention 5: Gout flare prophylaxis: Participants unable to take colchicine are permitted to take a short course of low-dose oral corticosteroids up to the Month 3 study visit

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL:  RDEA594-401
Protocol Title:
A Phase 4, Randomized, Double-Blind, Multicenter, 
Placebo-Controlled Study to Evaluate the Safety and Efficacy of 
Lesinurad 200 mg in Combination With a Xanthine Oxidase 
Inhibitor (XOI), Compared With an XOI Alone, in Subjects With 
Gout and Estimated Creatinine Clearance 30 to <60 mL/min Who 
Have Not Achieved Target Serum Uric Acid Levels on an XOI 
Alone
Brief Title:
Lesinurad in Subjects With Gout and Moderate Renal Impairment
Study Number:
RDEA594-401
Phase:
4
Investigational Product:
Lesinurad
Population/Indication:
Gout with estimated creatinine clearance 30 to <60 mL/min
Sponsor:
Ironwood Pharmaceuticals, Inc. 
Sponsor Medical 
Monitor:
Protocol Version:
3
Protocol Date:
21 June 2017
Confidentiality Statement
This document contains confidential information, which should not be copied, referred to, 
released, or published without prior written approval from Ironwood Pharmaceuticals, Inc.


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Protocol:  RDEA594-401
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PROTOCOL SYNOPSIS
Sponsor:
Ironwood Pharmaceuticals, Inc.
Name of Finished Product:
Lesinurad 200 mg tablets
Name of Active Ingredient:
Lesinurad
Protocol Title:  A Phase 4, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study 
to Evaluate the Safety and Efficacy of Lesinurad 200 mg in Combination With a Xanthine 
Oxidase Inhibitor (XOI), Compared With an XOI Alone, in Subjects With Gout and Estimated 
Creatinine Clearance 30 to <60 mL/min Who Have Not Achieved Target Serum Uric Acid 
Levels on an XOI Alone
Study Number:  RDEA594-401
Study Phase:  4
Study Type:  Postapproval Controlled Safety and Efficacy Study
Investigators and Study Sites:
Up to approximately 300 study sites in North America and Europe.
Primary Objective:

To evaluate the safety over 24 months of lesinurad 200 mg once daily (qd) when used in 
combination with a xanthine oxidase inhibitor (XOI), compared with XOI alone, in 
subjects with gout and moderate renal impairment (estimated creatinine clearance 30 to 
<60 mL/min) who have not reached target serum uric acid (sUA) levels on an XOI alone.
Efficacy Objective:

To evaluate the efficacy over 24 months of lesinurad 200 mg qd in combination with an
XOI, compared with XOI alone, in subjects with gout and moderate renal impairment 
who have not reached target sUA levels on an XOI alone.
Methodology:
Subjects with gout, moderate renal impairment (30 to <60 mL/min), and who are not at target 
sUA of <6.0 mg/dL on XOI alone will be enrolled in this study. The study will include an 
approximate 1-month Screening Period, a 24-month Double-Blind Treatment Period, and a 
1-month post-treatment Follow-Up Period.


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All subjects must be on a stable, medically appropriate dose of XOI as their sole urate-lowering 
therapy (ULT) indicated for the treatment of gout for at least 4 weeks prior to Screening and 
throughout the Screening Period. This stable dose of XOI will be maintained throughout the 
study period. Subjects who qualify for the study will be randomized in a double-blind fashion to 
1 of 2 treatment groups in a 1:1 ratio:

LESU + XOI:  lesinurad 200 mg qd and XOI

PBO + XOI:  placebo qd and XOI
Randomization will be stratified by estimated creatinine clearance (eCrCl) subgroup (30.0 to 
<45.0 mL/min or 45.0 to <60.0 mL/min using the average of the 2 Screening Visits and 
calculated by the Cockcroft-Gault formula using ideal body weight), Baseline measurable target 
tophi status (present/absent), and type of XOI (allopurinol or febuxostat). This study will enroll 
approximately 50% of subjects with eCrCl 30.0 to <45.0 mL/min and approximately 50% with 
eCrCl 45.0 to <60.0 mL/min.
Subjects will take investigational product (IP; lesinurad or placebo) qd in combination with their 
prescribed stable dose of XOI in the morning with adequate fluid intake for up to 24 months. 
Gout flare prophylaxis with colchicine is required from the Baseline Visit through the Month 6 
Study Visit, consistent with treatment guideline recommendations for gout flare prophylaxis to 
reduce the potential for acute gout flares associated with initiation of ULTs. Subjects who have a 
documented intolerance or allergy to colchicine or who are taking a concomitant medication 
contraindicated for use with colchicine are permitted to take low-dose oral corticosteroids 
(defined as ≤10 mg/day of prednisone, or prednisolone, or their equivalent) for a short course, 
such as through the Month 3 study visit. The use of nonsteroidal anti-inflammatory drugs 
(NSAIDs) for gout flare prophylaxis is not permitted.
After initiating IP, subjects will return to the study site at Month 1, at Month 3, and every 
3 months thereafter until the end of the Treatment Period (Month 24). At each visit, safety and 
efficacy assessments will be performed.
Subjects who complete the Treatment Period or who plan to withdraw from the study early 
should complete an End of Study Visit approximately 1 month after study completion/treatment 
discontinuation.
Subjects who permanently discontinue IP early for any reason, including inability to continue 
dosing with XOI, should complete an End of Treatment Visit as soon as possible followed by a 
Post-End of Treatment Visit 1 month after the End of Treatment Visit. Subjects should then 
continue on study and follow the protocol-defined schedule of events, including the End of Study 
Visit.
An independent Data Monitoring Committee (IDMC) will evaluate the safety data periodically to 
protect subject welfare and to identify potential safety signals. An independent Cardiovascular 
Endpoints Adjudication Committee (CEAC) will routinely assess all serious adverse events 
(SAEs) and other prospectively-defined adverse events (AEs) for cardiovascular (CV) related 
events. An independent Renal Events Adjudication Committee (REAC) will routinely evaluate
and categorize all serious prospectively-defined renal-related and kidney stone AEs, and any 
additional SAEs deemed by the REAC Chair to be relevant for adjudication, and will assess the 
likelihood that potential contributing factors, including IP, contributed to the event. CEAC and 


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REAC assessments will be performed in a blinded fashion.
AEs of special interest that will be evaluated in this study include renal events (eg, renal-related 
AEs and kidney stone AEs) that are serious or lead to permanent discontinuation of IP, and all 
potential CV events. Additional information will be required for these events and recorded on the 
case report forms (CRFs).
Number of Planned Subjects:
Approximately 600 subjects will be enrolled (300 per treatment group).
Eligibility Criteria (not a complete list):
Key Inclusion Criteria

Subject is male or female, ≥18 years and ≤85 years of age.

Subject has a diagnosis of gout.

Subject has moderate renal impairment with estimated creatinine clearance (eCrCl 
calculated by the Cockcroft-Gault formula using ideal body weight) 25.0 to 
≤65.0 mL/min at Screening Visits 1 and 2 and an average eCrCl for both screening visits 
of 30.0 to <60.0 mL/min.

Subject has been taking an XOI as ULT indicated for the treatment of gout for at least 
4 weeks prior to Screening and throughout the Screening Period at a stable, medically 
appropriate dose, as determined by the Investigator. The minimum dose of allopurinol is 
200 mg daily, and the minimum dose of febuxostat is the lowest approved dose per the 
local product label.

Subject has a serum uric acid level ≥6.0 mg/dL (357 µmol/L) at Screening Visits 1 and 2.
Key Exclusion Criteria

Subject had unstable angina, New York Heart Association class III or IV heart failure, 
myocardial infarction, or stroke within the last 6 months prior to randomization; or had a 
deep venous thrombosis within the previous 3 months prior to randomization.

Subject has uncontrolled hypertension (defined as systolic pressure above 160 or 
diastolic pressure above 95 mm Hg at either Screening Visits 1 or 2).

Subject has severe hepatic impairment (defined as Child-Pugh Class C) or is known 
human immunodeficiency virus (HIV) positive.

Subject is a solid organ transplant recipient.

Subject has a urine protein of 3+ or higher by dipstick by the central laboratory at 
Screening Visit 2.

Subject has a history of glomerulonephritis.

Subject is unable to initiate gout flare prophylaxis with colchicine or low-dose oral 
corticosteroids at Baseline.

Subject has a gout flare during the Screening Period.


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
Subject is pregnant or breastfeeding.
Investigational Product, Dose, and Mode of Administration:
Lesinurad tablets or matching placebo will be supplied by the Sponsor.
Dose:  200 mg qd.
All doses of IP should be taken in the morning with food and 1 cup (8 oz; 240 mL) of water and
must be taken at the same time as the XOI. Missed doses should not be taken later in the day 
(eg, in the afternoon or evening) or made up on the following day. Subjects should be instructed 
to drink 2 liters (68 oz) of liquid a day.
Other Study Treatments, Dose, and Mode of Administration:
Commercially available XOI (allopurinol or febuxostat) tablets will be provided at the stable 
dose that subjects were taking at Screening.
Dose:  the dose and dosing regimen of XOI should not be changed during the study, unless 
decreased for toxicity.
Commercially available gout flare prophylaxis, colchicine, will be provided through the Month 6 
study visit. The dose will be 0.5 or 0.6 mg qd based on the local label. The frequency may be 
adjusted based on the local label, medical history of the subject, and clinical judgement (ie, taken
every other day or 3 times a week if needed as appropriate, particularly for subjects with lower 
eCrCl). Subjects unable to take colchicine are permitted to take low-dose oral corticosteroids (ie, 
≤10 mg/day of prednisone, or prednisolone, or their equivalent) for a short course, such as 
through the Month 3 study visit based on the Investigator’s discretion.
Duration of Study and Treatment:
The overall duration of the study is anticipated to be approximately 5 years. The total duration of 
study participation for each subject (from Screening Visit 1 through the last study visit) is 
anticipated to be up to approximately 26 months.
Criteria for Evaluation:
Study Assessments:
Safety assessments will include an evaluation of AEs with particular focus on renal and CV 
events, clinical laboratory parameters (hematology, serum chemistry, urinalysis), and vital signs.
Efficacy assessments will be based on an evaluation of sUA levels. Additional efficacy 
assessments will explore gout flares, tophi resolution, and patient-reported outcomes (eg, 
EuroQol Five Dimensions Questionnaire 3 level, Sheehan Disability Score, and Work 
Productivity and Activity Impairment Questionnaire: Specific Health Problem).
Other assessments will include physical examinations and electrocardiograms (ECGs), as well as 
collecting medical history, Baseline gout characteristics, previous and concomitant therapies, and 
treatment compliance.
Safety Endpoints

Absolute and percent change from Baseline in eCrCl to Month 24.


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
Absolute and percent change from Baseline in eCrCl over the study period, including the 
last value on and off treatment.

Incidence of serum creatinine (sCr) elevations (≥1.5 × Baseline) over the study period.

Incidence of subjects meeting criteria (eg, based on sCr or eCrCl criteria) for treatment 
discontinuations over the study period.

Incidence of renal-related and kidney stone treatment-emergent AEs (TEAEs) and serious 
AEs (SAEs).

Prevalence of contributing factors to renal SAEs as adjudicated by the REAC.

Incidence of CEAC-adjudicated Major Adverse Cardiovascular Event (MACE; CV death, 
nonfatal myocardial infarction, and nonfatal stroke).

Incidence of CEAC-adjudicated MACE or hospitalization for unstable angina (MACE+).
Efficacy Endpoints

Key efficacy endpoint:  Proportion of subjects who achieve sUA <6.0 mg/dL at Month 6.

Absolute and percent change from Baseline in sUA at each visit.

Proportions of subjects who achieve sUA <6.0 mg/dL at each visit.
Exploratory Endpoints

Percent change from Baseline in the sum of the areas of all target tophi at scheduled 
visits, among subjects with ≥1 target tophus at Baseline.

Proportion of subjects who experienced complete resolution of at least 1 target tophus at 
any time during study, among subjects with ≥1 target tophus at Baseline.

Functional impairment as assessed employing the Sheehan Disability Scale (individual 
domains as well as total functional impairment) at last on-study visit.

Work productivity as assessed employing the Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem (absenteeism, presenteeism, work productivity 
loss, and activity impairment) at last on-study visit.

Health status as assessed employing the EuroQol Five Dimensions Questionnaire 3 level
(both descriptive system and visual analogue scale) at last on-study visit.

Proportion of subjects with gout flares at each 3-month interval during the study period.
Statistical Methods:
The Intent-to-Treat (ITT) Population will be defined as all randomized subjects who received 
at least 1 dose of IP (lesinurad or placebo). This will be the primary population for efficacy 
analyses and subjects will be analyzed based on the randomized treatment assigned.
The Safety Population will be defined as all randomized subjects who received at least 1 dose of 
IP (lesinurad or placebo). Subjects will be analyzed based on the randomized treatment assigned. 
Any major deviations from the randomized treatment assignment will be listed and considered 


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when interpreting the safety data.
The main estimands to address the safety objective are the absolute and percent changes from 
Baseline to Month 24 in eCrCl, assessed in the Safety Population, with treatment difference 
estimated using a mixed model repeated measures (MMRM) and missing data imputed 
separately for each treatment group assuming missing at random (MAR).
Absolute and percent changes from Baseline to Month 24 in eCrCl will be assessed using 
MMRM analysis that includes terms for treatment (lesinurad [LESU] + XOI and placebo 
[PBO] + XOI), visit, treatment by visit interaction, stratification factors (type of XOI [allopurinol 
or febuxostat], Baseline measurable target tophi status [present/absent], and Screening eCrCl 
[30.0 to <45.0 mL/min or 45.0 to <60.0 mL/min], as appropriate), and Baseline eCrCl as 
covariates. The model will assume an unstructured covariance matrix. Least-square (LS) mean 
by treatment and LS mean difference between LESU + XOI and PBO + XOI alone will be 
estimated from the MMRM analysis, along with the 95% confidence interval (CI) of LS mean 
difference.
All subjects should be followed for safety events even if they discontinue IP (lesinurad or 
placebo), as permitted. Prior to performing MMRM analysis, renal function data that are 
collected after subjects discontinue IP will be set to missing. All missing data will be imputed 
using multiple imputation methodology assuming MAR and separate imputation models for the 
LESU + XOI and PBO + XOI groups. Sensitivity analysis will include all available data 
(including data after subjects discontinue IP) and impute only for missing data assuming MAR. 
Additional sensitivity analysis will be performed using multiple imputation assuming missing 
not at random, depending on the nature of missing data and early treatment discontinuations 
(eg, subjects discontinuing early due to worsening renal function).
Proportion and exposure-adjusted incidence rate analyses will be performed for both renal
(including renal-related and kidney stone AEs) and CV outcomes. For exposure-adjusted 
incidence rate analyses, both on-treatment and on-study exposure will be calculated. In addition, 
time-to-event for MACE will be analyzed using Cox proportional hazard model.
All safety data will be listed and summarized by treatment group. All TEAEs will be coded and 
tabulated by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and 
preferred term. Similar methods for estimating proportions and exposure-adjusted incidence rates 
of TEAE, SAEs, and TEAEs leading to permanent discontinuation of IP will be applied. 
Changes from Baseline in laboratory and other safety parameters will be summarized and 
marked abnormalities will be noted.
Efficacy data will be summarized and analyzed in the ITT population. The key sUA efficacy 
endpoint (proportion of subjects with sUA <6.0 mg/dL at Month 6) will be summarized 
descriptively by treatment group and a comparison of the response rates will be presented using 
the Cochran Mantel Haenszel (CMH) test statistic, stratified by type of XOI, Baseline
measurable target tophus status (present/absent), and Screening eCrCl (30.0 to <45.0 mL/min or 
45.0 to <60.0 mL/min), as appropriate. Results will be expressed as proportions, corresponding 
adjusted 95% CI of the difference between response rates, and p-values. Subjects who are 
missing their Month 6 sUA results will be analyzed as non-responders. The key efficacy 
endpoint will be tested hierarchically, first in the overall study population at two-sided alpha 
level of 0.05; if successful, then it will be tested in the subset of subjects whose Screening eCrCl


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is 30.0 to <45.0 mL/min at two-sided alpha level of 0.05.
Determination of Sample Size
Approximately 600 subjects will be randomized in a 1:1 ratio to either the LESU + XOI or 
PBO + XOI group in this study.
For safety endpoint analyses, this sample size provides sufficient precision around the estimated 
between-treatment difference for the absolute and percent changes in eCrCl from Baseline to 
Month 24 based on the normal distribution CI with 95% two-sided confidence level. For the 
difference in absolute change from Baseline to Month 24, the estimated precision is ±1.6 mL/min 
assuming a common standard deviation (SD) for the change from Baseline in each treatment 
group of 10 mL/min estimated from the lesinurad Phase 3 development program. For the 
difference in percent change from Baseline to Month 24, the estimated precision is ±3.2% 
assuming a common SD for the percent change from Baseline in each treatment group of 20% 
estimated from the lesinurad Phase 3 development program. For the key efficacy endpoint 
analyses, this sample size will provide >90% power for the overall population and >80% power 
within each Screening eCrCl stratum to detect a treatment difference for the proportion of 
subjects achieving sUA <6.0 mg/dL at Month 6 of 15% (20% in the PBO + XOI group versus 
35% in the LESU + XOI group, as estimated from the lesinurad Phase 3 development program), 
using a binomial distribution at an alpha of 0.05 (two-sided).
Date of Protocol Version 3:  21 June 2017


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS............................................................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..............................................15
1.
INTRODUCTION..................................................................................................18
1.1.
Background ............................................................................................................18
1.2.
Known and Potential Benefits and Risks of Study Medication ................................18
1.2.1.
Known and Potential Benefits and Risks With Lesinurad in Combination 
With Xanthine Oxidase Inhibitors...........................................................................18
1.2.2.
Known and Potential Benefits and Risks With Xanthine Oxidase Inhibitors............19
1.2.3.
Known and Potential Benefits and Risks With Colchicine ......................................20
1.3.
Rationale for Study Design and Dose Selection ......................................................20
2.
STUDY OBJECTIVES...........................................................................................22
3.
INVESTIGATIONAL PLAN .................................................................................23
3.1.
Overall Study Design and Plan ...............................................................................23
3.2.
Study Endpoints .....................................................................................................26
3.2.1.
Safety Endpoints.....................................................................................................26
3.2.2.
Efficacy Endpoints .................................................................................................26
3.2.3.
Exploratory Endpoints............................................................................................26
3.3.
Study Duration .......................................................................................................27
4.
STUDY POPULATION SELECTION ...................................................................28
4.1.
Study Population ....................................................................................................28
4.2.
Inclusion Criteria....................................................................................................28
4.3.
Exclusion Criteria...................................................................................................28
5.
STUDY TREATMENT..........................................................................................30
5.1.
Description of Investigational Product ....................................................................30
5.1.1.
Lesinurad................................................................................................................30
5.1.2.
Placebo Comparator ...............................................................................................30
5.2.
Other Study Treatments..........................................................................................30
5.2.1.
Xanthine Oxidase Inhibitors ...................................................................................30
5.2.2.
Gout Flare Prophylaxis ...........................................................................................30
5.3.
Selection and Timing of Dose for Each Subject ......................................................31
5.3.1.
General Instructions for Dosing ..............................................................................31
5.3.2.
Dose Adjustments, Interruptions, and Discontinuations ..........................................31


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5.3.2.1.
Investigational Product and Xanthine Oxidase Inhibitors ........................................32
5.3.2.2.
Gout Flare Prophylaxis ...........................................................................................34
5.4.
Method of Assigning Subjects to Treatment Groups ...............................................34
5.5.
Blinding..................................................................................................................35
5.6.
Dispensing Investigational Product.........................................................................35
5.7.
Packaging and Labeling..........................................................................................36
5.8.
Study-Supplied Medications Receipt, Storage, Accountability, and Returns............36
5.8.1.
Site Receipt of Investigational Product ...................................................................36
5.8.2.
Site Storage ............................................................................................................36
5.8.3.
Home Storage.........................................................................................................37
5.8.4.
Compliance and Accountability..............................................................................37
5.8.5.
Return of Investigational Product to the Drug Depot...............................................37
5.8.6.
Destruction of XOI/Colchicine ...............................................................................37
6.
STUDY PROCEDURES AND ASSESSMENTS ...................................................38
6.1.
Informed Consent ...................................................................................................38
6.2.
Medical History......................................................................................................38
6.3.
Prior and Concomitant Medications........................................................................38
6.4.
Demographics.........................................................................................................38
6.5.
Physical Examination .............................................................................................38
6.6.
Vital Signs..............................................................................................................39
6.7.
Height and Weight..................................................................................................39
6.8.
Electrocardiography................................................................................................39
6.9.
Clinical Laboratory Tests........................................................................................39
6.9.1.
Clinical Safety Laboratory Assessments .................................................................39
6.9.2.
Additional Samples for Biomarkers ........................................................................41
6.10.
Efficacy Assessments .............................................................................................41
6.10.1.
Serum Uric Acid Levels..........................................................................................41
6.10.2.
Tophus Measurements............................................................................................41
6.10.3.
Patient-Reported Outcomes ....................................................................................42
6.10.3.1.
Sheehan Disability Scale.........................................................................................42
6.10.3.2.
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem..................................................................................................................42
6.10.3.3.
EuroQol Five Dimensions Questionnaire 3 Level ...................................................42


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6.10.4.
Gout Flares.............................................................................................................42
6.11.
Adverse Events.......................................................................................................43
6.11.1.
Adverse Event Definition .......................................................................................43
6.11.1.1.
Adverse Events of Special Interest..........................................................................43
6.11.2.
Timing....................................................................................................................43
6.11.3.
Severity ..................................................................................................................44
6.11.4.
Relationship............................................................................................................44
6.11.5.
Reporting Adverse Events ......................................................................................45
6.11.6.
Serious Adverse Events ..........................................................................................45
6.11.6.1.
Definition ...............................................................................................................45
6.11.6.2.
Managing Serious Adverse Events..........................................................................46
6.11.6.3.
Reporting Serious Adverse Events..........................................................................46
6.12.
Retest Requirements for Subjects With Changes in Kidney Function......................46
6.12.1.
Estimated Creatinine Clearance Decline From Baseline..........................................46
6.12.2.
Absolute Serum Creatinine ≥4.0 mg/dL or Estimated Creatinine Clearance 
<20 mL/min............................................................................................................47
6.13.
Management of Acute Gout Flares..........................................................................48
6.14.
Suspected Pregnancy (Exposure in Utero) ..............................................................48
6.15.
Overdose ................................................................................................................49
6.16.
Premature Withdrawal From the Study ...................................................................49
7.
STUDY RESTRICTIONS......................................................................................50
7.1.
Potential Drug Interactions .....................................................................................50
7.1.1.
Interactions With Lesinurad....................................................................................50
7.1.2.
Interactions With Xanthine Oxidase Inhibitors........................................................50
7.1.2.1.
Allopurinol.............................................................................................................51
7.1.2.2.
Interactions With Febuxostat ..................................................................................51
7.1.3.
Interactions With Colchicine...................................................................................51
7.2.
Food and Fluid Intake.............................................................................................52
7.3.
Subject Activity Restrictions...................................................................................52
7.4.
Contraception .........................................................................................................52
8.
STUDY ACTIVITIES............................................................................................53
8.1.
Screening Period (Day -28 to the Baseline Visit) ....................................................53
8.1.1.
Screening Visit 1 (Approximately 28 Days Before the Baseline Visit)....................53


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8.1.2.
Screening Visit 2 (Within 3 Weeks After Screening Visit 1 [±3 Days])...................54
8.1.3.
Baseline Visit (4 to 7 Days After Screening Visit 2) ...............................................54
8.2.
Rescreening of Subjects..........................................................................................55
8.3.
Treatment Period (Day 1 Through Month 24).........................................................55
8.3.1.
Day 1 (1 Day After Baseline Visit) .........................................................................55
8.3.2.
Month 1 (Day 28 ±7 Days) and Months 3 Through 21 (Visits Every 3 
Months ±7 Days) ....................................................................................................55
8.3.3.
Month 24 (±7 Days) and/or End of Treatment Visit ................................................56
8.4.
Follow-Up Period ...................................................................................................57
8.4.1.
Post-End of Treatment Visit for Subjects Who Discontinue Investigational 
Product But Remain on Study (~30 Days Post-Discontinuation) .............................57
8.4.2.
End of Study Visit ..................................................................................................58
9.
PLANNED STATISTICAL METHODS ................................................................60
9.1.
General Considerations...........................................................................................60
9.2.
Determination of Sample Size.................................................................................60
9.3.
Analysis Populations ..............................................................................................61
9.4.
Analysis Methods ...................................................................................................61
9.4.1.
Disposition, Demographics, and Baseline Characteristics .......................................61
9.4.2.
Safety Analyses ......................................................................................................61
9.4.2.1.
Change From Baseline in Estimated Creatinine Clearance ......................................62
9.4.2.2.
Renal-Related Outcomes ........................................................................................62
9.4.2.3.
Cardiovascular Outcomes .......................................................................................63
9.4.2.4.
General Safety........................................................................................................63
9.4.3.
Efficacy Analyses...................................................................................................64
9.4.4.
Exploratory Endpoints............................................................................................65
9.4.5.
Interim Analyses.....................................................................................................65
10.
QUALITY CONTROL AND ASSURANCE..........................................................66
11.
ADMINISTRATIVE CONSIDERATIONS............................................................67
11.1.
Ethics Committee Approval....................................................................................67
11.2.
Ethical Conduct of the Study ..................................................................................67
11.3.
Subject Information and Consent ............................................................................67
11.4.
Subject Confidentiality ...........................................................................................68
11.5.
Study Monitoring....................................................................................................68


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11.6.
Study Records and Case Report Forms ...................................................................68
11.6.1.
Study Records and Case Report Forms Records......................................................68
11.6.2.
Case Report Form...................................................................................................69
11.6.3.
Source Data and Source Documents .......................................................................70
11.6.4.
Participation Cards .................................................................................................70
11.6.5.
Subject Identification Information ..........................................................................71
11.7.
Use of Computerized Systems ................................................................................71
11.7.1.
Electronic Data Capture..........................................................................................71
11.7.2.
Interactive Voice/Web Response System................................................................71
11.7.3.
Centralized Data Check System..............................................................................71
11.8.
Independent Monitoring and Adjudication Committees ..........................................71
11.8.1.
Independent Data Monitoring Committee ...............................................................71
11.8.2.
Renal Events Adjudication Committee....................................................................72
11.8.3.
Cardiovascular Endpoints Adjudication Committee................................................72
11.9.
Protocol Violations/Deviations ...............................................................................72
11.10.
Retention of Data....................................................................................................72
11.11.
Financial Disclosure ...............................................................................................73
11.12.
Site Closure or Study Termination..........................................................................73
11.13.
Protocol Modification.............................................................................................73
11.14.
Publication and Disclosure Policy...........................................................................73
12.
REFERENCE LIST................................................................................................75
APPENDIX A.
SCHEDULE OF EVENTS.............................................................................77
APPENDIX B.
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW .....................................80
APPENDIX C.
RETESTING SCHEMA FOR SUBJECTS WITH CHANGES IN 
KIDNEY FUNCTION............................................................................................84
APPENDIX D.
SPONSOR SIGNATURES............................................................................85
APPENDIX E.
INVESTIGATOR’S SIGNATURE ................................................................86


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LIST OF TABLES
Table 1:
Clinical Safety Laboratory Tests.............................................................................40
LIST OF FIGURES
Figure 1:
Overview of Study Design Scheme.........................................................................25
Figure 2:
Laboratory Eligibility Requirements.......................................................................25


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ACR
American College of Rheumatology
ADR
adverse drug reaction
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
bid
twice daily
BMI
body mass index
CEAC
Cardiovascular Endpoints Adjudication Committee
CI
confidence interval
CMH
Cochran-Mantel Haenszel
CRF
Case Report Form
CTM
Clinical Trials Material
CV
Cardiovascular
CYP
cytochrome P450
EC
Ethics Committee
eCrCl
estimated creatinine clearance
ECG
Electrocardiogram
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EQ-5D
EuroQol Five Dimensions Questionnaire
EQ-5D-3L
EQ-5D 3 level
EU
European Union
EULAR
European League Against Rheumatism
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice


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HCG
human chorionic gonadotropin
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methyl-glutaryl-coenzyme A
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IDMC
independent Data Monitoring Committee
IEC
Independent Ethics Committee
IP 
investigational product
IRB
Institutional Review Board
ITT
Intent-to-Treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
JNC8
Joint National Committee on Detection, Evaluation and Treatment of High 
Blood Pressure
LESU
lesinurad 
LS
least-square
MACE
Major Adverse Cardiovascular Event
MACE+
MACE or hospitalization for unstable angina
MAR
missing at random
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measures
NSAID
nonsteroidal anti-inflammatory drug
OAT
organic anion transporter
PBO
Placebo
P-gp
P-glycoprotein
qd
once daily


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REAC
Renal Events Adjudication Committee
RCTC
Rheumatology Common Toxicity Criteria
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCr
serum creatinine
SD
standard deviation
SDS
Sheehan Disability Scale
SmPC
Summary of Product Characteristics
sUA
serum urate (also referred to as serum uric acid)
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
ULT
urate-lowering therapy
URAT1
uric acid transporter 1
US
United States
USPI
United States Product Insert
VAS
visual analogue scale
WPAI:SHP
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem
XOI
xanthine oxidase inhibitor


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1.
INTRODUCTION
1.1.
Background
Lesinurad 200 mg tablets were approved by the United States (US) Food and Drug 
Administration (FDA) in December 2015 and by the European Medicines Agency (EMA) in 
February 2016 for use in combination with a xanthine oxidase inhibitor (XOI; allopurinol or 
febuxostat) for the chronic treatment of hyperuricemia associated with gout in patients who have 
not achieved target serum uric acid (sUA) levels with an XOI alone.
Lesinurad is a selective uric acid reabsorption inhibitor that inhibits uric acid transporter 1 
(URAT1), which is responsible for the majority of the reabsorption of filtered uric acid from the 
renal tubular lumen (Reginato 2012, So 2010). By inhibiting URAT1, lesinurad increases uric 
acid excretion and thereby lowers sUA. Lesinurad also inhibits organic anion transporter 4 
(OAT4), a uric acid transporter involved in diuretic-induced hyperuricemia (Handler 2010).
Xanthine oxidase inhibitors act by reducing the production of uric acid, primarily in the liver and 
intestine. Combination therapy with lesinurad and an XOI targets both excretion (lesinurad) and 
production (XOI) of uric acid, providing a dual-mechanism approach to effectively lower sUA.
This post-marketing study is a randomized, double-blind, placebo-controlled study to evaluate 
safety (with particular focus on renal and cardiovascular [CV] events) and efficacy of lesinurad 
200 mg once daily (qd) in combination with an XOI for up to 24 months compared with XOI 
monotherapy, in subjects with gout and moderate renal impairment who have not reached target 
sUA levels (<6.0 mg/dL) on an XOI alone.
For the purpose of this document, “investigational product (IP)” is defined as lesinurad or 
matching placebo. “Study medication” is defined as study-supplied medications, which may 
include lesinurad or matching placebo, allopurinol or febuxostat, and colchicine.
1.2.
Known and Potential Benefits and Risks of Study Medication
1.2.1.
Known and Potential Benefits and Risks With Lesinurad in Combination With 
Xanthine Oxidase Inhibitors
As of 31 December 2016, more than 2600 subjects had been exposed to lesinurad in clinical 
trials. The maximum duration of exposure was approximately 700 days for lesinurad 
monotherapy, 1,500 days for lesinurad in combination with febuxostat, and 3,100 days for 
lesinurad in combination with allopurinol.
In 3 pivotal Phase 3, randomized, placebo-controlled studies of 12-month duration, lesinurad 
200 mg qd in combination with an XOI (allopurinol or febuxostat) demonstrated clinically 
meaningful and statistically significant added benefit compared with an XOI alone. When added 
to allopurinol in subjects with gout who were inadequate responders to an XOI alone (Studies
RDEA594-301 and RDEA594-302), lesinurad provided rapid, stable, and sustained sUA 
lowering resulting in approximately twice as many subjects achieving the target goal of sUA 
<6.0 mg/dL. When added to febuxostat in subjects with tophaceous gout (Study RDEA594-304), 
lesinurad provided rapid, stable, and sustained sUA lowering with significantly more subjects 
achieving sUA <5.0 mg/dL, <4.0 mg/dL, and <3.0 mg/dL. In addition to superior sUA lowering, 


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nearly twice the reduction in the total area of target tophi was seen with lesinurad in combination 
with febuxostat, compared with febuxostat alone in Study RDEA594-304.
Overall, lesinurad 200 mg qd in combination with an XOI was generally well tolerated with a 
similar adverse event (AE) profile to that observed with an XOI alone. Most treatment-emergent 
adverse events (TEAEs) were Grade 1 or 2 in severity and resolved while continuing lesinurad 
therapy. The most common TEAEs reported with lesinurad 200 mg in combination with an XOI 
were generally comparable to XOI alone. The following adverse drug reactions (ADRs) have 
been identified:  influenza, headache, gastroesophageal reflux disease, renal failure, renal 
impairment, nephrolithiasis, and blood creatinine increased.
A detailed analysis of renal safety in the pivotal Phase 3 combination therapy studies showed 
that lesinurad was associated with transient increases in serum creatinine (sCr). These sCr 
elevations generally resolved, most without treatment interruption. The incidence of renal-related 
serious TEAEs was low (≤1%), and the exposure-adjusted rates were not increased following 
long-term exposure during the extension studies.
In the pivotal Phase 3 combination therapy studies, overall rates of adjudicated Major Adverse 
CV Events (MACE) and of Investigator-reported CV-related AEs, AEs leading to 
discontinuation of IP, and serious AEs (SAEs) were low. The incidence of MACE was 
comparable for lesinurad 200 mg in combination with an XOI (4 subjects) and XOI alone 
(3 subjects). The small number of MACE observed in the pooled analysis of data from the 
pivotal Phase 3 combination therapy studies places limitations on assessment of 
treatment-associated differences in MACE risk.
Refer to the lesinurad Investigator’s Brochure (IB) for more information on lesinurad.
1.2.2.
Known and Potential Benefits and Risks With Xanthine Oxidase Inhibitors
Subjects must be on a stable, medically appropriate dose of XOI, which are recommended as the 
first line treatment for hyperuricemia associated with gout (Khanna 2012, Zhang 2006).
Allopurinol, approved in 1966 in the United States, is the most commonly used XOI. With 
allopurinol as a monotherapy, the most common AE is skin rash. Skin reactions may be severe 
and can be fatal. Other common AEs include diarrhea, nausea, and elevation in liver function 
tests (alkaline phosphatase, alanine aminotransferase [ALT], and aspartate aminotransferase 
[AST]). Furthermore, some allopurinol toxicities appear to be dose related, such as nausea, 
diarrhea, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Chao 2009, Halevy 2008).
Febuxostat, approved in 2009, is another XOI approved for the chronic management of 
hyperuricemia in patients with gout. The approved dosing in the US is 40 to 80 mg qd, and the 
approved dosing in the European Union (EU) is 80 to 120 mg qd. With febuxostat as 
monotherapy, a higher rate of CV thromboembolic events was seen in clinical studies, although a 
causal relationship has not been established. There have been reports of liver failure (some 
resulting in death) and rhabdomyolysis in patients taking febuxostat. Other AEs occurring in 
> 1% of febuxostat-treated patients included liver function abnormalities, nausea, arthralgia, and 
rash (Uloric [US package insert] Rev March 2013, Febuxostat 80 mg Tablets [SmPC] Rev 
December 2012).
The local product label for allopurinol (Allopurinol [US package insert] Rev July 2015,
Allopurinol 100 mg Tablets [SmPC] Rev February 2013) and febuxostat (Uloric [US package 


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insert] Rev March 2013, Febuxostat 80 mg Tablets [SmPC] Rev December 2012) should be 
consulted for detailed information regarding contraindications, warnings and precautions, drug 
interactions, dosage adjustment and patient monitoring recommendations, and use in special 
patient populations.
1.2.3.
Known and Potential Benefits and Risks With Colchicine
As many as 80% of patients experience an acute gout flare with initiation or increase in dose of 
urate lowering therapy (ULT) (Borstad 2004). Per the American College of Rheumatology
(ACR), European League Against Rheumatism (EULAR), and British Society of Rheumatology 
treatment guidelines, gout flare prophylaxis is recommended to reduce the potential for acute 
gout flares that can occur with the initiation of ULT (Khanna 2012, Zhang 2006). The EULAR 
guidelines note that evidence to support the use of low-dose colchicine for prophylaxis of acute 
attacks when beginning ULT is reasonable. As such, subjects in this study should take colchicine 
for gout flare prophylaxis during approximately the first 6 months on study.
Although generally well tolerated, low-dose colchicine has been associated with AEs such as 
diarrhea, abdominal pain, nausea, and vomiting. Rarely, more severe AEs such as myopathy, 
neuropathy, and myelosuppression have been reported with colchicine use. The local product 
label for colchicine should be consulted for detailed information regarding contraindications, 
warnings and precautions, drug interactions (eg, P-gp or strong/moderate CYP3A4 inhibitors, or 
3-hydroxy-3-methyl-glutaryl-coenzyme A [HMG-CoA] reductase inhibitors, or digitalis 
glycosides, see Section 7.1.3), dosage adjustment and patient monitoring recommendations, and 
use in special patient populations. Subjects unable to tolerate or that have known 
contraindications to colchicine will have the option of taking low-dose oral corticosteroids for 
gout flare prophylaxis. This alternative is also recommended by the ACR treatment guidelines
(Khanna 2012).
1.3.
Rationale for Study Design and Dose Selection
The efficacy and safety of lesinurad 200 mg qd in combination with an XOI (allopurinol or 
febuxostat) were demonstrated in 3 pivotal Phase 3 studies. The Phase 3 studies included 
subjects with normal renal function and those with mild to moderate renal impairment (estimated 
creatinine clearance [eCrCl] ≥30 mL/min). Subjects with eCrCl <30 mL/min were excluded. 
Among the limited number of subjects with moderate renal impairment (eCrCl 30 to 
<60 mL/min; N=294), including those with eCrCl 30 to <45 mL/min (N=84), lesinurad 200 mg 
in combination with an XOI demonstrated a consistent safety and efficacy profile irrespective of 
Baseline renal function of eCrCl ≥30 mL/min. Lesinurad 200 mg in combination with an XOI 
has been approved in the US and EU for the treatment of hyperuricemia associated with gout in 
patients who have not achieved target serum uric acid levels with an XOI alone.
This Phase 4 randomized, double-blind, placebo-controlled study is designed to provide 
additional safety and efficacy data with lesinurad 200 mg plus XOI in the important subgroup of 
subjects with gout and moderate renal impairment who have not achieved the target sUA level 
<6.0 mg/dL on a medically appropriate dose of an XOI alone. Long-term safety, particularly
renal safety, over a 24 month Treatment Period will be assessed. Eligible subjects are required to 
have an eCrCl 30.0 to <60.0 mL/min and be on a stable, medically appropriate dose of XOI for 
at least 4 weeks prior to Screening and throughout the Screening Period with sUA levels above 


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target. The minimum Baseline dose of allopurinol permitted is 200 mg daily; the minimum 
Baseline dose of febuxostat is the lowest approved dose per the local product label. The 
maximum dose of each XOI permitted is the highest approved dose per the local product label. 
Eligible subjects will be randomized to receive lesinurad 200 mg (the dose approved by FDA 
and EMA) or placebo in combination with their prescribed XOI for up to 24 months. Per the 
ACR, EULAR, and British Society of Rheumatology treatment guidelines, gout flare prophylaxis 
is also recommended to reduce the potential for acute gout flares that can occur with the 
initiation of ULTs (Khanna 2012, Zhang 2006). In this study, subjects are required to take
colchicine for gout flare prophylaxis from the Baseline Visit (1 day before starting IP) through 
their Month 6 study visit as long as they are on IP during this period (Khanna 2012). Subjects 
who have a documented intolerance or allergy to colchicine or who are taking a concomitant 
medication contraindicated for use with colchicine are permitted to take low-dose oral 
corticosteroids (ie, defined as ≤10 mg/day of prednisone, or prednisolone, or their equivalent) for 
a short course, such as through the Month 3 study visit. Nonsteroidal anti-inflammatory drugs 
(NSAIDs) for gout flare prophylaxis will not be permitted due to the potential for nephrotoxicity.
The primary objective of this study is to better understand the safety profile of lesinurad 200 mg 
in combination with an XOI in subjects with moderate renal impairment, focusing on renal 
safety. Safety endpoints include analyses of absolute and percent change from Baseline in renal 
function with treatment over a 24 month period and the incidence of renal-related, kidney stone, 
and CV AEs. The key efficacy endpoint is the proportion of subjects achieving sUA levels of 
<6.0 mg/dL at Month 6. This sUA target is below the saturation point for monosodium urate and 
is recommended by the current ACR and EULAR treatment guidelines for ULTs to treat 
hyperuricemia in order to promote crystal dissolution and prevent crystal formation (Richette 
2014, Khanna 2012, Jordan 2007).


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2.
STUDY OBJECTIVES
The objectives of this study are as follows:
Primary Objective:

To evaluate the safety over 24 months of lesinurad 200 mg once daily (qd) when used 
in combination with a xanthine oxidase inhibitor (XOI), compared with XOI alone, in 
subjects with gout and moderate renal impairment (estimated creatinine clearance 30 
to <60 mL/min) who have not reached target serum uric acid (sUA) levels on an XOI 
alone.
Efficacy Objective:

To evaluate the efficacy over 24 months of lesinurad 200 mg qd in combination with 
an XOI, compared with XOI alone, in subjects with gout and moderate renal 
impairment who have not reached target sUA levels on an XOI alone.


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3.
INVESTIGATIONAL PLAN
3.1.
Overall Study Design and Plan
This study will be conducted in up to approximately 300 sites in North America and Europe. 
Subjects with gout, moderate renal impairment, and who are not at target sUA of <6.0 mg/dL on 
XOI alone will be enrolled. The study will include an approximate 1-month Screening Period, a 
24-month Double-Blind Treatment Period, and a 1-month post-treatment Follow-Up Period.
To be eligible for the study, subjects must be on a stable, medically appropriate dose of XOI as 
their sole ULT indicated for the treatment of gout for at least 4 weeks prior to Screening and 
throughout the Screening Period. Investigators should have followed the treatment guidelines to 
determine the medically appropriate dose of XOI. During the Screening Period, subjects will 
complete 2 Screening Visits: Screening Visit 1 (approximately 1 month before the Baseline 
Visit) and Screening Visit 2 (3 weeks after Screening Visit 1 [±3 days]). To be eligible for the 
study, estimated creatinine clearance (eCrCl; calculated by the Cockcroft-Gault formula using 
ideal body weight) must be 25.0 to ≤65.0 mL/min at each Screening Visit and the average eCrCl 
of both Screening Visits must be 30.0 to <60.0 mL/min, which is the Screening eCrCl. 
Additionally, subjects must have an sUA level ≥6.0 mg/dL (387 µmol/L) at both Screening 
Visits.
Subjects who qualify for the study will be randomized at the Baseline Visit (4 to 7 days after 
Screening Visit 2) in a double-blind fashion to 1 of 2 treatment groups in a 1:1 ratio:

LESU + XOI:  lesinurad 200 mg qd and XOI.

PBO + XOI:  placebo qd and XOI.
Randomization will be stratified by the Screening eCrCl subgroup (30.0 to <45.0 mL/min or
45.0 to <60.0 mL/min), Baseline measurable target tophus status (present/absent), and type of 
XOI (allopurinol or febuxostat). This study will enroll approximately 50% of subjects with eCrCl 
30.0 to <45.0 mL/min and approximately 50% with eCrCl 45.0 to <60.0 mL/min. When the 
maximum number of subjects in one of the eCrCl subgroups has been reached, subsequent 
enrollment will be limited to subjects in the other eCrCl subgroup. There are no limitations on 
the number of subjects enrolled by type of XOI or Baseline tophus status.
After randomization at Baseline, subjects will be dispensed IP (lesinurad or placebo) and
study-supplied XOI at the same dose as the subject’s prescribed stable dose, which they will start 
the next day (Day 1). Subjects will take IP qd in combination with their stable dose of XOI for 
up to 24 months. Gout flare prophylaxis with colchicine is required from the Baseline Visit 
through the Month 6 study visit, while still on IP. Subjects who have a documented intolerance 
or allergy to colchicine or who are taking a concomitant medication contraindicated for use with 
colchicine (eg, P-glycoprotein [P-gp] or strong cytochrome P450 [CYP]3A4 inhibitors) are 
permitted to take low-dose oral corticosteroids (≤10 mg/day of prednisone, or prednisolone, or 
their equivalent) for a short course, such as through the Month 3 study visit. The use of NSAIDs 
for gout flare prophylaxis is not permitted. More information on gout flare prophylaxis dosing is 
provided in Section 5.3. In order to maintain the blind, post-Baseline sUA levels will remain 


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blinded to the sites, subjects, and study team; additional blinding information is provided in
Section 5.5.
After initiating IP, subjects will return to the study site at Month 1 (±7 days), at Month 3 (±7 
days), and every 3 months (±7 days) thereafter until the end of the Treatment Period (Month 24
±7 days). Safety assessments will include an evaluation of AEs with particular focus on renal and 
CV events, clinical laboratory parameters (hematology, serum chemistry, urinalysis), and vital 
signs. Efficacy assessments will be based on an evaluation of sUA levels with assessments on 
tophus measurements, patient-reported outcomes, and gout flares.
Subjects who permanently discontinue IP early should complete an End of Treatment Visit as 
soon as possible, followed by a Post-End of Treatment Visit 1 month after the End of Treatment 
Visit where all AEs must be recorded. Subjects should then continue on study (and may remain 
on their study-supplied XOI) and follow the protocol-defined schedule of events, including the 
End of Study Visit.
All subjects who complete the Treatment Period or who plan to withdraw early from the study 
should complete the End of Study Visit approximately 1 month after IP is completed or 
discontinued.
An independent Data Monitoring Committee (IDMC) will be appointed by the Sponsor and will 
evaluate the safety data periodically to protect subject welfare and to identify potential safety 
signals. An independent Cardiovascular Endpoints Adjudication Committee (CEAC) will 
routinely assess all SAEs and other prospectively-defined AEs for CV related events. An 
independent Renal Events Adjudication Committee (REAC) will routinely evaluate and 
categorize all serious prospectively-defined renal-related and kidney stone AEs, and any 
additional SAEs deemed by the REAC Chair to be relevant for adjudication, and will assess the 
likelihood that potential contributing factors, including IP, contributed to the event.
Figure 1 presents the overall study design scheme. Figure 2 presents the laboratory eligibility
criteria during the Screening Period.


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Figure 1:
Overview of Study Design Scheme
Abbreviations:  EOS, End of Study; EOT, End of Treatment; qd, once daily; SV, Screening Visit; wk, week; XOI, 
xanthine oxidase inhibitor.
Note: A clinical month is considered to be 28 days.
a Subjects will enter the study on a stable, medically appropriate dose of XOI (allopurinol or febuxostat) for at least 
4 weeks prior to Screening and throughout the Screening Period and will continue this dose (study-supplied after 
Baseline) throughout the study.
b Gout flare prophylaxis, colchicine, will be taken through the Month 6 study visit as tolerated. If low-dose 
corticosteroids are used as gout flare prophylaxis, the course may be through the Month 3 study visit.
c Subjects will start investigational product (lesinurad/placebo) and study-supplied XOI on Day 1 (1 day after the 
Baseline Visit). Day 1 is not a study visit. Gout flare prophylaxis may be started at the Baseline Visit.
d Subjects who permanently discontinue lesinurad/placebo early should complete an EOT Visit as soon as possible 
followed by a Post-End of Treatment Visit 1 month later. Subjects should then continue to follow the protocol-
defined schedule of events.
e Subjects who complete the study or plan to withdraw from the study early should complete an EOS Visit 
approximately 28 days after study treatment completion or discontinuation.
Figure 2:
Laboratory Eligibility Requirements
Abbreviations:  BL, Baseline; eCrCl estimated creatinine clearance; IP, investigational product; sUA, serum uric 
acid; SV, Screening Visit; XOI, xanthine oxidase inhibitor.


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3.2.
Study Endpoints
3.2.1.
Safety Endpoints

Absolute and percent change from Baseline in eCrCl to Month 24.

Absolute and percent change from Baseline in eCrCl over the study period, including 
the last value on and off treatment.

Incidence of sCr elevations (≥1.5 × Baseline) over the study period.

Incidence of subjects meeting criteria (eg, based on sCr or eCrCl criteria) for 
treatment discontinuations over the study period.

Incidence of renal-related and kidney stone TEAEs and SAEs.

Prevalence of contributing factors to renal SAEs as adjudicated by the REAC.

Incidence of CEAC-adjudicated MACE (CV death, nonfatal myocardial infarction, 
and nonfatal stroke).

Incidence of CEAC-adjudicated MACE or hospitalization for unstable angina 
(MACE+).
3.2.2.
Efficacy Endpoints

Key efficacy endpoint: Proportion of subjects who achieve sUA <6.0 mg/dL at 
Month 6.

Absolute and percent change from Baseline in sUA at each visit.

Proportions of subjects who achieve sUA <6.0 mg/dL at each visit.
The efficacy endpoints will be repeated by Baseline eCrCl subgroups.
3.2.3.
Exploratory Endpoints

Percent change from Baseline in the sum of the areas of all target tophi at scheduled 
visits, among subjects with ≥1 target tophus at Baseline.

Proportion of subjects who experienced complete resolution of at least 1 target tophus 
at any time during study, among subjects with ≥1 target tophus at Baseline.

Functional impairment assessed employing the Sheehan Disability Scale (SDS; 
individual domains as well as total functional impairment) at last on-study visit.

Work productivity as assessed employing the Work Productivity and Activity 
Questionnaire: Specific Health Problem (WPAI:SHP; absenteeism, presenteeism, 
work productivity loss, and activity impairment) at last on-study visit.

Health status as assessed employing the EuroQol Five Dimensions Questionnaire 
3 level (EQ-5D-3L; both descriptive system and visual analogue scale) at last 
on-study visit.

Proportion of subjects with gout flares at each 3-month interval during the study 
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3.3.
Study Duration
The overall duration of the study is anticipated to be approximately 5 years. The total duration of 
study participation for each subject (from Screening Visit 1 through the last study visit) is 
anticipated to be up to approximately 26 months.
For regulatory reporting purposes, the end of the study is defined as the date of the last subject’s 
last assessment (scheduled or unscheduled).


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4.
STUDY POPULATION SELECTION
4.1.
Study Population
Approximately 600 subjects will be enrolled (300 per treatment group).
4.2.
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subject is able to understand the study procedures, the risks involved, and willing to 
provide written informed consent before the first study related activity.
2. Subject is willing to adhere to the protocol schedule.
3. Subject is ≥18 years and ≤85 years of age.
4. Subject has a diagnosis of gout.
5. Subject has moderate renal impairment with estimated creatinine clearance (eCrCl 
calculated by the Cockcroft-Gault formula using ideal body weight) 25.0 to 
≤65.0 mL/min at Screening Visits 1 and 2 and an average eCrCl for both screening visits 
of 30.0 to <60.0 mL/min.
6. Subject has been taking an XOI as urate-lowering therapy (ULT) indicated for the 
treatment of gout for at least 4 weeks prior to Screening at a stable, medically appropriate 
dose, as determined by the Investigator. The minimum dose of allopurinol is 200 mg 
daily, and the minimum dose of febuxostat is the lowest approved dose per the local 
product label.
7. Subject has a serum uric acid level ≥6.0 mg/dL (357 µmol/L) at Screening Visits 1 and 2.
8. Subject is male or female; females must not be pregnant or breastfeeding and females of 
childbearing potential must agree to use non-hormonal contraception during the 
Screening Period and while taking IP.
9. Subject has a body mass index <45 kg/m2.
4.3.
Exclusion Criteria
Subjects who meet the following criterion will be excluded from the study:
1. Subject had unstable angina, New York Heart Association class III or IV heart failure, 
myocardial infarction, or stroke within the last 6 months prior to randomization; or had a 
deep venous thrombosis within the previous 3 months prior to randomization.
2. Subject has uncontrolled hypertension (defined as systolic pressure above 160 or diastolic 
pressure above 95 mm Hg at either Screening Visits 1 or 2).
3. Subject has severe hepatic impairment (defined as Child-Pugh Class C) or is known 
human immunodeficiency virus (HIV) positive.
4. Subject is a solid organ transplant recipient.


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5. Subject has a urine protein of 3+ or higher by dipstick by the central laboratory at 
Screening Visit 2.
6. Subject has a history of glomerulonephritis.
7. Subject is taking valpromide, progabide, valproic acid, or other known inhibitors of 
epoxide hydrolase, or subject is taking ranolazone, cyclosporine, azathioprine or 
mercaptopurine.
8. Subject is receiving chronic treatment with more than 325 mg of salicylates per day.
9. Subject is unable to initiate gout flare prophylaxis with colchicine or low-dose oral 
corticosteroids at Baseline.
10. Subject is taking any other drug approved for use as a urate-lowering medication other 
than allopurinol or febuxostat (eg, pegloticase, probenecid, benzbromarone) within 
4 weeks prior to Screening or during Screening.
11. For subjects who will be taking colchicine for gout flare prophylaxis:  Subject is taking, 
or anticipated to take during the first 6 months on study, moderate or strong CYP3A 
inhibitors (ie, verapamil or diltiazem, clarithromycin, and fluconazole; see Section 7.1.3
for more details) or grapefruit or grapefruit juice.
12. Subject previously participated in a clinical study involving lesinurad (RDEA594) or 
verinurad (RDEA3170) and received active treatment or placebo, or has taken 
commercially-available lesinurad.
13. Subject has a gout flare during the Screening Period.
14. Subject is pregnant or breastfeeding.
15. Subject consumes more than 14 drinks of alcohol per week (eg, 1 drink = 5 oz [150 mL] 
of wine, 12 oz [360 mL] of beer, or 1.5 oz [45 mL] of hard liquor).
16. Subject has a history of malignancy and has been on active treatment within the previous 
5 years prior to randomization with the exception of non-melanoma skin cancer, treated 
in situ Grade 1 cervical cancer, or treated ductal carcinoma in situ of the breast.
17. Subject has been hospitalized (other than for elective surgery) or received intravenous 
contrast (eg, for CT scan or any angiography) within 1 month prior to Screening or 
during Screening.
18. Subject has participated in a clinical trial within 8 weeks prior to Screening.
19. Subject has any other medical or psychological condition, which in the opinion of the 
Investigator might create undue risk to the subject or interfere with the subject’s ability to 
comply with the protocol requirements or to complete the study.
20. The maximum number of subjects in the eCrCl stratification subgroup has been reached.


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5.
STUDY TREATMENT
All subjects will receive IP (lesinurad or matching placebo) and study-supplied XOI (allopurinol 
or febuxostat), which must be taken in combination. All subjects will also receive colchicine as
gout flare prophylaxis through their Month 6 study visit as tolerated. Subjects unable to take 
colchicine (described in Section 5.2.2.) are permitted to take a short course of low-dose oral 
corticosteroids.
5.1.
Description of Investigational Product
5.1.1.
Lesinurad
Lesinurad will be supplied as 200 mg tablets in 100-count high-density polyethylene (HDPE)
bottles with induction seals and screw-on polypropylene closures. Lesinurad 200 mg tablets are 
blue, oval shaped tablets.
5.1.2.
Placebo Comparator
Placebo tablets matching the lesinurad 200 mg tablets will be provided by the Sponsor in 
100-count HDPE bottles with induction seals and screw-on polypropylene closures.
5.2.
Other Study Treatments
Commercially available allopurinol, febuxostat, and colchicine drug product will be used.  The 
relevant product labeling will be provided to Investigators.
5.2.1.
Xanthine Oxidase Inhibitors
XOI (allopurinol or febuxostat) tablets will be provided at Baseline based on the individual 
subject’s stable dose during screening. The minimum Baseline dose of allopurinol permitted is 
200 mg daily; the minimum Baseline dose of febuxostat is the lowest approved dose per the local 
product label. The maximum dose of each XOI permitted is the highest approved dose per the 
local product label. The dose and dosing regimen of XOI should not be changed during the 
study, unless decreased for toxicity.
5.2.2.
Gout Flare Prophylaxis
Gout flare prophylaxis, colchicine, will be provided through the Month 6 study visit. The dose of 
colchicine will be 0.5 or 0.6 mg qd based on the local label. The frequency may be adjusted 
based on the local label, medical history of the subject, and clinical judgement (ie, dosed every 
other day or 3 times a week if needed as appropriate, particularly for subjects with lower eCrCl). 
Subjects unable to take colchicine (ie, those who have a documented intolerance or allergy to 
colchicine or who are taking a concomitant medication contraindicated for use with colchicine 
[eg, P-gp or strong/moderate CYP3A4 inhibitors, see Section 7.1.3]) are permitted to take 
low-dose oral corticosteroids (ie, ≤10 mg/day of prednisone, or prednisolone, or their equivalent) 
for a short course, such as through the Month 3 study visit, at the discretion of the Investigator. 
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prophylaxis and potential side effects of persistent corticosteroid use, such as in relation to 
comorbid conditions.
If IP is permanently discontinued prior to the end of the gout flare prophylaxis period, the gout 
flare prophylaxis should be discontinued. If IP is interrupted and re-initiated, subjects can 
re-initiate gout flare prophylaxis at the discretion of the Investigator. Investigators should 
consider reinitiating gout flare prophylaxis based on the clinical circumstances.
The use of NSAIDs for gout flare prophylaxis is not permitted.
5.3.
Selection and Timing of Dose for Each Subject
5.3.1.
General Instructions for Dosing
Lesinurad 200 mg once daily is the currently approved dose by the FDA and EMA and is under 
evaluation in this study. Only doses of XOI that are approved by the local product labels are 
permitted in this study.
All doses of IP should be taken daily, in the morning with food and 1 cup (8 oz; 240 mL) of 
water. Subjects should be instructed to drink 2 liters (68 oz) of liquid a day. For example, another 
3 cups (24 oz; 720 mL) of liquid during the 3 to 4 hours after taking the IP should be 
encouraged, and then the subject should remain well hydrated (an additional 4 cups [32 oz; 
960 mL] of liquid) throughout the day.
IP must be taken at the same time as the morning dose of XOI. Missed doses of IP should not be 
taken later in the day (eg, in the afternoon or evening) or made up on the following day.
Subject should take gout flare prophylaxis, colchicine, from the Baseline Visit until their
Month 6 study visit as long as they are still on IP. Colchicine will be provided. In the US, 
colchicine 0.6 mg qd or twice daily (bid) is recommended for subjects with eCrCl >45 mL/min 
and qd to once every other day for subjects with eCrCl <45 mL/min (Colcrys [US package 
insert] Rev December 2016). Based on medical history and the clinical judgement of the 
Investigator, decreasing the frequency to once every other day (or 3 times per week) is permitted.
In the EU, colchicine 0.5 mg qd or bid is recommended. For patients with mild/moderate renal 
impairment (creatinine clearance 10 to 50 mL/min), the prescribing information recommends to
reduce the dose or increase the interval between doses (Colchicine 500 micrograms Tablets 
[SmPC] Rev October 2015), such as decreasing to once every other day or every other day (3
times a week). Subjects who have a documented intolerance or allergy to colchicine or who are 
taking a concomitant medication contraindicated for use with colchicine (eg, P-gp or strong or 
moderate CYP3A4 inhibitors; see Section 7.1.3) are permitted to take low-dose oral 
corticosteroids (≤10 mg/day of prednisone, or prednisolone, or their equivalent) for a short 
course, such as through the Month 3 study visit, at the discretion of the Investigator. NSAIDs for 
gout flare prophylaxis will not be permitted due to the potential for nephrotoxicity.
Study site staff should refer to the local product labels for a description and complete prescribing 
information on XOI and gout flare prophylaxis.
5.3.2.
Dose Adjustments, Interruptions, and Discontinuations
IP, XOI, and gout flare prophylaxis should not be interrupted or discontinued if a subject 
experiences an acute gout flare.


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5.3.2.1.
Investigational Product and Xanthine Oxidase Inhibitors
IP (lesinurad or placebo) is only permitted at 200 mg qd. No dose reductions or dose escalations 
of IP are permitted. The prescribed dose and dosing regimen of XOI should also be continued 
unchanged throughout the study, unless adjusted for toxicity. Study treatment (IP or XOI) may 
be interrupted due to AEs or for suspected toxicity.
If XOI is interrupted for any reason, IP must be interrupted concurrently. When medically 
appropriate, the XOI should be resumed, at which time IP may also be resumed. The XOI may 
be resumed at the same dose; lower doses (if available) are only permitted if the XOI had been 
interrupted due to a TEAE considered related to that XOI. If resumed at a lower dose, the XOI 
should be increased up to the original dose, as tolerated. Subjects should not be maintained on a 
dose of allopurinol <200 mg daily.
If IP is interrupted for any reason, the subject is permitted to continue XOI, as tolerated. When 
medically appropriate, IP should be resumed, but must only be resumed if the subject is taking 
XOI.
5.3.2.1.1. Interruption or Discontinuation of Investigational Product Due to Changes in 
Kidney Function
Kidney function will be monitored throughout the study by measuring sCr and calculating eCrCl 
by Cockcroft-Gault formula using ideal body weight. All clinically meaningful changes in 
kidney function should be evaluated and managed as medically appropriate, including 
interrupting IP and study medications if needed.
IP must be temporarily interrupted if a subject experiences an absolute sCr ≥4.0 mg/dL or an 
eCrCl <20 mL/min (based on central laboratory results), and the subject will be required to 
return to the site for retesting (see Section 6.12). IP may be resumed at the Investigator’s 
discretion if eCrCl is within 15% of Baseline if this occurs through the Month 12 study visit, or 
if eCrCl is within 20% of Baseline if this occurs from the Month 12 study visit through the 
Month 24 study visit.
IP should be permanently discontinued if there are more than 3 episodes of interruption of IP 
due to any of the following:

If the Investigator or Healthcare Provider temporarily interrupts IP due to changes in 
kidney function, 

If the Investigator or Healthcare Provider temporarily interrupts IP due to any safety 
concerns due to IP, or

Protocol-specified criteria for interruption are met (ie, sCR ≥4.0 mg/dL or eCrCl 
<20 mL/min).
An episode is defined as the interruption and then re-initiation of IP, regardless of the duration of 
the interruption. The fourth interruption should be considered permanent when based on the 
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5.3.2.1.2. Other Reasons, and Procedures, for Permanent Discontinuation of
Investigational Product
As much as possible and permitted by the protocol, subjects should be encouraged to continue on 
IP for the full 24-month Treatment Period.
Subjects have the right to permanently discontinue IP at any time for any reason. Investigators 
may also discontinue IP if they determine that it is not in the best interest of the subject to 
continue. All subjects should be encouraged to remain in the study even if IP has been 
discontinued for any reason.
IP must be permanently discontinued if the subject meets any of the following criteria:

Subject permanently discontinues XOI.

Subject becomes pregnant.

Subject initiates chronic therapy with any of the following medications:

valpromide, progabide, valproic acid, or other known inhibitors of epoxide 
hydrolase.

any approved ULT indicated for the treatment of gout (eg, benzbromarone, 
probenecid, pegloticase, commercially-available lesinurad), except those required 
per protocol (allopurinol and febuxostat).

azathioprine or mercaptopurine.

Subject requires dialysis or kidney transplantation.

Subject has temporarily interrupted IP for more than 3 separate episodes at any time 
on study due to changes in kidney function, based on any safety concern due to IP by 
the Investigator or Healthcare Provider, or where protocol-specified criteria for 
interruption have been met (ie, sCr ≥4.0 mg/dL or an eCrCl <20 mL/min).
The date and the reason must be recorded on the appropriate Case Report Form (CRF) for all 
subjects who discontinue IP. If the reason is an AE, the specific AE must be identified on the 
CRF.
Subjects who permanently discontinue IP early should complete an End of Treatment Visit 
(Section 8.3.3) as soon as possible followed by a Post-End of Treatment Visit (Section 8.4.1) 
1 month after the End of Treatment Visit. Subjects should then continue on study and follow the 
protocol-defined schedule of events, through Month 24. The subject has the option to continue 
on study-supplied XOI during this time. Although all assessments are encouraged, at a minimum, 
it is requested that collection of AEs and collection of a blood sample for Analytes 1 (see 
Table 1) occur. Alternatively, if the subject does not agree to this option, a modified follow-up 
including, eg, regular telephone contacts or a contact at Month 24, should be arranged, if agreed 
to by the subject and in compliance with local data privacy laws/practices. Subjects who do not 
wish to continue on study after discontinuing IP should complete an End of Study Visit 
(Section 8.4.2) 1 month after treatment discontinuation.
If IP is permanently discontinued prior to the Month 6 study visit, then gout flare prophylaxis 
should also be discontinued.


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5.3.2.2.
Gout Flare Prophylaxis
Gout flare prophylaxis should generally only be continued through the Month 6 study visit as 
tolerated (ie, colchicine alone, or if colchicine is replaced with oral corticosteroids). It is 
recognized that if oral corticosteroids alone are used for gout flare prophylaxis, the course will 
generally be shorter. If XOI and IP are interrupted, gout flare prophylaxis may be re-initiated 
when the study medications are resumed per the discretion of the Investigator based on the 
clinical circumstances. If IP is permanently discontinued prior to the end of the gout flare 
prophylaxis period, the gout flare prophylaxis should be discontinued.
5.3.2.2.1. Colchicine
Subjects are required to continue gout flare prophylaxis with colchicine through their Month 6 
study visit unless they become intolerant or develop toxicity to the colchicine. Gout flare 
prophylaxis with colchicine may be interrupted or discontinued prior to the expected Month 6 
study visit due to an AE or tolerability. If colchicine is interrupted for any reason in the gout 
flare prophylaxis period, it should be restarted when medically appropriate. Subjects should be 
encouraged to continue on colchicine as tolerated through the Month 6 study visit, but may 
decrease the dose or increase the interval between doses (ie, from once daily to once every other 
day).
If a subject requires treatment with cyclosporine, ranolazine, or strong/moderate CYP3A 
inhibitors (eg, clarithromycin, fluconazole, diltiazem; see Section 7.1.3) prior to their Month 6 
study visit, then colchicine must be interrupted or discontinued.
Subjects who are unable to take colchicine during the gout flare prophylaxis period should, when 
medically appropriate, switch to a short course of low-dose oral corticosteroids. If switching is 
not medically appropriate, randomized subjects may continue in the study without gout flare 
prophylaxis.
5.3.2.2.2. Low-Dose Corticosteroids
Subjects unable to take colchicine (ie, those who have a documented intolerance or allergy to 
colchicine or who initiate a concomitant medication contraindicated for use with colchicine 
[eg, P-gp or strong CYP3A4 inhibitors]) are permitted to take low-dose oral corticosteroids (ie, 
≤10 mg/day of prednisone, or prednisolone, or their equivalent) for a short course, such as 
through the Month 3 study visit, at the discretion of the Investigator, individualizing for each 
subject the need for gout flare prophylaxis and potential side effects of persistent steroid use, 
such as in relation to comorbid conditions.
Gout flare prophylaxis with corticosteroids may be interrupted or discontinued due to an AE or 
tolerability. Subjects should be encouraged to continue on low-dose corticosteroids through the 
Month 3 study visit but may decrease the dose as needed.
5.4.
Method of Assigning Subjects to Treatment Groups
Approximately 600 subjects will be randomized in a 1:1 ratio to lesinurad 200 mg or placebo in 
combination with an XOI. Subjects will be randomized at their Baseline Visit after the 
Investigator has verified that they meet all of the study eligibly criteria (Section 4.2 and 
Section 4.3) and after all screening assessments have been completed (Appendix A). 


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Randomization will take place across all study sites using a centralized Interactive Voice 
Response System/Interactive Web Response System (IVRS/IWRS) and will be stratified by 
Screening eCrCl (30.0 to <45.0 mL/min or 45.0 to <60.0 mL/min), Baseline measurable target 
tophus status (present/absent), and type of XOI (allopurinol or febuxostat).
Subject randomization numbers will be generated by the IVRS/IWRS company. Subject 
eligibility information will be provided by the Investigator or the Investigator’s research staff to 
the IVRS/IWRS at randomization. Two site staff members must verify the information entered 
into the IVRS/IWRS prior to randomization to ensure accuracy and reduce stratification errors. 
Each subject meeting eligibility criteria and completing all Screening assessments will be 
randomized, assigned a unique randomization number, and a randomization confirmation will be 
sent by the IVRS/IWRS to the site.
No subject may begin IP prior to randomization and assignment of a randomization number. 
Subjects who have been randomized but withdraw from the study may not be replaced.
5.5.
Blinding
Treatment group assignments will be blinded to minimize bias in study assessments and 
monitoring. In order to maintain the blind, the randomization list generated by the IVRS/IWRS,
as well as sUA results post-Baseline, will not be available to subjects, study site staff, or the 
Sponsor’s project team (including the team at the Clinical Research Organization, as applicable) 
until after database lock with the following exceptions:

The Clinical Trials Material [CTM] staff is authorized to receive the randomization 
list to facilitate drug packaging and monitor site inventory for IP.

The Good Manufacturing Practice Quality Assurance staff is authorized to receive the 
randomization list to facilitate packaging and release of all CTM.
The IDMC will receive unblinded data to periodically review safety data during the study. For 
more information on this committee, see Section 11.8.
The pharmacovigilance staff will break the blind only for individual subjects who have SAEs 
that are both unexpected and suspected to be causally related to IP in order to allow appropriate 
safety reporting to regulatory authorities. Blinding will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual subject have been 
made and documented.
In the cases of emergency unblinding for safety concerns such as medical emergencies when the 
appropriate management of the subject requires knowledge of the treatment randomization, the 
Investigator or designee should contact the Sponsor or designee prior to unblinding a subject’s 
treatment assignment. The IVRS/IWRS will provide the site with the subject’s treatment 
assignment.
5.6.
Dispensing Investigational Product
IP will be dispensed at the Baseline Visit and every 3 months thereafter through Month 21 of the 
Treatment Period. Each bottle will be identified with a unique medication number to protect the 
blind.


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5.7.
Packaging and Labeling
IP will be packaged and labeled under the responsibility of the Sponsor in a manner consistent 
with the study design and according to local regulatory requirements. No repackaging and/or 
relabeling activities at the study site are allowed. Investigational product will be identified as an 
investigational compound.
Study site staff should refer to the local product labels for packaging and labeling information for 
XOIs and gout flare prophylaxis, provided by the Sponsor.
5.8.
Study-Supplied Medications Receipt, Storage, Accountability, and 
Returns
The Investigator must maintain accurate records of all IP, XOI, and colchicine administered as 
per protocol, including date received, number of units received, and lot number. The Investigator 
must also ensure that all study-supplied medications are kept secured and accounted for with 
access limited to only those individuals authorized by the Investigator. The Investigator, his/her 
designee, or the pharmacist must also maintain adequate records of distribution and dispensing of 
all study-supplied medications, as well as return of IP to the Drug Depot and destruction of all 
other study-supplied medications, to be able to reconcile their records (ie, accountability or 
dispensing logs) periodically throughout the study.
All records must be readily available for inspection by the site monitor and/or auditor. No 
medications may be returned to the Sponsor or designee (IP) or disposed of at the study site 
(XOI and colchicine) until the site monitor has verified the accuracy of the records at the study 
site. All returns, disposals, or destruction must be approved by the Sponsor.
For more complete information regarding study-supplied medication receipt, storage, 
accountability, return (IP), and destruction (XOI and colchicine), refer to the Study Reference 
Manual.
5.8.1.
Site Receipt of Investigational Product
Within approximately 48 hours upon receipt of study-supplied IP at the study site, the 
appropriate trained site staff should review the contents and record receipt of the shipment in 
IVRS/IWRS.
5.8.2.
Site Storage
Bottles containing IP must be stored at 15 to 30°C/59 to 86°F. XOI and colchicine should be 
stored according to the product label. Appropriate storage conditions in the pharmacy or drug 
storage area must be ensured and temperature must be recorded.
Access to study-supplied medications should be restricted to designated study personnel.
The site monitor should review the supplies of study-supplied medications held by the 
Investigator or pharmacist at each monitoring visit to ensure accountability and appropriate 
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5.8.3.
Home Storage
The study staff is responsible for providing subjects with instructions on storing all 
study-supplied medications.
Subjects should be instructed to keep all study-supplied medications in a secure location.
5.8.4.
Compliance and Accountability
Accountability will be assessed by maintaining adequate medication dispensing records. 
Study-supplied medications must be dispensed by a qualified member of the study site staff. 
Study site staff is responsible for providing subjects with instructions on correct medication
administration.
At each study visit, subjects will return all bottles of IP, XOI, and colchicine (used and unused),
and study staff will ask about their treatment compliance. The number of tablets returned should 
be counted and documented in the source documentation. Study site staff is also responsible for 
accurately completing the subject’s medications CRF and appropriate systems (ie, clinical 
database and IVRS/IWRS).
Study-supplied XOI and colchicine that are returned may be redispensed to the same subject 
provided accurate accountability records are maintained.
Subjects will be asked to bring study-supplied IP dispensed at Baseline to their Month 1 study 
visit for compliance check. This IP will be redispensed to the same subject at the Month 1 visit.
Study-supplied medications that are returned should not be redispensed to a different subject.
5.8.5.
Return of Investigational Product to the Drug Depot
After accountability has been verified by the site monitor, IP bottles will be returned to the drug 
depot. The return will be documented within the source documentation and processed by site 
monitor in IVRS/IWRS prior to shipment to the depot.
5.8.6.
Destruction of XOI/Colchicine
After accountability has been verified by the site monitor, returned supplies of XOI and 
colchicine will be destroyed per the study site’s process. The destruction will be documented 
within the source documentation and processed by the site monitor.


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6.
STUDY PROCEDURES AND ASSESSMENTS
The following describes the study procedures and assessments that will be performed during the 
study. See Section 8 and Appendix A for the schedule of events for the study.
6.1.
Informed Consent
Prior to undergoing any study-specific procedures and after completing the consent process, the 
subject must sign a written Informed Consent Form (ICF) that has been approved by an Ethics 
Committee (EC; eg, an Institutional Review Board [IRB] or an Independent EC [IEC]). The date 
and time of consent must be documented. Withdrawal of consent must be obtained and 
documented by the Investigator, or designee, in the CRF and source documentation. Withdrawal 
of consent is defined to mean that a subject proactively withdraws consent to contribute any 
additional outcome information.
6.2.
Medical History
Medical history data relevant to study inclusion and exclusion criteria will be collected during 
Screening.  A complete medical history will be collected at the Baseline Visit for subjects who 
meet the eligibility criteria and proceed to randomization. Data collected will include medical 
and surgical history, select comorbidities, gout diagnosis and disease characteristics, and history 
of alcohol and tobacco use.
6.3.
Prior and Concomitant Medications
Prior ULT, including screening XOI and dose, indicated for the treatment of gout will be 
recorded on the appropriate CRFs.
Gout flare prophylaxis and treatment for gout flares during the study will be recorded on the
appropriate CRFs.
Other concomitant therapies (ongoing at study entry or initiated during the study) must be 
recorded on the Concomitant Medication CRF. For subjects entering the study on stable doses of 
medication for chronic medical conditions, any medication dose changes should be documented 
on the appropriate CRF. When concomitant medication dose changes are the result of the 
worsening of an ongoing condition, this worsening condition should also be documented on the 
AE CRF.
6.4.
Demographics
Subject demographics include age, sex, race, and ethnicity.
6.5.
Physical Examination
Physical examinations include the following: head, eyes, ears, nose, and throat; cardiovascular; 
respiratory; abdominal; musculoskeletal; neurological; lymph nodes; dermatological; 
extremities/joints; and the presence or absence of measurable target tophi. Urogenital and rectal 
examinations are not necessary, unless clinically indicated.


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6.6.
Vital Signs
Vital signs include systolic and diastolic blood pressure and pulse. Subjects should be advised to 
avoid smoking, caffeine, or exercise 30 minutes prior to the assessment. Subjects should also be 
seated quietly for 5 minutes before taking vital signs. Blood pressure should be taken with the 
subject seated with a straight supported back and with feet flat on the floor. The arm should be 
supported on a flat surface with the upper arm at heart level, and the appropriate-sized blood 
pressure cuff should be used. Blood pressure should be managed as appropriate by the subject’s 
health care providers in accordance with guidelines, such as the Joint National Committee on 
Detection, Evaluation and Treatment of High Blood Pressure (JNC8) with a target blood pressure 
goal of less than 140/90 for patients with renal diseases (James 2014).
6.7.
Height and Weight
Height and weight will be measured, and body mass index (BMI) will be calculated 
(BMI = weight [kg]/height [m]2).
6.8.
Electrocardiography
Subjects must be in a supine (includes sitting in a recliner chair) position for at least 5 minutes 
before performing the 12-lead electrocardiogram (ECG) test. The results will be reviewed by the 
Investigator.
6.9.
Clinical Laboratory Tests
See the Laboratory Manual for sample collection, processing, storage, and shipping procedures.
6.9.1.
Clinical Safety Laboratory Assessments
Blood and urine samples will be collected for clinical safety laboratory tests (hematology, serum 
chemistry, and urinalysis) and will be tested by a central laboratory. Any clinical safety 
laboratories results post-Baseline that are considered possibly significant may be repeated (see 
Section 6.12).
See Table 1 for a list of clinical safety laboratory tests.


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Table 1:
Clinical Safety Laboratory Tests
Hematology:

Hematocrit 

Hemoglobin 

Mean corpuscular hemoglobin

Mean corpuscular hemoglobin 
concentration

Mean corpuscular volume 

Platelet count

Red blood cell count 

Red blood cell morphology

White blood cell count with differential 
Urinalysis:

Appearance

Bilirubin

Color

Glucose

Ketones

Nitrite 

Occult blood

pH

Protein

Specific gravity

Urobilinogen

Microscopic examination of sediment 
including uric acid crystals 
Additional urine analyses:

Creatinine

Total protein
Serum Chemistry:
Analytes 1

Blood urea nitrogen

Creatinine (enzymatic method)

Glucose

Uric acida
Analytes 2

Albumin

Calcium

Carbon dioxide

Chloride

Phosphorus

Potassium

Sodium

Total cholesterol

Triglycerides 
Analytes 3

Alkaline phosphatase

Alanine aminotransferase

Aspartate aminotransferase

Total bilirubin

Creatine kinase
Pregnancy and fertility testing

Human chorionic gonadotropinb

Follicle-stimulating hormonec
a Serum uric acid (sUA) will be used for efficacy analyses. All study personnel, except for those defined in 
Section 5.5, will be blinded to sUA results collected after Baseline through database lock.
b At Screening Visit 2 for all females and again at Month 12 for all females except those who are surgically sterile 
or not of childbearing potential as confirmed by the Screening Visit 2 follicle-stimulating hormone test.
c At Screening Visit 2.  Only for females with 12 months of spontaneous amenorrhea who are not surgically sterile.


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Estimated CrCl at each visit will be calculated by the Cockcroft-Gault formula using ideal body 
weight (based on height measured at Screening) as follows:

eCrCl (male) = [(140 – age) × ideal body weight (kg)] / [72 × serum creatinine 
(mg/dL)].

eCrCl (female) = 0.85 × [(140 – age) × ideal body weight (kg)] / [72 × serum 
creatinine (mg/dL)].
Ideal body weight is calculated as follows:

Ideal body weight (male) = 50 kg + [2.3 × (height (in) – 60)].

Ideal body weight (female) = 45.5 kg + [2.3 × (height (in) – 60)].

If height <60 in, then ideal body weight = 50 kg for males and 45.5 kg for 
females. 
For any post-randomization laboratory abnormality considered potentially clinically significant, 
a retest should be considered prior to the subject’s next visit.
Cases where a subject shows elevations in liver biochemistry may require further evaluation, and 
occurrences of AST or ALT ≥3 × upper limit of normal (ULN) together with total bilirubin 
≥2 × ULN may need to be reported as SAEs. Please refer to Appendix B for further instruction 
on cases of increases in liver biochemistry and evaluation of Hy’s Law.
6.9.2.
Additional Samples for Biomarkers
Plasma and urine samples will be collected for the measurement of metabolic, vascular, and 
pro-inflammatory biomarkers. These samples may not be used for genetic testing and will be 
stored for a maximum of 10 years or as allowed by local laws or institutional guidelines.
6.10.
Efficacy Assessments
6.10.1.
Serum Uric Acid Levels
Efficacy will be assessed based on sUA levels. Serum uric acid levels will be measured using the 
clinical safety serum chemistry samples and will be tested by a central laboratory. All study 
personnel, except for those defined in Section 5.5, will be blinded to sUA results collected after 
screening through database lock.
6.10.2.
Tophus Measurements
In subjects with tophi at Baseline, 5 target tophi on the hands/wrists and feet/ankles 
≥5 millimeters and ≤20 millimeters in the longest diameter will be selected for evaluation of 
measurable tophi. If the subject has <5 tophi in these specified locations, then the maximum 
number of tophi should be selected. Draining, acutely inflamed, or tophi that have ever been 
infected must not be selected. Tophi will be measured using digital calipers to capture both the 
longest diameter and longest perpendicular measurement. Calipers will be provided by the 
Sponsor. Refer to the Study Reference Manual for instructions on selection, measurement, and 
documentation of tophi.


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6.10.3.
Patient-Reported Outcomes
Health status as patient-reported outcomes will be assessed employing the EuroQol Five 
Dimensions Questionnaire 3 level (EQ-5D-3L), work productivity as assessed employing the 
Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP) V2.0, and functional impairment as assessed employing the Sheehan Disability 
Scale (SDS) (Sheehan 1996). These patient-reported outcomes will be collected from the 
subjects at the scheduled study visits.
6.10.3.1.
Sheehan Disability Scale
The SDS is a patient-rated instrument measuring functional impairment in 3 domains: work 
impairment, social impairment, and impairment of family life/home responsibilities (Sheehan 
1996). Disability scores are reported for each of the questions and a total disability score is 
calculated as the sum of scores for each question. Higher scores reflect greater impairment.
6.10.3.2.
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem
The WPAI:SHP questionnaire quantitatively measures health-related work productivity loss for 
the employed population. Six questions are used to elicit work productivity over the prior 7 days.
Four scores can be determined for absenteeism, presenteeism, work productivity loss, and 
activity impairment.
6.10.3.3.
EuroQol Five Dimensions Questionnaire 3 Level
The EQ-5D-3L is a standardized instrument for use as a measure of health outcome developed 
by the EuroQol Group. The descriptive system of the questionnaire comprises 5 dimensions
(EQ-5D; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each 
dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and 
extreme problems). An EQ visual analogue scale (EQ VAS) will also be included, which records 
self-rated health on a 20 cm vertical visual analog scale with bottom rate (0) corresponding to 
"the worst health you can imagine", and the highest rate (100) corresponding to "the best health 
you can imagine".
6.10.4.
Gout Flares
Acute gout flares occur when monosodium urate crystals in the joint(s) cause acute 
inflammation. A flare is characterized by pain, redness, swelling, and warmth lasting days to 
weeks. Pain may be mild or excruciating. Most initial attacks occur in lower extremities. The 
typical presentation in the metatarsophalangeal joint of the great toe (podagra) is the presenting 
joint for 50% of people with gout (http://www.cdc.gov/arthritis/basics/gout.html, accessed
6 October 2016).
Gout flares will be recorded on the CRF, including information regarding the start and stop date; 
patient-reported severity (mild/moderate/severe); and the treatment that was required, if any.
Medications used for gout flare treatment will be documented on the concomitant medications
CRF.


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6.11.
Adverse Events
6.11.1.
Adverse Event Definition
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver), or the abnormal 
results of an investigation (eg, laboratory findings, electrocardiogram). In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including the screening 
period, even if no study treatment has been administered.
Gout flares will not be captured on the AE form. New tophi or enlarging tophi that are not
clinically adverse will not be captured on the AE form. However, gout flares or changes in tophi
that meet the definition of an SAE must be reported as an SAE (Section 6.11.6).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible, the reporting Investigator uses the 
clinical rather than the laboratory term (eg, anemia versus low hemoglobin value). In the absence 
of clinical signs or symptoms, clinically-relevant deteriorations should be reported as AE(s).
Protocol-mandated permanent discontinuation of IP per the sCr/eCrCl criteria described in
Section 5.3.2.1.1 should be reported as an AE.  Additional CRFs will be completed for any 
mandated sCr retests (Section 6.12) and for certain diagnostic tests.
6.11.1.1.
Adverse Events of Special Interest
AEs of special interest that will be evaluated in this study include renal events (eg, renal-related 
AEs and kidney stone AEs) that are serious or lead to permanent discontinuation of IP, and all 
potential CV events. Additional information will be required for these events and recorded on the 
CRFs.
All renal SAEs and all potential CV events will be adjudicated by the REAC or the CEAC, 
respectively. For information on the adjudication committees, see Section 11.8.
6.11.2.
Timing
AEs will be assessed from the time the subject provides informed consent through at least 
28 days after the last dose of IP. For subjects who permanently discontinue IP and do not 
continue on study, SAEs should be collected for at least 28 days after the last dose of IP unless 
the subject has withdrawn consent.
AEs that start on or after the first dose of IP in this study, or those AEs with onset prior to the 
first dose of IP but worsen after the first dose of IP, will be considered TEAEs. AEs that start on 
or after the date of informed consent but before the date of first dose of IP (ie, non-TEAEs) will 
be considered pretreatment AEs.
If the subject permanently discontinues IP due to an AE and does not continue with 
protocol-specific procedures, every effort should be made to follow the AE through resolution or 
stabilization. Subjects with ongoing AEs/SAEs, including clinically-relevant laboratory 


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abnormalities, should be followed up by the Investigator for as long as medically indicated. The 
Sponsor retains the right to request additional information for any subject with ongoing 
AEs/SAEs at the end of the study, if judged necessary.
6.11.3.
Severity
Severity of AEs should be assessed by the Investigator according to the following definitions that 
are based on the Rheumatology Common Toxicity Criteria (RCTC) version 2.0 (Woodworth 
2007):

Grade 1 (Mild):  asymptomatic or transient, short in duration (<1 week), no change 
in lifestyle, and/or no medications required.

Grade 2 (Moderate):  symptomatic, duration (1 to 2 weeks), alters lifestyle 
occasionally, medication relieves symptoms (may be prescription), and/or IP is 
continued.

Grade 3 (Severe): prolonged symptoms, reversible, major functional impairment; 
prescription medications provide partial relief; may be hospitalized <24 hours; 
temporary or permanent IP discontinuation.

Grade 4 (includes Life Threatening):  at risk of death; substantial disability, 
especially if permanent; hospitalized >24 hours; permanent IP discontinuation.
6.11.4.
Relationship
The Investigator should assess the causal relationship between each AE and either IP, XOI, or
gout flare prophylaxis (if applicable) individually and answer “yes” or “no” to the question, “Do 
you consider that there is a reasonable possibility that the event may have been caused by the IP, 
XOI, or gout flare prophylaxis?” For SAEs, causal relationship will also be assessed for each 
study medication and study procedures. Note that for SAEs that could be associated with any 
study procedure, the causal relationship is implied as “yes.”

Not related (No): there is no evidence for a ‘reasonable possibility’ of a causal 
relationship for the individual event. An AE for which an alternative explanation is 
more likely, eg, concomitant medication(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely.

Related (Yes): there is evidence for a ‘reasonable possibility’ of a causal relationship 
for the individual event. The expression ‘reasonable possibility’ of a causal 
relationship is meant to convey, in general, that there are facts (evidence) or 
arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’. Causal relationship in cases where the disease 
under study has deteriorated due to lack of effect should be classified as no reasonable 
possibility.


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6.11.5.
Reporting Adverse Events
The Investigator must record all AEs in the source documents (eg, medical record), and report 
the data on the appropriate CRF pages. The Investigator will notify the local EC per the EC 
requirements.
AEs must be collected from the Screening Visit 1 through at least 28 days post treatment.
The information recorded will be based on the signs or symptoms reported by the subject. A 
clinical diagnosis should be provided to the extent feasible instead of listing individual signs or 
symptoms. Signs and symptoms are to be recorded clearly in a concise manner using standard, 
acceptable medical terminology to eliminate vague, ambiguous, or colloquial expressions. The 
Sponsor is responsible for the ongoing collection of safety data and their evaluation in 
accordance with local and federal guidelines and regulatory requirements. The Sponsor will 
inform all central EC(s), Investigators (if applicable), and regulatory authorities of findings that 
could adversely affect the safety of subjects or affect the conduct of the study and will report to 
regulatory authorities in conformity with expedited and periodic reporting requirements.
6.11.6.
Serious Adverse Events
6.11.6.1.
Definition
An SAE is defined as any AE occurring during any study phase that fulfills one or more of the 
following criteria:

Results in death.

Is immediately life-threatening.

Requires in-patient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions.

Is a congenital abnormality or birth defect.

Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.
Note that an AE or suspected adverse reaction is considered "life-threatening" for reporting as an 
SAE if, in the view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death. It does not include an AE or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.
The following events do not meet the definition of an SAE: planned hospitalization for a 
condition present prior to the subject’s enrollment in the study; hospitalization of the subject for 
compliance/convenience reasons; planned hospitalization for an elective medical/surgical 
procedure, scheduled treatments, or routine check-ups; or a hospitalization or an emergency 
room visit lasting less than 24 hours.


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6.11.6.2.
Managing Serious Adverse Events
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible and be treated as medically appropriate. Appropriate laboratory tests will be 
conducted until all parameters return to normal or are otherwise explained or stable. The subject 
will be followed until the SAE resolves or until the subject is medically stabilized.
6.11.6.3.
Reporting Serious Adverse Events
The Investigator or designee will notify the Sponsor immediately and not later than 24 hours
after knowledge of the SAE and at the outcome of the SAE. SAE reporting instructions 
(including forms, e-mail addresses, and facsimile and telephone numbers) will be provided in the 
Study Reference Manual. An SAE report must follow within 24 hours of knowledge, including a 
full description (to the extent possible) of the event and any sequelae.
6.12.
Retest Requirements for Subjects With Changes in Kidney Function
Retesting of laboratory values, including sCr and eCrCl, as well as the interruption of IP due to 
safety concerns, can occur any time on study at the Investigator’s discretion. 
If a subject experiences any of the following changes in kidney function (using central laboratory 
results), the subject must return to the site for retesting and be evaluated for potential 
contributing factors:

eCrCl declines >30% from Baseline in the period starting at Baseline through 
Month 12 study visit, or eCrCl declines >40% from Baseline in the period from the
Month 12 study visit through the Month 24 study visit.

Absolute sCr ≥4.0 mg/dL or eCrCl <20 mL/min at any time on study (Note: this is 
also the criteria for when IP must be interrupted; see Section 6.12.1.)
The underlying cause of the change in kidney function should be evaluated, treated, and 
managed as medically appropriate by the Investigator. Additional information will be collected 
on these events in the CRFs.
During any Retest periods throughout the study period, IP does not need to be interrupted 
unless warranted as determined by the Investigator and treating Healthcare Providers or if 
specific criteria are met (sCr ≥ 4.0 mg/dL or an eCrCl < 20 mL/min; see Section 6.12.2).
For IP discontinuation criteria see Section 5.3.2.1.2. Retesting schema for subjects with changes 
in kidney function is presented in Appendix C.
6.12.1.
Estimated Creatinine Clearance Decline From Baseline
Baseline Through the Month 12 Study Visit
From Baseline through the Month 12 study visit, if a subject experiences an eCrCl decline >30% 
from Baseline, the subject will return to the site within 1 to 2 weeks (Retest 1) for a retest.

If any retest eCrCl declines ≤15% from Baseline, no further retests are required and 
the subject may continue the protocol-scheduled visits.


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
If the Week 1 to 2 retest (Retest 1) eCrCl declines >15% from Baseline, the subject 
will return to the site for a retest approximately 3 to 4 weeks (Retest 2) after the initial 
eCrCl decline was noted.

If the Week 3 to 4 retest (Retest 2) eCrCl declines >15% from Baseline, the subject 
will return to the site for a retest approximately 7 to 8 weeks (Retest 3) after the initial 
eCrCl decline was noted.

Thereafter, additional retests may be done at the Investigators discretion or the 
subject may continue the protocol-scheduled visits. If subject’s eCrCl does not return 
to ≤15% of Baseline, IP can be continued and additional retesting is not required; 
medical treatment and evaluation should be sought as appropriate.
If a subject has persistent decline in their renal function (ie, stable at an eCrCl level 15% to 30% 
below Baseline) or has permanently discontinued IP, retesting may be at the Investigator’s 
discretion based on medical appropriateness.
Month 12 Study Visit to Month 24 Study Visit
From the Month 12 study visit to the Month 24 study visit, if a subject experiences an eCrCl 
decline >40% from Baseline, the subject will return to the site within 1 to 2 weeks for a retest
(Retest 1).

Retests 2 (Weeks 3 to 4) and 3 (Weeks 7 to 8) should be performed unless eCrCl 
declines ≤20% from Baseline.

If any retest eCrCl declines ≤20% from Baseline, no further retests are required and 
the subject may continue the protocol-scheduled visits.

If a subject has persistent decline in their renal function (ie, stable at an eCrCl level 
20% to 40% below Baseline) or has permanently discontinued IP, retesting may be at 
the Investigator’s discretion based on medical appropriateness.
Investigators are encouraged to keep subjects on IP during the Retest periods as clinically 
appropriate and providing sCr is <4.0 mg/dL and eCrCl ≥20.0 mL/min.
6.12.2.
Absolute Serum Creatinine ≥4.0 mg/dL or Estimated Creatinine Clearance
<20 mL/min
If a subject experiences an absolute sCr ≥4.0 mg/dL or an eCrCl <20 mL/min at any time during 
the study, IP must be temporarily interrupted, and the subject will return to the site within 1 to 
2 weeks (Retest 1) for a retest.
Baseline Through the Month 12 Study Visit

From Baseline through the Month 12 study visit, if any retest eCrCl declines ≤15% 
from Baseline and sCr <4.0 mg/dL and an eCrCl ≥20 mL/min, no further retests are 
required and the subject may restart IP, at the Investigator’s discretion, and continue 
the protocol-scheduled visits. The re-initiation of IP may occur regardless of the 
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
If Retest 1 eCrCl declines >15% from Baseline or sCr ≥4.0 mg/dL or an eCrCl 
<20 mL/min, the subject will return to the site for a retest approximately 3 to 4 weeks 
(Retest 2) after the initial decline was noted.

If Retest 2 eCrCl declines >15% from Baseline or sCr ≥4.0 mg/dL or an eCrCl 
<20 mL/min, the subject will return to the site for a retest approximately 7 to 8 weeks 
(Retest 3) after the initial decline was noted.

After Retest 3, subjects should continue the protocol-scheduled visits. If eCrCl is 
≤15% of the Baseline and sCr <4.0 mg/dL and eCrCl ≥20 mL/min, the subject may 
restart IP, at the Investigator’s discretion.
Month 12 Study Visit to Month 24 Study Visit

From the Month 12 study visit to the Month 24 study visit, Retests 2 (Weeks 3 to 4) 
and 3 (Weeks 7 to 8) should be performed if eCrCl declines >20% from Baseline or 
sCr ≥4.0 mg/dL or eCrCl <20 mL/min.

If any retest eCrCl declines ≤20% from Baseline and sCr <4.0 mg/dL and an eCrCl 
≥20 mL/min, no further retests are required and the subject may restart IP, at the 
Investigator’s discretion, and continue the protocol-scheduled visits. The re-initiation 
of IP may occur regardless of the duration of the interruption.
6.13.
Management of Acute Gout Flares
If a subject experiences an acute gout flare, study medications, including gout flare prophylaxis,
should continue uninterrupted. Gout flares should be treated aggressively as appropriate by the 
treating Healthcare Providers individualized to the subject and the clinical circumstances.
There are no current specific guidelines for the treatment of acute gout flares in patients with 
chronic kidney disease (CKD). Corticosteroids are often the preferred treatment option (alone or 
in combination, as applicable, with ongoing colchicine prophylaxis) for patients with CKD 
though dosages and administration (ie, oral or intra-articular) vary for individual patients (Curiel 
2012, Gaffo 2008, El-Zawawy 2010). EULAR guidelines state that acute gout flares can be 
managed using intra-articular aspiration and injection of a long acting steroid, especially when 
safety or tolerability concerns limit the use of NSAIDs and colchicine (Zhang 2006).
Treatment with NSAIDs should generally be avoided (or used judiciously) for acute gout flares
(Curiel 2012, Gaffo 2008, El-Zawawy 2010) and is not permitted for gout flare prophylaxis 
(Section 5.2.2).
6.14.
Suspected Pregnancy (Exposure in Utero)
If a subject becomes pregnant, IP, XOI, and gout flare prophylaxis (if applicable) should be 
discontinued immediately. The Investigator or other site personnel must notify the Sponsor or 
designee of a pregnancy associated with IP exposure within 1 day; ie, immediately, but no later 
than 24 hours, after the Investigator becomes aware of it and record the event and the course of 
the pregnancy, including perinatal and neonatal outcome (when is known) on the Pregnancy 
Report Form that will be provided to each site. The same timelines apply when outcome 
information is available.


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Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should be followed up and documented even if the subject was 
withdrawn from the study. Partner pregnancy data may not be collected.
6.15.
Overdose
An overdose is defined as a daily dose of IP more than 200 mg (>1 tablet).
AEs associated with an overdose should be recorded on the appropriate AE CRF; however, all 
overdoses, including those not associated with an AE, should be recorded on the appropriate
CRF.
6.16.
Premature Withdrawal From the Study
Subjects are free to withdraw from the study at any time without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AE. The Investigator will follow up AEs outside of the clinical study. At the time of study 
withdrawal, subjects should complete the End of Study Visit. If a subject withdraws from 
participation in the study, then his/her enrollment/randomization code cannot be reused. Subjects 
who withdraw early from the study will not be replaced.
Possible reasons for early withdrawal of subjects from the study include the following:

Subject withdraws consent

Death

Lost to follow up.
To ensure validity of study data, it is important to collect as much data as possible throughout the 
study. It is essential that Investigators maintain contact with the subjects. This contact will assist 
with subject retention and prevent missing data. Several approaches may be implemented to 
increase communication and retention (eg, telephone calls to the subject’s emergency contact, 
emails, texts, offers of transportation arrangements, etc). Certain approaches must be approved 
by appropriate IRBs/ECs in compliance with local privacy laws/practices.
For subjects who withdraw early or do not have an End of Study Visit, the site or delegate should 
attempt to collect vital status information (dead or alive). Vital status, based on publicly available 
sources, may also be investigated at Month 24 for subjects who did not complete the study.
The date and the reason must be recorded on the CRF for all subjects who withdraw early from 
the study. See Section 8.4.1 for End of Study Visit procedures.


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7.
STUDY RESTRICTIONS
7.1.
Potential Drug Interactions
7.1.1.
Interactions With Lesinurad
CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, and CYP2C9 Inducers
Lesinurad exposure is increased when it is co-administered with inhibitors of CYP2C9, and in 
CYP2C9 poor metabolizers. Lesinurad should be used with caution in patients taking moderate 
inhibitors of CYP2C9 (eg, fluconazole, amiodarone) and in CYP2C9 poor metabolizers.
Lesinurad exposure is decreased when lesinurad is coadministered with moderate inducers of 
CYP2C9 (eg, rifampin, carbamazepine), which may decrease the therapeutic effect of lesinurad.
CYP3A Substrates
In interaction studies with lesinurad and CYP3A substrates conducted in healthy subjects, 
lesinurad reduced the plasma concentrations of sildenafil and amlodipine. Although there was 
not a clinically significant interaction with atorvastatin, HMG-CoA reductase inhibitors that are 
sensitive CYP3A substrates may be affected. The possibility of reduced efficacy of concomitant 
drugs that are CYP3A substrates should be considered and their efficacy (eg, blood pressure and 
cholesterol levels) should be monitored.
Salicylates
Salicylates at doses higher than 325 mg per day may decrease the sUA lowering activity of 
lesinurad in combination with allopurinol. There are no restrictions for doses of salicylates of 
325 mg or less per day (ie, for CV protection).
7.1.2.
Interactions With Xanthine Oxidase Inhibitors
Investigators should be aware of potentially serious interactions when allopurinol and febuxostat 
are given in combination with other drugs. The following sections list the drugs that should not 
be administered or should be administered with caution (eg, may require dose adjustments or 
additional patient monitoring) with allopurinol and febuxostat according to the United States 
Product Insert (USPI) and/or the Summary of Product Characteristics (SmPC) (Febuxostat 80 mg 
Tablets [SmPC] Rev December 2012, Allopurinol [US package insert] Rev July 2015,
Allopurinol 100 mg Tablets [SmPC] Rev February 2013, Uloric [US package insert] Rev March 
2013). Refer to the local product labels for complete information on drug interactions.


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7.1.2.1.
Allopurinol
Drugs that should not be administered or should be administered with caution while taking
allopurinol include, but are not limited to, the following:

6-mercaptopurine 

azathioprine

coumarin anticoagulants

theophylline

captopril

ampicillin/amoxicillin

cyclosporine

didanosine

vidarabine (adenine arabinoside)

oxipurinol

thiazide diuretics

cyclophosphamide

tolbutamide

chlorpropamide
7.1.2.2.
Interactions With Febuxostat
Febuxostat should not be administered with 6-mercaptopurine or azathioprine.
7.1.3.
Interactions With Colchicine
Moderate or strong CYP3A inhibitors that should not be administered while taking colchicine 
prophylaxis include, but are not limited to, the following:

atazanavir

clarithromycin

darunavir

indinavir

itraconazole

ketoconazole

lopinavir

nefazodone

nelfinavir 

ritonavir

tipranavir

saquinavir

telithromycin

amprenavir

aprepitant

diltiazem

erythromycin

fluconazole

fosamprenavir

verapamil


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Inhibitors of P-gp that are prohibited while taking colchicine prophylaxis include, but are not 
limited to, the following:

cyclosporine

ranolazine
Potentially significant drug interactions have been reported between colchicine and HMG-CoA 
reductase inhibitors, other lipid-lowering drugs, and digitalis glycosides. Subjects receiving these 
medications are to be carefully monitored for any signs or symptoms of muscle pain, tenderness, 
or weakness, particularly during initial therapy with colchicine.
Refer to the local product label for complete information on drug interactions with colchicine or 
other gout flare prophylaxis medications (eg, prednisone, prednisolone, or their equivalent).
Subjects must discontinue colchicine for gout flare prophylaxis (expected through the Month 6 
study visit) if inhibitors of P-gp or moderate or strong CYP3A inhibitors are administered while 
on colchicine. This includes intake of grapefruit or grapefruit juice.
Subjects who are randomized and who subsequently develop intolerance or toxicity to colchicine 
or need to take inhibitors of P-gp or moderate to strong CYP3A inhibitors prior to the Month 6 
study visit should, when medically appropriate, switch to the alternate gout flare prophylaxis, 
low-dose oral corticosteroids for a short course, such as through the Month 3 study visit. If 
switching is not medically appropriate, randomized subjects may continue in the study without 
gout flare prophylaxis.
7.2.
Food and Fluid Intake
All doses of study treatment should be taken with water. Subjects should be encouraged to stay 
well hydrated. Grapefruit juice, a moderate CYP3A inhibitor, should not be consumed if the 
subject is taking colchicine.
7.3.
Subject Activity Restrictions
There are no special requirements or restrictions on activity level.
7.4.
Contraception
Current data from nonclinical studies suggest that lesinurad is not a reproductive hazard and 
showed no evidence of a genotoxic risk to humans at the planned lesinurad dosing in this study 
(see lesinurad IB for more information). There are no available human data on use of lesinurad in 
pregnant women. As a precaution, female subjects of childbearing potential (including 
peri-menopausal women who had menstrual bleeding within 1 year) must use an effective 
non-hormonal method of birth control (see Study Reference Manual) while taking IP. Because of 
a potential for lesinurad to affect the efficacy of hormonal contraceptives, subjects using a 
hormonal contraceptive must also use an effective non-hormonal method of birth control.
Male study subjects and their partners are not required to use contraception during this study.


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8.
STUDY ACTIVITIES
This section lists study activities by study day or month. In this study, a month is defined as 
28 days. Unless there is a safety concern, every effort should be made to avoid protocol 
deviations. Additional visits will be required if subjects experience changes in renal function as 
outlined in Section 6.12.
During the Double-Blind Treatment Period, all visits will occur at the end of the study month (ie, 
the Month 3 Visit will occur on Day 84 [±7 days]). All scheduled visits should be referenced 
back to the Baseline Visit.
See Section 6 and the Study Reference Manual for detailed information on study procedures. See 
Appendix A for the schedule of events.
NOTE:  subjects will be required to return to the site for additional visits if they have changes in 
renal function as outlined in Section 6.12. At timepoints when there are multiple assessments,
patient-reported outcomes (including SDS, WPAI:SHP, EQ-5D-3L),vital sign measurements,
and ECG (if applicable) should be performed prior to other assessments, particularly prior to 
laboratory sample collections.
8.1.
Screening Period (Day -28 to the Baseline Visit)
At the start of the Screening Period, prospective study subjects will be fully informed about the 
nature of the study and possible AEs. Subjects must read the ICF and sign the document after the 
Investigator has answered all questions to the subject’s satisfaction. Further procedures can begin 
only after the consent form has been signed. Prospective subjects will be evaluated for entry into 
the study according to the eligibility criteria. The Investigator must evaluate the results of all 
examinations, clinical laboratory tests, and medical history to determine each subject’s suitability 
for the study prior to randomization and starting IP.
8.1.1.
Screening Visit 1 (Approximately 28 Days Before the Baseline Visit)
The following procedures and assessments will be performed:

Obtain written informed consent.

Review eligibility criteria.

Record demographics.

Record prior ULTs (including current XOI with dose) indicated for the treatment of 
gout.

Take vital signs.

Measure height and weight measurements and calculate BMI.

Assess AEs (pretreatment events).

Collect blood sample for the following serum chemistry analyses:

Analytes 1.


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8.1.2.
Screening Visit 2 (Within 3 Weeks After Screening Visit 1 [±3 Days])
The following procedures and assessments will be performed:

Review eligibility criteria (including a review of targeted medical history and 
concomitant medications).

Take vital signs.

Assess AEs (pretreatment events).

Assess compliance with prescription XOI.

Collect blood sample for the following serum chemistry analyses:

Analytes 1.

Human chorionic gonadotropin (HCG) pregnancy test for all females and follicle-
stimulating hormone (FSH) test for females who report 12 months of spontaneous 
amenorrhea and are not surgically sterile.

Collect urine sample for the following analysis:

Urinalysis.
8.1.3.
Baseline Visit (4 to 7 Days After Screening Visit 2)
The following procedures and assessments will be performed:

Review gout flare history prior to Screening and during the Screening period.

Confirm continued eligibility.

Record complete medical history.

Record concomitant medications.

Administer patient report outcome assessments.

Take vital signs.

Record 12-lead ECG.

Assess AEs (pretreatment).

Perform physical examination.

Identify and measure target tophi.

Collect blood sample for hematology.

Collect blood sample for the following serum chemistry analyses:

Analytes 1.

Analytes 2.

Analytes 3.


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
Collect blood sample for plasma biomarkers.

Collect urine sample for the following analyses:

Urinalysis.

Protein-creatinine ratio.

Urine biomarkers.

Assess compliance with prescription XOI and discontinue.

Randomize subject.

Dispense IP (lesinurad or placebo), XOI, and colchicine (if applicable).
8.2.
Rescreening of Subjects
Subjects who fail to meet the eligibility requirements for the study may be rescreened up to 
3 times, as appropriate, using a new screening number each time. The minimum time required 
before each rescreening is 1 month (28 days).
8.3.
Treatment Period (Day 1 Through Month 24)
Subjects must meet all of the eligibility criteria listed in Section 4.2 and Section 4.3 before being
randomized and starting IP, study-supplied XOI, and colchicine (as applicable). Subjects will 
receive IP in combination with an XOI for up to 24 months. Subjects who permanently 
discontinue IP early should complete an End of Treatment Visit (Section 8.3.3) as soon as 
possible after discontinuing IP, and a Post-End of Treatment Visit (Section 8.4.1) 1 month after 
the End of Treatment Visit, but should remain on the study and follow the protocol-scheduled 
visits.
8.3.1.
Day 1 (1 Day After Baseline Visit)
This is not a study visit. Subjects will receive study-supplied medications (IP, XOI, and 
colchicine, as applicable) at their Baseline Visit and will start taking these medications at home
on Day 1 (1 day after Baseline Visit). Colchicine may be taken at Baseline. All study-supplied 
medications should be taken in the morning. Refer to Section 5.3 for details on administration of 
study-supplied medications.
8.3.2.
Month 1 (Day 28 ±7 Days) and Months 3 Through 21 (Visits Every 3 Months ±7 
Days)
The following procedures and assessments will be performed at each visit, except where 
otherwise noted:

Administer patient-reported outcome assessments (except at Month 1).

Review gout flares that occurred since the last study visit.

Take vital signs.

Assess AEs.

Record concomitant medications.


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
Assess compliance with IP (lesinurad/placebo).

Assess compliance with XOI.

Assess compliance with gout flare prophylaxis (Months 1, 3, and 6).

Measure target tophi (Months 6, 12, 18).

Collect blood sample for hematology (Months 6, 12, and 18).

Collect blood sample for the following serum chemistry analyses:

Analytes 1.

Analytes 2.

Analytes 3 (Months 6, 12, and 18).

Pregnancy test for women of childbearing potential (Month 12).

Collect blood sample for plasma biomarkers (Months 6, 12, and 18).

Collect urine sample for the following analyses:

Urinalysis.

Protein-creatinine ratio (Months 6, 12, and 18).

Urine biomarkers (Months 6, 12, and 18).

Except at Month 1, dispense IP (lesinurad or placebo), XOI, and colchicine (as 
needed at Month 3).
For subjects that have permanently discontinued IP, maintaining the visit schedule is 
recommended. Although all assessments are encouraged, at a minimum, it is requested that 
collection of AEs and collection of a blood sample for Analytes 1 occur.
8.3.3.
Month 24 (±7 Days) and/or End of Treatment Visit
The following procedures and assessments will be performed at Month 24 (for subjects who 
complete the Treatment Period) or as soon as possible after permanently discontinuing IP (for 
subjects who discontinue IP early):

Collect reasons for discontinuing IP, if applicable.

Administer patient-reported outcome assessments.

Review gout flares that occurred since the last study visit.

Take vital signs.

Measure weight.

Assess AEs.

Record concomitant medications.

Assess compliance with IP (lesinurad/placebo).

Assess compliance with XOI.


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
Measure target tophi.

Collect blood sample for hematology.

Collect blood sample for the following serum chemistry analyses:

Analytes 1.

Analytes 2.

Analytes 3.

Pregnancy test for females of childbearing potential.

Collect blood sample for plasma biomarkers.

Collect urine sample for the following analyses:

Urinalysis.

Protein-creatinine ratio.

Urine biomarkers.

Dispense XOI.
8.4.
Follow-Up Period
All subjects who complete the Treatment Period will return to the site for an End of Study Visit 
1 month later (Section 8.4.2).
Subjects who permanently discontinue IP early should return to the site for an End of Treatment 
visit (Section 8.3.3) as soon as possible after discontinuing IP, then a Post-End of Treatment 
Visit (Section 8.4.1) 1 month after the End of Treatment Visit. They should remain on study and 
follow the protocol schedule (with the exception of dispensing and taking IP) and have an End of 
Study Visit (Section 8.4.2) at the conclusion of their study period. Alternatively, if the subject 
does not agree to this option, a modified follow-up including, eg, regular telephone contacts or a 
contact at Month 24, should be arranged, if agreed to by the subject and in compliance with local 
data privacy laws/practices. Subjects who do not wish to continue on study after discontinuing IP 
should complete an End of Study Visit 1 month after treatment discontinuation (Section 8.4.1), 
which should be performed in place of the Post-End of Treatment Visit.
8.4.1.
Post-End of Treatment Visit for Subjects Who Discontinue Investigational 
Product But Remain on Study (~30 Days Post-Discontinuation)
Subjects who permanently discontinue IP but remain on study should complete a Post-End of 
Treatment Visit approximately 28 days after the End of Treatment Visit. The following 
procedures and assessments will be performed:

Administer patient-reported outcome assessments.

Review gout flares that occurred since the last study visit.

Take vital signs.

Assess AEs.


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
Record concomitant medications.

Measure target tophi.

Collect blood sample for hematology.

Collect blood sample for the following serum chemistry analyses:

Analytes 1.

Analytes 2.

Analytes 3.

Collect urine sample for the following analyses:

Urinalysis.

Protein-creatinine ratio.

Assess compliance with XOI, if applicable.

Dispense XOI, if applicable.
8.4.2.
End of Study Visit
All subjects should complete an End of Study Visit. This visit should occur approximately 
28 days after completing the Treatment Period or after permanent treatment discontinuation if 
the subject is no longer continuing in the study. Subjects should return all study supplies to the 
site. The following procedures and assessments will be performed:

Collect reasons for early study withdrawal if applicable.

Administer patient-reported outcome assessments.

Review gout flares that occurred since the last study visit.

Take vital signs.

Assess AEs.

Record concomitant medications.

Measure target tophi.

Collect blood sample for hematology.

Collect blood sample for the following serum chemistry analyses:

Analytes 1.

Analytes 2.

Analytes 3.

Collect blood sample for plasma biomarkers.

Collect urine sample for the following analyses:

Urinalysis.


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
Protein-creatinine ratio.

Urine biomarkers.

Assess compliance with XOI, if applicable.


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9.
PLANNED STATISTICAL METHODS
This section describes the statistical considerations and data analyses to address the objectives of 
the study. Further details will be provided in the Statistical Analysis Plan (SAP).
9.1.
General Considerations
All subjects will be randomized to either lesinurad 200 mg or matching placebo in combination 
with an XOI in a 1:1 ratio and stratified by the following stratification factors:

Screening eCrCl: the average eCrCl of Screening Visit 1 and Screening Visit 2 (30.0 
to <45.0 mL/min or 45.0 to <60.0 mL/min).

Baseline measurable target tophus status: present or absent.

Type of XOI: allopurinol or febuxostat.
This study will enroll approximately 50% of subjects with eCrCl 30.0 to <45.0 mL/min and 
approximately 50% with eCrCl 45.0 to <60.0 mL/min. There is no planned sample size 
requirement on the number of subjects enrolled by type of XOI or Baseline tophus status.
However, a stratification variable (eg, Baseline measurable target tophus status [present/absent]) 
may be dropped from the stratified analysis (eg, mixed model repeated measures [MMRM] or 
Cochran Mantel Haenszel [CMH]) if the number of subjects in any stratum is very low 
(eg, <10% of total subjects). The decision to drop a stratification variable will be made prior to 
database lock and will be documented in the SAP.
All safety and efficacy data will be listed and summarized by treatment group.
Baseline is defined as the last observed measurement prior to the first dose of IP, unless 
otherwise specified.
Descriptive statistics will consist of the number of subjects (n), mean, standard deviation (SD), 
median, minimum, and maximum for continuous variables, and counts and percentages for 
categorical variables.
Unless otherwise specified, all confidence intervals (CIs) will be calculated at the 95% level and 
all hypothesis tests will be performed at the 0.05 level. All analyses including summaries and 
listings will be performed using SAS® software version 9.1 or higher.
9.2.
Determination of Sample Size
Approximately 600 subjects will be randomized 1:1 to either the lesinurad (LESU) + XOI or 
placebo (PBO) + XOI group in this study.
For safety endpoint analyses, this sample size provides sufficient precision around the estimated 
between-treatment difference for the absolute and percent changes in eCrCl from Baseline to 
Month 24 based on the normal distribution CI with 95% two-sided confidence level. For the 
difference in absolute change from Baseline to Month 24, the estimated precision is ±1.6 mL/min 
assuming a common SD for the change from Baseline in each treatment group of 10 mL/min 
estimated from the lesinurad Phase 3 development program. For the difference in percent change 
from Baseline to Month 24, the estimated precision is ±3.2% assuming a common SD for the 


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percent change from Baseline in each treatment group of 20% estimated from the lesinurad 
Phase 3 development program.
For the key efficacy endpoint analyses, this sample size will provide >90% power for the overall 
population and >80% power within each Screening eCrCl stratum to detect a treatment 
difference for the proportion of subjects achieving sUA <6.0 mg/dL at Month 6 of 15% (20% in 
the PBO + XOI group versus 35% in the LESU + XOI group, as estimated from the lesinurad 
Phase 3 development program), using a binomial distribution at an alpha of 0.05 (two-sided). 
Based on the assumptions above, this sample size provides sufficient precision such that the 
minimum statistically significant difference in response rate is approximately 10% in the overall 
population, and approximately 11% in the Screening eCrCl 30.0 to <45.0 mL/min stratum, at the 
two-sided 5% level.
9.3.
Analysis Populations
The Intent-to-Treat (ITT) Population will be defined as all randomized subjects who received 
at least 1 dose of IP (lesinurad or placebo). This will be the primary population for efficacy 
analyses and subjects will be analyzed based on the randomized treatment assigned.
The Safety Population will be defined as all randomized subjects who received at least 1 dose of 
IP (lesinurad or placebo). Subjects will be analyzed based on the randomized treatment assigned. 
Any major deviations from the randomized treatment assignment will be listed and considered 
when interpreting the safety data.
The Per-Protocol Population will be defined as all subjects in the ITT population without major
protocol deviations, defined prior to unblinding of the study. Select analyses (to be specified in 
the SAP), will be repeated on the PP population.
9.4.
Analysis Methods
9.4.1.
Disposition, Demographics, and Baseline Characteristics
Subject disposition, demographics, gout diagnosis, and Baseline disease and treatment 
characteristics will be summarized for the ITT Population.
Compliance with IP (lesinurad or placebo) will be summarized and will include the number of 
subjects estimated to be <80% compliant, 80% to 120% compliant, and >120% compliant. The 
total dose and average daily dose will also be summarized.
9.4.2.
Safety Analyses
Safety data will be analyzed descriptively using the Safety Population.
The main estimands to address the safety objective are the absolute and percent changes from 
baseline to Month 24 in eCrCl, assessed in the Safety population, with treatment difference 
estimated using MMRM and missing data imputed separately for each treatment group assuming 
missing at random (MAR).


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9.4.2.1.
Change From Baseline in Estimated Creatinine Clearance
Absolute and percent changes from Baseline to Month 24 in eCrCl will be assessed using a 
MMRM analysis that includes terms for treatment (LESU + XOI and PBO + XOI), visit, 
treatment by visit interaction, stratification factors (type of XOI [allopurinol or febuxostat], 
Baseline measurable target tophi status [present/absent], and Screening eCrCl [30.0 to 
<45.0 mL/min or 45.0 to <60.0 mL/min], as appropriate as stated in Section 9.1), and Baseline 
eCrCl as covariate. The model will assume an unstructured covariance matrix. If convergence 
issues are encountered, alternative covariance structure will be explored (details will be provided 
in the SAP). Least-square (LS) mean by treatment and LS mean difference between 
LESU + XOI and PBO + XOI alone will be estimated from the MMRM analysis, along with the 
95% CI of LS mean difference.
All subjects should be followed for safety events even if they discontinue IP (lesinurad or 
placebo), as permitted. Prior to performing MMRM analysis, renal function data that are 
collected after subjects discontinue IP will be set to missing. All missing data will be imputed 
using multiple imputation methodology assuming MAR and separate imputation models for the 
LESU + XOI and PBO + XOI groups. Sensitivity analysis will include all available data 
(including data after subjects discontinue IP) and impute only for missing data assuming MAR. 
Additional sensitivity analysis will be performed using multiple imputation assuming missing 
not at random, depending on the nature of missing data and early treatment discontinuations 
(eg, subjects discontinuing early due to worsening renal function).
In addition to using the Cockcroft-Gault equation for eCrCl, renal function will also be evaluated 
using estimated glomerular filtration rate (eGFR) equations (eg, the Modification of Diet in 
Renal Disease [MDRD]), and may be explored using similar methods as above.
9.4.2.2.
Renal-Related Outcomes
The following renal-related outcomes will be reported as both incidence proportions and 
exposure-adjusted incidence rates:

Incidence of sCr elevation (≥1.5 × Baseline).

Incidence of subjects meeting criteria (eg, based on sCr or eCrCl criteria) for 
treatment discontinuations.

Incidences of renal-related and kidney stone TEAEs and SAEs.

Prevalence of contributing factors to renal SAEs as adjudicated by the REAC.
The proportion will be calculated as the number of subjects with an outcome of interest 
(ie, unique subjects) during the study divided by the total number of subjects in that treatment 
group. The 95% CIs will be calculated based on the Wilson Score method.
The on-treatment exposure-adjusted incidence rates for an outcome of interest will be calculated 
as the number of subjects with that outcome of interest during the Treatment Period divided by 
the total duration of treatment in each treatment group (ie, “on-treatment” analysis). Similarly, 
the on-study exposure-adjusted incidence rates will be calculated as the number of subjects with
outcome of interest during the study divided by the total duration of study in each treatment 
group (ie, “on-study” analysis). Exposure-adjusted incidence rates and associated exact CIs 


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based on the Poisson distribution will be calculated for each treatment group and reported per 
100 patient-years.
Similar exposure-adjusted analysis will also be performed with the number of events as the 
numerator dividing by on-treatment or on-study exposure as described above.
Estimates of treatment differences with corresponding 95% CIs will be calculated. The 
appropriate approaches may depend on the number of events observed during blinded data 
review and will be detailed in the SAP prior to database lock.
Additional assessments may include the proportion of subjects who require dialysis, those who 
advance in their chronic kidney disease, those who have persistent decreases in eCrCl, and those 
who have persistent sCr elevations.
9.4.2.3.
Cardiovascular Outcomes
The following cardiovascular outcomes will be reported as both incidence proportions and 
exposure-adjusted incidence rates: 

Incidence of CEAC-adjudicated MACE (CV death, nonfatal myocardial infarction, 
and nonfatal stroke).

Incidence of CEAC-adjudicated MACE or hospitalization for unstable angina 
(MACE+).
Similar methods for estimating incidence proportions and exposure-adjusted incidence rates will 
be applied, as described in Section 9.4.2.2. In addition, the incidences of the individual MACE+ 
components will also be reported.
In addition, the time-to-event of MACE will be analyzed using Cox proportional hazards model
with treatment as the only predictor (base model). The estimated hazard ratio and associated 95% 
CI will be presented. Extended models (eg, including stratification factors, other Baseline 
covariates, etc.) may be explored depending on the number of events observed.
Two types of analyses will be conducted: on-study analysis and on-treatment analysis. For the 
on-study analysis, subjects with an event during the study will contribute actual time of first 
occurrence, while those without an event will be censored at the end of study. For the
on-treatment analysis, subjects with an event during the Treatment Period will contribute actual 
time of first occurrence, while those without an event during Treatment Period will be censored 
at the end of treatment. Sensitivity analysis may be conducted to explore different ascertainment 
windows for which to attribute the MACE outcome to treatment (eg, 1 month post-treatment 
discontinuation).
9.4.2.4.
General Safety
All AEs will be coded and tabulated by Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class and preferred term. Similar methods will be applied for estimating 
proportions and exposure-adjusted incidence rates (ie, on-study and on-treatment 
exposure-adjustment) of TEAE, SAEs, and TEAEs leading to permanent discontinuation of IP, 
as described in Section 9.4.2.2.


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Associated laboratory parameters such as hepatic profile, renal function, serum chemistry,
hematology, and urinalysis values will be grouped and presented together. Individual subject 
values will be listed and values outside of the standard reference range will be flagged. Marked 
abnormalities meeting RCTC version 2.0 grading will also be noted. Shift tables and analyses of 
changes from Baseline will be included.
The change from Baseline for each of the vital signs variables will be summarized.
9.4.3.
Efficacy Analyses
Efficacy data will be summarized and analyzed in the ITT population.
The key sUA efficacy endpoint (proportion of subjects with sUA <6.0 mg/dL at Month 6) will be 
summarized descriptively by treatment group and a comparison of the response rates will be 
presented using the CMH test statistic, stratified by type of XOI, Baseline measurable target 
tophus status (present/absent), and Screening eCrCl (30.0 to <45.0 mL/min or 45.0 to 
<60.0 mL/min), as appropriate as stated in Section 9.1. Results will be expressed as proportions, 
corresponding adjusted 95% CI of the difference between response rates, and p-values. Subjects 
who are missing their Month 6 sUA results will be analyzed as non-responders.
The LESU + XOI group will be deemed superior compared with the PBO + XOI group if there is 
sufficient statistical evidence to reject the following null hypothesis:
Ho: p1 = p2 ie, no evidence that the proportion of subjects achieving an sUA response by 
Month 6 in the LESU + XOI group is different from the PBO + XOI group.
and in favor of the alternative hypothesis:
H1: p1 ≠p2 ie, the proportion of subjects achieving an sUA response by Month 6 in the 
LESU + XOI group is different from the PBO + XOI group.
The key efficacy endpoint will be tested in the overall study population as well as the subset of 
subjects whose Screening eCrCl is 30.0 to <45.0 mL/min. To account for multiplicity, a 
hierarchical testing procedure will be performed to preserve an overall alpha at 0.05 level. First, 
the null hypothesis for the key efficacy endpoint will be tested in the overall population at an 
alpha level of 0.05. If the null hypothesis is not rejected, the testing will be stopped. Otherwise, 
the endpoint will then be tested in the subset of subjects whose screening eCrCl is 30.0 to
<45.0 mL/min at an alpha level of 0.05.
Sensitivity analyses (eg, observed cases or other imputation approaches) will be explored to 
assess the impact of missing data (details provided in the SAP).
Absolute and percent change from Baseline in sUA concentration will be summarized by visit 
and analyzed using MMRM that includes terms for treatment (LESU + XOI and PBO + XOI), 
visit, treatment by visit interaction, stratification factors (type of XOI [allopurinol or febuxostat], 
Baseline measurable target tophi status [present/absent], and Screening eCrCl [30.0 to 
<45.0 mL/min or 45.0 to <60.0 mL/min], as appropriate as stated in Section 9.1), and Baseline 
sUA as covariates. The model will assume an unstructured covariance matrix. If convergence 
issues are encountered, alternative covariance structure will be explored (details will be provided 
in SAP). LS mean by treatment and LS mean difference between LESU + XOI and PBO + XOI 
alone will be estimated from the MMRM analysis, along with the 95% CI of LS mean difference.


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The proportion of subjects reaching sUA <6.0 mg/dL at each visit will also be presented. 
Additional efficacy analyses to support the key efficacy endpoint will include the proportion of 
subjects reaching sUA <6.0 mg/dL at multiple consecutive visits (eg, Months 3 and 6). CMH 
estimates of 95% CI for difference will also be presented.
9.4.4.
Exploratory Endpoints
For all exploratory endpoints, descriptive statistics will be provided at each scheduled visit.
For percent change from Baseline in the sum of target tophi area among subjects with target 
tophus at Baseline, the between-treatment difference will be assessed using similar MMRM 
analysis as appropriate as in Section 9.4.2.1.
For the proportion of subjects with target tophi at Baseline who experience complete resolution 
of at least 1 target tophus at any time during study, the between-treatment difference in tophus 
resolution rates in this subset of subjects will be assessed using the CMH test statistic, stratified 
by type of XOI, and Screening eCrCl (as appropriate as stated in Section 9.1). Results will be 
summarized by randomized treatment group and expressed as proportions and corresponding 
adjusted 95% CI of the difference between response rates.
The proportion of subjects reporting gout flares will also be summarized at each visit.
The patient-reported outcomes (ie, SDS, WPAI:SHP, and EQ-5D-3L) will be summarized by 
visit (Visits 3, 6, 9, . . . 24). In addition, the mean score at last on-study visit will be analyzed 
using analysis of covariance (ANCOVA), which include terms for treatment stratification factors 
(as appropriate as stated in Section 9.1) and Baseline patient reported outcome value as 
covariate.
9.4.5.
Interim Analyses
No formal interim analysis is planned.


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10.
QUALITY CONTROL AND ASSURANCE
Quality assurance and quality control systems will be implemented and maintained with 
Standard Operating Procedures by the Sponsor and its designee(s), as appropriate, to ensure that 
this clinical study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation (ICH) E6 Good 
Clinical Practice (GCP): Consolidated Guidance, and the applicable regulatory requirements.
This study will be monitored by the Sponsor in accordance with GCP, and may be audited or 
reviewed by an independent Quality Assurance department, EC, and/or regulatory authorities. 
This implies that monitors and auditors/inspectors will have the right to inspect the study sites at 
any time during and/or after completion of the study and will have direct access to data/source 
documents, including the subject’s file. By participating in this study, Investigators agree to this 
requirement.
Measures will be undertaken to protect the confidentiality of records that could identify subjects, 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements.


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11.
ADMINISTRATIVE CONSIDERATIONS
11.1.
Ethics Committee Approval
At a minimum, the following documents must be reviewed and approved by ECs (including 
IRBs and IECs), as required by local laws and EC requirements, before subjects are screened for 
entry into the study:

Study protocol and amendment(s).

Written Informed Consent Form(s) and consent form updates.

Subject recruitment procedures (eg, advertisements).

Written information to be provided to subjects.

IB and available safety information. Note:  ECs do not approve IBs but are 
responsible for acknowledging receipt.

Information about payments and compensation available to subjects.
The EC approval must be in writing, clearly identifying the study (by protocol date and/or 
version), the documents reviewed, including informed consent form, and date of the review. The 
Investigator has the responsibility to provide the Sponsor with the written EC approval prior to 
initiating any study-related procedures. The Investigator also has the responsibility to inform the 
EC of serious and unexpected AEs and protocol deviations, and to provide the EC with a 
synopsis of the study report upon study completion according to the EC’s policy.
11.2.
Ethical Conduct of the Study
This study is to be conducted in accordance with the protocol, ICH E6 GCP, and all other 
applicable regulatory requirements. Investigators must immediately notify the Sponsor or 
designee (if applicable) of serious breaches in GCP that have occurred at their study site, which 
are likely to effect to a significant degree (a) the safety or physical or mental integrity of the 
subjects of the study or (b) the scientific value of the study.
11.3.
Subject Information and Consent
Note: all references to “subject” in this section refer to the study subject or his/her legally 
acceptable representative.
Prior to participation in any study-specific procedures, each subject must sign and date an 
EC-approved written ICF in a language the subject can understand.
The language in the written information about the study should be as non-technical as practical, 
and should be understandable to the subject. Before informed consent is obtained, the 
Investigator should provide the subject ample time and opportunity to inquire about the study 
and to decide whether or not to participate.
All questions about the study should be answered to the satisfaction of the subject. The written 
ICF should be signed and personally dated by the subject and by the person who conducted the 


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informed consent discussion, with any additional signatures obtained as required by applicable 
local regulations and EC requirements. Each subject will be informed that participation is 
voluntary and that he/she can withdraw from the study at any time. All subjects will receive a 
copy of their signed and dated ICF.
11.4.
Subject Confidentiality
The collection of personal data for this study will be limited to data that are necessary to 
investigate the utility of the IP used in this study. These data will be processed with adequate 
precautions to ensure confidentiality according to local laws.
The Sponsor ensures that the personal data are as follows:

Collected for a specified and legitimate purpose.

Processed fairly and lawfully.

Accurate and up to date.
Explicit consent for the processing of personal data will be obtained prospectively from the 
participating subject.
The Sponsor, whose responsibilities require access to personal data, agrees to keep the identity of 
study subjects confidential. This confidentiality will be maintained throughout the complete data 
processing.
Study subjects will be entitled to request confirmation of the existence of personal data held by 
the Sponsor and will have the right to rectify erroneous or inaccurate data up until database lock.
11.5.
Study Monitoring
The Sponsor will monitor this clinical study through central analysis, on-site monitoring visits,
and remote data checks to check the adequacy of site staff and facilities, and to ensure adherence 
to the protocol, study procedures, and applicable regulations. The site monitor will also assess 
proper CRF completion and source document retention. The Investigator and study site staff are 
expected to provide adequate space for monitoring visits and to allocate sufficient time to permit 
adequate review of the study’s progress. The Investigator will permit study-related monitoring, 
audits, EC review and regulatory inspection(s), providing direct access to source data/documents 
and study-related facilities (eg, pharmacy, diagnostic laboratories).
11.6.
Study Records and Case Report Forms
11.6.1.
Study Records and Case Report Forms Records
The Investigator and affiliated institution shall maintain the study documents and records as 
specified in “Essential Documents for the Conduct of a Clinical Trial” (ICH E6 Section 8), and 
as required by the applicable regulatory requirement(s). These include, but are not limited to, the 
protocol, CRFs, AE reports, subject source data (original records or certified copies), 
correspondence with health authorities and EC, consent forms, Investigator’s curriculum vitae, 
monitor visit logs, laboratory reference ranges and laboratory certification or quality control 
procedures, and laboratory director curriculum vitae. Subject source data must be maintained as 


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original records or a certified copy (ie, copy of original information that has been verified, as 
indicated by a dated signature, as an exact copy having all of the same attributes and information 
as the original). The Investigator and affiliated institution should take measures to prevent 
accidental or premature destruction of documents.
Study sites may utilize site-owned electronic medical record systems and/or other computer 
systems to generate, collect, and store subject source data. When such systems will be used for 
the study, their use and supporting infrastructure (eg, access/security, written procedures, 
technical support, and training as applicable) will be identified and documented in site 
assessment or site visit reports by the Sponsor or designee, and will be reviewed and monitored 
in accordance with applicable procedures and regulatory requirements. If electronic medical 
records are maintained (eSource data), the method of verification must be agreed upon between 
the investigational staff and the Sponsor or designee prior to enrollment of the first subject.
11.6.2.
Case Report Form
A CRF must be completed for each subject who has given informed consent. In the case of a 
screening failure, at a minimum the following data will be entered into the CRF: visit date, 
demography, and reason for screening failure. All entries into the CRF are ultimately the 
responsibility of the Investigator before adding his/her signature.
The CRF must be completed at the time of, or shortly after, the subject's visit, with the exception 
of results of tests performed outside the Investigator's office, so that they always reflect the latest 
observations of the subjects participating in the study. If certain information is Not Done, Not 
Available, or Not Applicable, the Investigator must record this according to the CRF completion 
instructions.
The CRF and source documents must be made available to the site monitor. During monitoring 
visits, the site monitor will review the CRF entries and evaluate them for completeness and 
consistency. The CRF entries will be compared with the source documents to ensure that there 
are no discrepancies between critical data. All entries, corrections, and alterations are to be made 
by the responsible Investigator or his/her designee. The site monitor may query the data, but 
cannot edit CRF entries recorded by the site designee.
A copy of each subject’s CRF will be maintained by the Investigator.
In addition to the clinical data management systems/databases, other systems may be used to 
collect and analyze study data:

A Safety Database will be used by the Sponsor or designee to collect, medically 
evaluate, document, report, and store SAEs as individual case safety reports, and to 
generate periodic reports, as required.

Laboratory Information Systems or proprietary systems will be used by laboratories 
for storing and/or analyzing safety and bioanalytical laboratory data collected 
throughout the study.

Statistical software will be used for the statistical analysis of the study data, as 
outlined in the SAP.


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
Electronic Document Management Systems will be used for storing essential 
documents (electronic trial master file).
11.6.3.
Source Data and Source Documents
The nature and location of all source documents will be identified to ensure that all sources of 
original data required to complete the CRF are known to the Sponsor or designee and 
investigational staff. These source documents are to be accessible for verification by the site 
monitor.
Source documents should at minimum include the following information for each subject:

Subject identification (name, year of birth, sex).

Documentation that subject meets eligibility criteria, eg, medical history, gout 
diagnosis, laboratory results (to support inclusion and exclusion criteria).

Participation in study (including study number).

Date and time of informed consent(s).

Dates of visits including last study visit.

Documentation that protocol-specific procedures were performed.

Study-supplied medication dispensing and accountability.

All AEs and other safety parameters (including AE start and stop dates, Investigator 
assessment of severity and relationship to and actions taken for study medications).

All gout flare events (including start date, stop date, and subject-reported severity 
[mild/moderat/severe]) and corresponding medications (to be recorded on the 
concomitant medications CRF).

Concomitant medications (including start and stop dates and indication for use).

Date and reason for permanently discontinuing IP, if applicable.

Date of study completion and reason for early withdrawal, if applicable.

Documentation of withdrawal of consent, if applicable.
The author of an entry in the source documents, as well as the date of the entry, should be 
identifiable. Direct access to source documentation (medical records) must be allowed for the 
purpose of verifying that the data recorded in the CRF are consistent with the original source 
data. The Investigator will provide certified copies of the subject’s medical records in the event 
that site’s policy does not permit direct access to the electronic medical records.
11.6.4.
Participation Cards
An EC-approved participation card will be provided to the site by the Sponsor for studies 
involving IPs or investigational use of marketed products. This card should be provided to study 
subjects, where required.


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11.6.5.
Subject Identification Information
To permit easy identification of the individual subject during and after the study, the Investigator 
is responsible for keeping an updated log that contains the subject identification information. 
This document will be reviewed by the site monitor for completeness. However, in order to 
ensure the subject’s confidentiality, the document will be maintained at the site and no copy will 
be made.
11.7.
Use of Computerized Systems
Information on the computerized systems will be provided to the Investigator, site personnel, and 
other personnel as appropriate. Measures will be taken to ensure data security and accuracy, 
including, but not limited to, user training, granting of user accounts and privileges to trained and 
authorized personnel in a role-based manner, username/password/electronic signature 
requirements enforcement, programmed and manual edit checks as outline in data validation 
specifications, computer-generated audit trails, centralized data management, and routine study 
monitoring. The systems used will be compliant with US 21 Code of Federal Regulations Part 11 
and Annex 11 on Computerized Systems (annex to the Guide to Good Manufacturing Practice 
for Medicinal Products) in the EU and Canada, and the data collected will be archived (at 
minimum) for the period specified by applicable regulatory requirements.
11.7.1.
Electronic Data Capture
An electronic data capture system will be used to capture protocol-required subject data. Sites 
will enter data from source documents onto electronic CRFs for each study visit using a 
web-based interface. Study monitors, data management, and safety personnel will use this 
system to review data and generate queries and reports as needed.
11.7.2.
Interactive Voice/Web Response System
An IVRS/IWRS will be used to randomize subjects, manage IP inventory, and facilitate IP 
reconciliation. Sites will enter data from source documents into IWRS for Screening and each 
study visit using a web-based interface. Study monitors will use this system to review data and 
generate queries and reports as needed.
The IVRS/IWRS will also be used  to request IP as needed during the treatment Period.
11.7.3.
Centralized Data Check System
A centralized analytics monitoring tool will be used to integrate data from different clinical data 
streams for the purpose of identifying data patterns and flagging unexpected data.
11.8.
Independent Monitoring and Adjudication Committees
11.8.1.
Independent Data Monitoring Committee
An IDMC will be appointed by the Sponsor to assess the safety of subjects participating in the 
study, to evaluate data periodically, to protect subject welfare, and to identify potential safety 
signals.


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The IDMC will consist of members with clinical expertise in a variety of specialties, as 
appropriate, and will operate under a written, detailed IDMC Charter. The IDMC members will 
have had no involvement in the design or conduct of the study except through their role on the 
IDMC, and have no financial or other important connections to the Sponsor other than their 
compensation for serving on the IDMC.
The IDMC will be responsible for evaluating the safety of lesinurad in combination with an XOI 
based on unblinded safety data, which includes SAE reports, nonserious AEs, and laboratory 
data. A list of CEAC- and REAC-adjudicated AEs and the committees’ findings will be provided 
to the IDMC, who will assess the frequency and significance of those events for the study.
The IDMC may also advise the Sponsor if the safety data suggest that lesinurad be stopped or the 
study be modified or prematurely terminated for any reason.
11.8.2.
Renal Events Adjudication Committee
An independent REAC will routinely evaluate and categorize all serious prospectively-defined 
renal-related and kidney stone AEs. In addition, the REAC chair will review all other SAEs in 
the clinical database and determine whether any additional SAEs should be adjudicated by the 
REAC. The REAC, in a blinded fashion, will assess the likelihood that potential contributing 
factors, including IP, contributed to the event. The committee will operate under a written, 
detailed REAC Charter. See the REAC Charter for details.
11.8.3.
Cardiovascular Endpoints Adjudication Committee
An independent CEAC will routinely adjudicate all SAEs and other prospectively-defined AEs 
for CV-related events in a blinded fashion using MACE and non-MACE CV criteria. The CEAC 
will operate under a written, detailed CEAC Charter. See the CEAC charter for details.
11.9.
Protocol Violations/Deviations
Unless there is a safety concern, there should be no deviations to or violations of the study 
protocol. In the event of a safety concern, the Investigator or designee must document and 
explain the reason for any deviation from the approved protocol. The Investigator may 
implement a deviation from, or a change to, the protocol to eliminate an immediate hazard to 
study subjects without prior EC approval. Immediately after the implemented deviation or 
change, the Investigator must submit a report explaining the reasons for the protocol violation or 
deviation to the EC and the Sponsor. The Sponsor is responsible for notifying the regulatory 
authorities, if required.
11.10.
Retention of Data
The Sponsor will inform the Investigator in writing when it is acceptable to dispose of any study 
records. To enable evaluation and/or audits from regulatory authorities or the Sponsor, the 
Investigator agrees to keep records, including the identity of all study subjects (eg, subject 
identification code list and all source documents), all original signed ICFs, copies of all CRFs, 
original laboratory reports, detailed records of IP disposition, and all essential documents for the 
conduct of a clinical study. To comply with international regulations, the records should be 
retained by the Investigator for at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an 


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ICH region, or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the IP. However, the Investigator may need to retain these documents for a 
longer period if required by the local regulatory requirements or by an agreement with the 
Sponsor.
11.11.
Financial Disclosure
The Investigator’s disclosable financial interests must be obtained prior to initiation of the study
site, at completion of the study at the investigational site, and 1 year following study completion.
The Investigator should promptly update this information if any relevant changes occur during 
the above described period.
Disclosable financial interests will be recorded on the Investigator Financial Disclosure Form.
Any Investigator(s) added as investigational staff to the form FDA 1572 must complete the 
Investigator Financial Disclosure Form at the beginning of his/her participation in the study.
Any Investigator(s) leaving the study site during the study period will be required to provide 
disclosable financial interest changes prior to leaving the study site.
11.12.
Site Closure or Study Termination
The Sponsor reserves the right to close any investigational site(s) or terminate the study at any 
time for any reason. Reasons for the closure of a study site or termination of a study by the 
Sponsor may include (but are not limited to) the following:

Successful completion of the study at the investigational site.

The required number of subjects for the study has been recruited.

Failure of the Investigator to comply with the protocol, GCP guidelines, or local 
requirements.

Safety concerns.

Inadequate recruitment of subjects by the Investigator.
11.13.
Protocol Modification
This protocol cannot be modified except in a formal protocol amendment by the Sponsor.
11.14.
Publication and Disclosure Policy
The data and results of the study will be owned solely by the Sponsor and shall be confidential 
information of the Sponsor, subject to the Investigator's publication rights outlined in the 
agreement between the Investigator/institution and the Sponsor regarding the conduct of the 
clinical study (the “Clinical Study Agreement”). It is understood by the Investigator that the 
Sponsor may use the information developed in this clinical study in connection with the 
development of its compounds and therefore, may disclose it as required to other clinical 
investigators or to regulatory agencies. To allow for the use of the information derived from this 
clinical study, the Investigator understands that he/she has an obligation to provide and disclose 
test results and all data developed during this study to the Sponsor.


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Any publication or presentation of the results of this clinical study by the Investigator may only 
be made in strict compliance with the provisions of the Clinical Study Agreement. The 
Investigator should understand that it is not the Sponsor’s intention to prevent publication of the 
data generated in the clinical study. However, the Sponsor reserves the right to control the form 
and timing of such publication for commercial reasons.


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12.
REFERENCE LIST
Allopurinol 100 mg Tablets [SmPC]. Teva UK Limited―UK; Rev February 2013.
Allopurinol [US package insert]. Qualitest Pharmaceuticals - US; Rev July 2015.
Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for 
prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 
2004;31(12):2429-2432.
Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for 
hyperuricemia in gout. Curr Rheumatol Rep. 2009;11(2):135-140.
Colchicine 500 micrograms Tablets [SmPC]. Wockhardt UK Ltd; Rev October 2015.
Colcrys [US package insert]. Takeda Pharmaceuticals America Inc.—US; Rev December 2016.
Curiel RV, Guzman NJ. Challenges associated with the management of gouty arthritis in patients 
with chronic kidney disease: a systematic review. Semin Arthritis Rheum. 2012;42(2):166-178.
El-Zawawy H, Mandell BF. Managing gout: how is it different in patients with chronic kidney 
disease? Cleve Clin J Med. 2010;77(12):919-928.
Febuxostat 80 mg Tablets [SmPC]. Menarini International Operations―Luxembourg S.A.; Rev 
December 2012.
Gaffo AL, Saag KG. Management of hyperuricemia and gout in CKD. Am J Kidney Dis. 
2008;52(5):994-1009.
Halevy S, Ghislain P-D, Mockenhaupt M, et al. Allopurinol is the most common cause of 
Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad 
Dermatol. 2008;58(1):25-32.
Handler J. Managing hypertensive patients with gout who take thiazide. J Clin Hypertens 
(Greenwich). 2010;12(9):731-735.


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James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high 
blood pressure in adults: report from the panel members appointed to the Eighth Joint National 
Committee (JNC 8). JAMA. 2014;311(5):507-520.
Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health 
Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford). 
2007;46(8):1372-1374.
Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines 
for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic 
approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431-1446.
Reginato AM, Mount DB, Yang I, Choi HK. The genetics of hyperuricaemia and gout. Nat Rev 
Rheumatol. 2012:1-12.
Richette P, Doherty M, Pascual E, et al. Updated EULAR evidence-based recommendations for 
the management of gout [EULAR abstract SAT0531]. Ann Rheum Dis. 2014;73(suppl 2).
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin 
Psychopharmacol. 1996;11(suppl 3):89-95.
So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010;120(6):1791-1799.
Uloric [US package insert]. Takeda Pharmaceuticals America, Inc.—US; Rev March 2013.
Woodworth T, Furst DE, Alten R, et al. Standardizing assessment and reporting of adverse 
effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J 
Rheumatol. 2007;34(6):1401-1414.
Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout, part 
II: management: report of a task force of the EULAR Standing Committee for International 
Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1312-1324.


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APPENDIX A. SCHEDULE OF EVENTS
Assessment/Procedure
Screening Period
Double-Blind Treatment Perioda
Follow-Up Period
SV1
SV2
(3 weeks 
[±3 days] after 
SV1)
Baseline Visit
(4-7 days after 
SV2)
Day 1
(not a 
visit)
M1, 3, 6, 9, 
12, 15, 18, 21
Month 24/
EOT Visit
Post-EOT 
Visit for 
Subjects 
off IPb
Month 25/
EOS Visitc
Obtain informed consent
X
Review eligibility criteria
X
X
X
Record demographics
X
Record prior ULTs, including 
XOI and dose
X
Assess AEs
X
X
X
Xd
X
X
X
Randomize in IVRS/IWRS
Xe
Complete medical history
X
Record concomitant 
medications
X
X
X
X
X
Administer patient-reported 
outcomes
X
X
(except at 
M1)
X
X
X
Vital signs
X
X
X
X
X
X
X
Physical examination
X
Height and weight (BMI)
X
Weight only
12-lead ECG 
X
Assess gout flaresf
X
X
X
X
X
Measure target tophi
X
M6, 12, 18
X
X
X
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Abbreviations:  AE, adverse event; BMI, body mass index; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; IP, investigational product; 
IVRS, Interactive Voice Response System; IWRS, Interactive Web Response System; M, study month, SV, Screening Visit; ULT, urate-lowering therapy; XOI, 
xanthine oxidase inhibitor.
Note:  A clinical month is considered to be 28 days. All scheduled visits should be referenced to the Baseline Visit. See Section 6 for more information on study 
procedures and assessments. Additional visits will be required if subjects experience changes in renal function as outlined in Section 6.12.
a The visit window during the Double-Blind Treatment Period is ±7-days beginning with the Month 1 Visit.
b Subjects who permanently discontinue IP early but remain on study should complete a Post-End of Treatment Visit approximately 28 days after the End of 
Treatment Visit.
c All subjects should complete an End of Study Visit approximately 28 days after completing the Treatment Period or withdrawing early from the study.
d For subjects who have permanently discontinued IP, at a minimum AE should be assessed and blood drawn for Analyte panel 1.
e Investigator must confirm eligibility prior to randomization.
f Baseline assessment is an assessment of gout flare history and post-Baseline assessment is an assessment of gout flares since the last visit.
g The estimated creatinine clearance (eCrCl) for each Screening Visit and the average of both Screening Visits (the “Screening eCrCl”) will be calculated by the 
Cockcroft-Gault formula using ideal body weight.
h The follicle-stimulating hormone (FSH) test will be done at SV2 only, and only for females with 12 months of spontaneous amenorrhea who are not surgically 
sterile.  The human chorionic gonadotropin (HCG) test will be done at SV2 for all females and again at Month 12 for all females except those who are surgically 
sterile or not of childbearing potential as confirmed by the SV2 FSH.
i Includes assessment of protein by dipstick by the central laboratory.
j After a subject permanently discontinues IP, dispensing and compliance are not required.
k Colchicine will be dispensed at Baseline Visit and Month 3 Visit as applicable.
l Prescription XOI compliance will be assessed from Screening to Baseline. Study-supplied XOI compliance will be assessed from Day 1 through Month 25/End 
of Study.
m Corticosteroids for gout flare prophylaxis may be taken through Month 3.


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APPENDIX B. ACTIONS REQUIRED IN CASES OF INCREASES IN 
LIVER BIOCHEMISTRY AND EVALUATION OF HY’S 
LAW
1.
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets potential 
Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with the Sponsor clinical project representatives, in review 
and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. 
HL criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
adverse events (AE) and serious adverse events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
2.
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥2 × ULN at any point during the study following the 
start of study medication irrespective of an increase in alkaline phosphatase (ALP).
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.
For PHL and HL, the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations 
in transaminases and TBL must occur.


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3.
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in isolation 
or in combination:

ALT ≥3 × ULN.

AST ≥3 × ULN.

TBL ≥2 × ULN.
When a subject meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the Investigator (also sent to the Sponsor 
representative).
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met. Where this is the case, the Investigator will:

Notify the Sponsor representative.

Request a repeat of the test (new blood draw) by the central laboratory.

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result.
When the identification criteria are met from central or local laboratory results, the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results).
4.
Follow-Up
4.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet PHL criteria the Investigator will:

Inform the Sponsor representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria Met
If the subject does meet PHL criteria the Investigator will:

Notify the Sponsor representative who will then inform the central Study Team.
The Study Physician contacts the Investigator to provide guidance, to discuss and agree on an 
approach for the study subjects’ follow-up, and for the continuous review of data. Subsequent to 
this contact the Investigator will:


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
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or Baseline levels, or as long as medically 
indicated.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which tests available in 
the Hy’s law lab kit should be used.

Complete the 3 Liver CRF Modules as information becomes available.

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
5.
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP. The 
Sponsor Study Physician and Global Safety Physician will also be involved in this review,
together with other subject matter experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF.

If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF 
accordingly and follow the Sponsor’s standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to the Sponsor’s standard 
processes.

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply.

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.


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If there is an unavoidable delay of longer than 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review.
6.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’:
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf




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APPENDIX D. SPONSOR SIGNATURES
Protocol Title:
A Phase 4, Randomized, Double-Blind, Multicenter, 
Placebo-Controlled Study to Evaluate the Safety and Efficacy
of Lesinurad 200 mg in Combination With a Xanthine Oxidase 
Inhibitor (XOI), Compared With an XOI Alone, in Subjects 
With Gout and Estimated Creatinine Clearance 30 to 
<60 mL/min Who Have Not Achieved Target Serum Uric Acid 
Levels on an XOI Alone
Study Number:
RDEA594-401
Protocol Version:
3
This clinical study protocol was approved by the following:
The electronic signatures are appended.
Name
Function
Associate Medical Director, Clinical Research
Ironwood Pharmaceuticals, Inc.
Name
Function
Executive Medical Director, Clinical Development
Ardea Biosciences, Inc.


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APPENDIX E. INVESTIGATOR’S SIGNATURE
Protocol Title:
A Phase 4, Randomized, Double-Blind, Multicenter, 
Placebo-Controlled Study to Evaluate the Safety and Efficacy
of Lesinurad 200 mg in Combination With a Xanthine Oxidase 
Inhibitor (XOI), Compared With an XOI Alone, in Subjects 
With Gout and Estimated Creatinine Clearance 30 to 
<60 mL/min Who Have Not Achieved Target Serum Uric Acid 
Levels on an XOI Alone
Study Number:
RDEA594-401
Protocol Version:
3
I have read the protocol described above. I agree to comply with all applicable regulations and 
guidelines and to conduct the study as described in the protocol.
Signed:
Date:
<enter name and credentials>
<enter title>
<enter affiliation>
<enter address>
<enter phone number>






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Protocol Sign-Off Sheet
Protocol RDEA594-401 Amendment 1
A Phase 4, Randomized, Double-Blind, Multicenter, Placebo 
Controlled Study to Evaluate the Safety and Efficacy of Lesinurad 
200 mg in Combination With a Xanthine Oxidase Inhibitor (XOI), 
Compared With an XOI Alone, in Subjects With Gout and 
Estimated Creatinine Clearance 30 to <60 mL/min Who Have Not 
Achieved Target Serum Uric Acid Levels on an XOI Alone
Reviewed and approved by the Sponsor:
The electronic signature is appended.
Name
Function
Ironwood Pharmaceuticals, Inc.
Name
Function
Ardea Biosciences, Inc.


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TABLE OF CONTENTS
PROTOCOL SIGN-OFF SHEET................................................................................................2
1.
RATIONALE FOR AMENDMENT.........................................................................4
2.
SUMMARY OF CHANGES ....................................................................................4
2.1.
Addition of a Site Visit at Month 1 (Day 28 ± 7 Days)..............................................4
2.2.
Inclusion and Exclusion Criteria ...............................................................................5
2.3.
Pregnancy and Fertility Testing ................................................................................6
2.4.
Medical History........................................................................................................6
2.5.
Rescreening of Subjects............................................................................................6
2.6.
Study Medications ....................................................................................................6
2.6.1.
Sourcing and Dispensing of Study Medications ........................................................6
2.6.2.
XOI Use Prior to Randomization ..............................................................................6
2.6.3.
XOI Use After Permanent Discontinuation of IP.......................................................7
2.6.4.
Interruption and Discontinuation of Study Medications.............................................7
2.6.5.
Gout Flare Prophylaxis .............................................................................................7
2.7.
Premature Discontinuation From the Study...............................................................8
2.8.
Analysis Populations ................................................................................................8
2.9.
Definition of Adverse Events....................................................................................8
2.10.
Analyses of Adverse Events......................................................................................8
2.11.
Adverse Events of Special Interest............................................................................8
2.12.
Gout Flare Assessments............................................................................................9
2.13.
Centralized Data Checking Tool...............................................................................9
2.14.
Updated Lesinurad Exposure Information.................................................................9


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Clinical Study Protocol
Protocol RDEA594-401 Amendment 1
A PHASE 4, RANDOMIZED, DOUBLE-BLIND, MULTICENTER, 
PLACEBO CONTROLLED STUDY TO EVALUATE THE
SAFETY AND EFFICACY OF LESINURAD 200 MG IN 
COMBINATION WITH A XANTHINE OXIDASE INHIBITOR 
(XOI), COMPARED WITH AN XOI ALONE, IN SUBJECTS 
WITH GOUT AND ESTIMATED CREATININE CLEARANCE 30 
TO <60 ML/MIN WHO HAVE NOT ACHIEVED TARGET 
SERUM URIC ACID LEVELS ON AN XOI ALONE
1.
RATIONALE FOR AMENDMENT
The primary purpose of this amendment is to address regulatory feedback and to add a Month 1 
study visit.  Per the original protocol, the first on-treatment visit was scheduled for Month 3.
In addition, minor revisions to improve clarity or provide additional detail have been made to
language describing study entry criteria; pregnancy and fertility testing; sourcing, dispensing, 
and dosing of study medications; premature discontinuation from the study; analysis populations; 
definition of adverse events (AEs); AEs of special interest; gout flare assessments; and current 
cumulative lesinurad exposure data.
Finally, minor editorial changes have been made to improve readability; these changes will not 
be discussed in this document.
2.
SUMMARY OF CHANGES
2.1.
Addition of a Site Visit at Month 1 (Day 28 ± 7 Days)
The Month 1 visit will include all of the same assessments and procedures as the Month 3 visit, 
except for patient-report outcomes (PROs) and dispensing of study medication. In addition to 
data collection, it will be an earlier opportunity for subject education regarding the importance of 
study medication compliance, particularly taking investigational product (IP; lesinurad or 
placebo) in combination with their xanthine oxidase inhibitor (XOI).
This additional visit is reflected in the following sections of the protocol:

Synopsis (Methodology section)


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
Section 3.1. Overall Study Design and Plan

Section 8.3.2. Month 1 (Day 28 ±7 days) and Months 3 Through 21 (Visits Every 
3 Months ±7 days)

Appendix A Schedule of Events.
2.2.
Inclusion and Exclusion Criteria
The language regarding ineligibility of women who are pregnant or breastfeeding has been 
strengthened (appearing now under both Inclusion Criteria and Exclusion Criteria), an exclusion 
criterion for subjects with a history of glomerulonephritis has been added, and the exclusion 
criterion regarding concomitant use of CYP3A inhibitors has been revised to specify that it 
applies to subjects who will be taking colchicine for gout flare prophylaxis.
These changes are reflected in the following sections of the protocol:

Synopsis (Eligibility Criteria section)

Section 4. Study Population Selection
In addition, in order to emphasize the distinction between the key eligibility criteria in the 
Synopsis and the full list of criteria presented in Section 4, the following changes have been 
made in the Synopsis:

“(not a complete list)” has been added to the Eligibility Criteria heading.

The criteria are bulleted rather than numbered.

The list of Key Exclusion Criteria has been shortened by removing the following 
criteria:
6.
Subject is taking valpromide, progabide, valproic acid, or other known 
inhibitors of epoxide hydrolase, or subject is taking azathioprine or 
mercaptopurine.
7.
Subject is receiving chronic treatment with more than 325 mg of salicylates per 
day.
9.
Subject is taking any other drug approved for use as a urate-lowering 
medication other than allopurinol or febuxostat (eg, pegloticase, probenecid, 
benzbromarone) within 4 weeks prior to Screening or during Screening.
10. Subject previously participated in a clinical study involving lesinurad 
(RDEA594) or verinurad (RDEA3170) and received active treatment or 
placebo, or has taken commercially-available lesinurad.
Finally, the following have been added under Key Exclusion Criteria in the Synopsis:
Subject has a history of glomerulonephritis.
Subject is pregnant or breastfeeding.


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2.3.
Pregnancy and Fertility Testing
A follicle-stimulating hormone test (FSH) test has been added.  The FSH test will be done at 
Screening Visit 2 (SV2) only, and only for females with 12 months of spontaneous amenorrhea 
who are not surgically sterile.  The human chorionic gonadotropin (HCG) test will be done at 
SV2 for all females and again at Month 12 for all females except those who are surgically sterile 
or not of childbearing potential as confirmed by the SV2 FSH.
Text regarding pregnancy and fertility tests is included in the following sections of the protocol:

6.9.1. Clinical Safety Laboratory Assessment

8.1.2. Screening Visit 2 (3 Weeks After Screening Visit 2 [±3 Days])

Appendix A. Schedule of Events.
2.4.
Medical History
Section 6.2. Medical History was revised to clarify that a complete medical history will not be 
collected until the Baseline Visit; only medical history data needed to determine subject 
eligibility for the study will be collected during Screening.
Text in the following sections was revised accordingly:

8.1.1. Screening Visit 1 (Approximately 28 Days Before Day 1)

Appendix A. Schedule of Events.
2.5.
Rescreening of Subjects
Section 8.1.4. Option for Rescreening was renumbered and renamed Section 8.2 Rescreening of 
Subjects.  Text specifying that a subject being rescreened should receive a new screening number 
was added.
2.6.
Study Medications
2.6.1.
Sourcing and Dispensing of Study Medications
Text has been added to Section 5.2. Other Study Treatments to specify that commercially 
available allopurinol, febuxostat, and colchicine drug product will be used, and that the relevant 
product labeling will be provided to Investigators.
Section 5.8.1. Site Receipt was revised to clarify that it is specific to IP.
Section 5.8.4. Compliance and Accountability was revised to specify that except at the Month 1 
Visit, IP will not be redispensed.
2.6.2.
XOI Use Prior to Randomization
Text in the following sections has been revised to consistently specify that subjects should be on 
a stable, medically appropriate dose of XOI for at least 4 weeks prior to Screening and 
throughout the Screening Period:

Synopsis (Methodology section)


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
Synopsis (Eligibility Criteria section)

1.3. Rationale for Study Design and Dose Selection

3.1. Overall Study Design and Plan.
2.6.3.
XOI Use After Permanent Discontinuation of IP
Text in the following sections of the protocol was amended to reflect that subjects who 
discontinued IP have the option to continue on study-supplied XOI until their End of Study Visit:

Section 3.1. Overall Study Design and Plan

Section 5.3.2.1.2. Other Reasons, and Procedures, for Permanent Discontinuation of 
Investigational Product.

Section 8.4. Follow-Up Period.

Appendix A. Schedule of Events.
2.6.4.
Interruption and Discontinuation of Study Medications
Section 5.3 Selection and Timing of Dose for Each Subject was reorganized as follows to clarify 
in which subsection the Investigator can find instructions on each topic:
5.3.1. General Instructions for Dosing
5.3.2. Dose Adjustments, Interruptions, and Discontinuations
5.3.2.1. Investigational Product and Xanthine Oxidase Inhibitors
5.3.2.1.1. Interruption or Discontinuation of Investigational Product due to 
Changes in Kidney Function
5.3.2.1.2. Other Reasons, and Procedures, for Permanent Discontinuation of 
Investigational Product
5.3.2.2. Gout Flare Prophylaxis
5.3.2.2.1.Colchicine
5.3.2.2.2.Low-Dose Corticosteroids
In addition, text was added to Section 5.3.2.1.2. to stress the importance of subject retention in 
the study after discontinuation of IP.
2.6.5.
Gout Flare Prophylaxis
The protocol now more clearly states that gout flare prophylaxis is required, and the rationale for 
this requirement has been added to the Synopsis.
The following sections of the protocol are affected:

Synopsis (Methodology section)

1.3. Rationale for Study Design and Dose Selection

3.1. Overall Study Design and Plan


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
Colchicine.
2.7.
Premature Discontinuation From the Study
Section 6.16. Early Study Withdrawal has been renamed “Premature Discontinuation from the 
Study” to clarify that the text covers all reasons for subject failure to complete the study, whether 
subject-initiated or not.  “Investigator decision” has been added as a potential reason for 
premature discontinuation.  In addition, language encouraging Investigators to maximize subject 
retention and minimize missing data has been added.
2.8.
Analysis Populations
The following text has been added to Section 9.3. Analysis Populations:  “The Per-Protocol 
Population will be defined as all subjects in the Intent-to-Treat (ITT) population without major
protocol deviations, defined prior to unblinding of the study. Select analyses (to be specified in 
the Statistical Analysis Plan [SAP]), will be repeated on the PP population.”
2.9.
Definition of Adverse Events
The language in Section 6.11.1. Adverse Event Definition was revised to remove redundant text, 
clarify that any clinically relevant deterioration in clinical laboratory values or vital signs should 
be reported as an AE, and to specify that protocol-mandated permanent discontinuation of IP per 
the sCr/eCrCl criteria described should be reported as an AE.
2.10.
Analyses of Adverse Events
To improve clarity, the amended protocol specifies that the incidences of treatment-emergent 
adverse events (TEAEs), TEAEs leading to permanent discontinuation of IP, and serious TEAEs 
(SAEs) will be summarized by treatment group.
The revised text is in the following sections of the protocol:

Synopsis (Statistical Methods section)

Section 9.4.2.2. Renal-Related Outcomes.
2.11.
Adverse Events of Special Interest
Text regarding the proposed assessments of renal and cardiovascular (CV) safety has been 
amended to more clearly describe the planned assessments and the roles of the adjudication 
committees.
An independent Renal Events Adjudication Committee (REAC) will routinely evaluate all 
serious prospectively-defined renal-related and kidney stone AEs, which will be defined in the 
REAC Charter. In addition, the REAC chair will review all other SAEs in the clinical database 
and determine whether any additional SAEs should be adjudicated by the REAC. The REAC, 
blinded to treatment group and serum uric acid (sUA) levels, will assess the likelihood that 
potential contributing factors, including IP, contributed to the event.
An independent Cardiovascular Endpoints Adjudication Committee (CEAC) will routinely 
adjudicate all SAEs and other prospectively-defined AEs for CV-related events in a blinded 


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fashion using MACE and non-MACE CV criteria. The CEAC will also operate under a written, 
detailed CEAC Charter.  The incidences of MACE (CV death, nonfatal myocardial infarction, 
and nonfatal stroke), MACE+ (MACE or hospitalization for unstable angina), and the individual 
components of MACE+ will be reported by treatment.
The AEs of special interest are defined as renal events (eg, renal-related AEs and kidney stone 
AEs) that are serious or lead to permanent discontinuation of IP, and all potential CV events.
The amended text regarding AEs of special interest can be found in the following sections of the 
protocol:

Synopsis (Methodology section)

Synopsis (Safety Endpoints section)

Section 3.1. Overall Study Design and Plan

Section 3.2.1. Safety Endpoints

Section 6.11.1.1. Adverse Events of Special Interest

Section 9.4.2.2. Renal-Related Outcomes

Section 9.4.2.3. Cardiovascular Outcomes

11.8.2. Renal Events Adjudication Committee

11.8.3. Cardiovascular Endpoints Adjudication Committee.
2.12.
Gout Flare Assessments
Subject-reported gout flare severity (mild/moderate/severe) will be assessed, in addition to start 
and stop dates, and any treatment for the flare.  Investigators are directed to the concomitant 
medications case report form (CRF) to record medications used for gout flare treatment.
This is reflected in the following sections of the protocol:

Section 6.10.4. Gout Flares

Section 11.6.3. Source Data and Source Documents.
2.13.
Centralized Data Checking Tool
A new section was added:  Section 11.7.3. Centralized Data Check System.
2.14.
Updated Lesinurad Exposure Information
Updated, cumulative lesinurad exposure data is now provided in Section 1.2.1. Known and 
Potential Benefits and Risks With Lesinurad in Combination With Xanthine Oxidase Inhibitors.




CLINICAL STUDY PROTOCOL:  RDEA594-401
AMENDMENT 2
Protocol Title:
A Phase 4, Randomized, Double-Blind, Multicenter, 
Placebo-Controlled Study to Evaluate the Safety and Efficacy of 
Lesinurad 200 mg in Combination With a Xanthine Oxidase 
Inhibitor (XOI), Compared With an XOI Alone, in Subjects With 
Gout and Estimated Creatinine Clearance 30 to <60 mL/min Who 
Have Not Achieved Target Serum Uric Acid Levels on an XOI 
Alone
Brief Title:
Lesinurad in Subjects With Gout and Moderate Renal Impairment
Study Number:
RDEA594-401
Phase:
4
Investigational Product:
Lesinurad
Population/Indication:
Gout with estimated creatinine clearance 30 to <60 mL/min
Sponsor:
Ironwood Pharmaceuticals, Inc.
Sponsor Medical 
Monitor:
Amendment Number:
Amendment Date:
2
21 June 2017
Confidentiality Statement
This document contains confidential information, which should not be copied, referred to, 
released or published without prior written approval from Ironwood Pharmaceuticals, Inc.


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
2
Protocol Sign-Off Sheet
Protocol RDEA594-401 Amendment 2
A Phase 4, Randomized, Double-Blind, Multicenter, Placebo 
Controlled Study to Evaluate the Safety and Efficacy of Lesinurad 
200 mg in Combination With a Xanthine Oxidase Inhibitor (XOI), 
Compared With an XOI Alone, in Subjects With Gout and 
Estimated Creatinine Clearance 30 to <60 mL/min Who Have Not 
Achieved Target Serum Uric Acid Levels on an XOI Alone
Reviewed and approved by the Sponsor:
The electronic signature is appended.
Name
Function
Ironwood Pharmaceuticals, Inc.
Name
Function
Ardea Biosciences, Inc.


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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Investigator Protocol Agreement
Protocol RDEA594-401 Amendment 2
I have read the protocol described above.  I agree to the following:

To assume responsibility for the proper conduct of this clinical study at this site and 
to conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by the Sponsor.

That I am aware of, and will comply with, the internationally recognized code of 
Good Clinical Practices (GCP) and all other applicable regulatory requirements to 
obtain written and dated approval from the Ethics Committee (eg, Institutional or 
Central Review Board [IRB] or Independent Ethics Committee [IEC]) for the study 
protocol, written informed consent, consent-form updates, subject-recruitment 
procedures (eg advertisements), and any other written information to be provided to 
the subjects before initiating this clinical study.

Not to implement any changes to, or deviations from the protocol without prior 
agreement from the Sponsor and review and documented approval from the EC, 
except to eliminate an immediate hazard to the study subjects, or when change(s) 
involves only logistical or administrative aspect of the clinical study.

To permit direct monitoring and auditing by the Sponsor or Sponsor’s representatives 
and inspection by the appropriate regulatory authority(ies).

That I am thoroughly familiar with the appropriate use of the investigational 
product(s) and other study medication(s) (if applicable), as described in this protocol, 
and any other information provided by the Sponsor or designee, including, but not 
limited to, the current Investigator’s Brochure or equivalent document and marketed 
prescription information (if applicable).

To provide sufficient time and adequate numbers of qualified staff and facilities for 
the foreseen duration of the clinical study to conduct the study properly, ethically and 
safely.

To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and 
functions.
Signed:
Date:
Printed Name:
enter name and credentials


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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TABLE OF CONTENTS
PROTOCOL SIGN-OFF SHEET................................................................................................2
INVESTIGATOR PROTOCOL AGREEMENT .........................................................................3
1.
RATIONALE FOR AMENDMENT.........................................................................5
2.
SUMMARY OF CHANGES ....................................................................................5
2.1.
Protocol Synopsis, Methodology Section..................................................................6
2.2.
Section 3.1  Overall Study Design and Plan ..............................................................6
2.3.
Section 5.3.2.1.2.  Other Reasons, and Procedures, for Permanent 
Discontinuation of Investigational Product................................................................7
2.4.
Section 5.8  Study-Supplied Medications Receipt, Storage, Accountability, 
and Returns...............................................................................................................8
2.5.
Section 5.8.6  Destruction of XOI/Colchicine ...........................................................8
2.6.
Section 6.15.  Overdose ............................................................................................8
2.7.
Section 6.16.  Premature Discontinuation Withdrawal From the Study......................9
2.8.
Section 8  STUDY ACTIVITIES..............................................................................9
2.9.
Section 8.1  Screening Period (Day -3028 to Day 1the Baseline Visit).....................9
2.10.
Section 8.1.1  Screening Visit 1 (Approximately 28 Days Before Day 1the 
Baseline Visit)..........................................................................................................9
2.11.
Section 8.3.  Treatment Period (Day 1 Through Month 24).......................................9
2.12.
Section 8.3.3.  Month 24 (±7 Days) and/or End of Treatment Visit .........................10
2.13.
Section 8.4.  Follow-Up Period...............................................................................10
2.14.
Section 8.4.2  End of Study Visit ............................................................................11
2.15.
Section 11.8.2.  Renal Events Adjudication Committee...........................................11
2.16.
Appendix A.  Schedule of Events............................................................................12


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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Clinical Study Protocol
Protocol RDEA594-401 Amendment 2
A Phase 4, Randomized, Double-Blind, Multicenter, Placebo 
Controlled Study to Evaluate the Safety and Efficacy of Lesinurad 
200 mg in Combination With a Xanthine Oxidase Inhibitor (XOI), 
Compared With an XOI Alone, in Subjects With Gout and 
Estimated Creatinine Clearance 30 to <60 mL/min Who Have Not 
Achieved Target Serum Uric Acid Levels on an XOI Alone
1.
RATIONALE FOR AMENDMENT
The primary purpose of this amendment is to address a request from the United States Food and 
Drug Administration (FDA) to omit “Investigator decision” and “Sponsor’s decision” from the 
list of possible reasons for early discontinuation from the study (comments from the Division of 
Pulmonary, Allergy, and Rheumatology Drug Products, dated 25 May 2017, on Amendment 1 of 
the protocol).
The FDA also requested revisions to the charter of the Renal Events Adjudication Committee 
(REAC), and protocol language related to the responsibilities of the REAC has been amended to 
reflect those revisions.
In addition, minor editorial changes have been made to improve clarity and consistency with 
respect to the following:

Treatment “discontinuation” and study “withdrawal”

Subjects who prematurely discontinue investigational product (IP)

Referencing study visits to the Baseline Visit, rather than to Day 1

Destruction of unused XOI and colchicine

Recording of overdoses

Dispensing of XOI at the Month 24 Visit

Vital status assessment at the End of Study Visit.
2.
SUMMARY OF CHANGES
Revisions are presented below in order of their appearance in the protocol.  Revisions are 
indicated by bold font, with deleted text as strikethrough and new text underlined.


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
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2.1.
Protocol Synopsis, Methodology Section
. . .
Subjects who complete the Treatment Period or who plan to withdraw from the study early 
should complete an End of Study Visit approximately 1 month after study completion/treatment 
withdrawaldiscontinuation.
Subjects who permanently discontinue IP early for any reason, including inability to continue 
dosing with XOI, should complete an End of Treatment Visit as soon as possible followed by a 
Post-End of Treatment Visit 1 month after the End of Treatment Visit. Subjects should then 
continue on study and follow the protocol-defined schedule of events, including the End of Study 
Visit.
. . .
An independent Renal Events Adjudication Committee (REAC) will routinely evaluate and 
categorize all serious prospectively-defined renal-related and kidney stone AEs, and any 
additional SAEs deemed by the REAC Chair to be relevant for adjudication, to and will assess 
the likelihood that potential contributing factors, including IP, contributed to the event. CEAC 
and REAC assessments will be performed in a blinded fashion.
. . .
2.2.
Section 3.1 Overall Study Design and Plan
. . .
To be eligible for the study, subjects must be on a stable, medically appropriate dose of XOI as 
their sole ULT indicated for the treatment of gout for at least 4 weeks prior to Screening and 
throughout the Screening Period. Investigators should have followed the treatment guidelines to 
determine the medically appropriate dose of XOI. During the Screening Period, subjects will 
complete 2 Screening Visits:  Screening Visit 1 (approximately 1 month before Day 1 the 
Baseline Visit) and Screening Visit 2 (3 weeks after Screening Visit 1 [±3 days]). To be eligible 
for the study, estimated creatinine clearance (eCrCl; calculated by the Cockcroft-Gault formula 
using ideal body weight) must be 25.0 to ≤65.0 mL/min at each Screening Visit and the average 
eCrCl of both Screening Visits must be 30.0 to <60.0 mL/min, which is the Screening eCrCl. 
Additionally, subjects must have an sUA level ≥6.0 mg/dL (387 µmol/L) at both Screening 
Visits.
. . .
Subjects who permanently discontinue IP early should complete an End of Treatment Visit as 
soon as possible, followed by a Post-End of Treatment Visit 1 month after the End of Treatment 
Visit where all AEs must be recorded. Subjects should then continue on study (and may remain
on their study-supplied XOI) and follow the protocol-defined schedule of events, including the 
End of Study Visit.
. . .
An independent Renal Events Adjudication Committee (REAC) will routinely evaluate and 
categorize all serious prospectively-defined renal-related and kidney stone AEs, and any 


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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additional SAEs deemed by the REAC Chair to be relevant for adjudication, to and will assess 
the likelihood that potential contributing factors, including IP, contributed to the event.
. . .
Figure 1:Overview of Study Design Scheme
Abbreviations:  EOS, End of Study; EOT, End of Treatment; qd, once daily; SV, Screening 
Visit; wk, week; XOI, xanthine oxidase inhibitor.
Note:  A clinical month is considered to be 28 days.
a Subjects will enter the study on a stable, medically appropriate dose of XOI (allopurinol or febuxostat) for at least 
4 weeks prior to Screening and throughout the Screening Period and will continue this dose (study-supplied after 
Baseline) throughout the study.
b Gout flare prophylaxis, colchicine, will be taken through the Month 6 study visit as tolerated. If low-dose 
corticosteroids are used as gout flare prophylaxis, the course may be through the Month 3 study visit.
c Subjects will start investigational product (lesinurad/placebo) and study-supplied XOI on Day 1 (1 day after the 
Baseline Visit). Day 1 is not a study visit. Gout flare prophylaxis may be started at the Baseline Visit.
d Subjects who permanently discontinue lesinurad/placebo early should complete an EOT Visit as soon as possible 
followed by a Post-End of Treatment Visit 1 month later. Subjects should then continue to follow the protocol-
defined schedule of events.
e Subjects who complete the study or plan to withdraw from the study early should complete an EOS Visit 
approximately 28 days after study treatment completion or withdrawal discontinuation.
. . .
2.3.
Section 5.3.2.1.2.  Other Reasons, and Procedures, for Permanent 
Discontinuation of Investigational Product
. . .
Subjects who permanently discontinue IP early should complete an End of Treatment Visit 
(Section 8.3.3) as soon as possible followed by a Post-End of Treatment Visit (Section 8.4.1) 
1 month after the End of Treatment Visit. Subjects should then continue on study and 
follow the protocol-defined schedule of events, through Month 24. If the subject 
discontinues IP, the scheduled study visits, data collection, and procedures should continue 
through Month 24. The subject has the option to continue on study-supplied XOI during this 
time. Although all assessments are encouraged, at a minimum, it is requested that collection of 
AEs and collection of a blood sample for Analytes 1 (see Table 1) occur. Alternatively, if the 
subject does not agree to this option, a modified follow-up including, eg, regular telephone 


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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contacts or a contact at study closure Month 24, should be arranged, if agreed to by the subject 
and in compliance with local data privacy laws/practices. Subjects who do not wish to 
continue on study after discontinuing IP should complete an End of Study Visit 
(Section 8.4.2) 1 month after treatment discontinuation.
If IP is permanently discontinued prior to the Month 6 study visit, then gout flare prophylaxis 
should also be discontinued.
Subjects who permanently discontinue IP early should complete an End of Treatment Visit 
(Section 8.3.3) as soon as possible followed by a Post Treatment Visit (Section 8.4.1) 
1 month after the End of Treatment Visit. Subjects should then continue on study and 
follow the protocol defined schedule of events, including the End of Study Visit.
2.4.
Section 5.8  Study-Supplied Medications Receipt, Storage, 
Accountability, and Returns
The Investigator must maintain accurate records of all IP, XOI, and colchicine administered as 
per protocol, including date received, number of units received, and lot number. The Investigator 
must also ensure that all study-supplied medications are kept secured and accounted for with 
access limited to only those individuals authorized by the Investigator. The Investigator, his/her 
designee, or the pharmacist must also maintain adequate records of distribution, and dispensing,
and return of all study-supplied medications, as well as return of IP to the Drug Depot and 
destruction of all other study-supplied medications, to be able to reconcile their records (ie, 
accountability or dispensing logs) periodically throughout the study.
All records must be readily available for inspection by the site monitor and/or auditor. No 
medications may be returned to the Sponsor or designee (IP) or disposed of at the study site 
(XOI and colchicine) until the site monitor has verified the accuracy of the records at the study 
site. All returns, disposals, or destruction must be approved by the Sponsor.
For more complete information for regarding study-supplied medication receipt, storage, 
accountability, and returns (IP), and destruction (XOI and colchicine), refer to the Study 
Reference Manual.
2.5.
Section 5.8.6  Destruction of XOI/Colchicine
After accountability has been verified by the site monitor, returned supplies of XOI and 
colchicine will be destroyed per the study site’s process. The destruction will be 
documented within the source documentation and processed by the site monitor.
2.6.
Section 6.15.  Overdose
An overdose is defined as a daily dose of IP more than 200 mg (>1 tablet).
AEs associated with an overdose should be recorded on the appropriate AE CRF; however, all 
overdoses, including those not associated with an AE, should be recorded on the appropriate
CRFs. An overdose should be reported even if it does not result in an AE.


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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2.7.
Section 6.16.  Premature Discontinuation Withdrawal From the 
Study
. . .
Possible reasons for early discontinuationwithdrawal of subjects from the study include the 
following:

Subject withdraws consent

Death

Lost to follow up

Investigator decision

Sponsor’s decision
. . .
For subjects who discontinuewithdraw early or do not have an End of Study Visit, the site or 
delegate should attempt to collect vital status information (dead or alive). Vital status, based on 
publicly available sources, may also be investigated at the scheduled study end (ie, Month 254)
for subjects who did not complete the study.
The date and the reason must be recorded on the CRF for all subjects who discontinuewithdraw
early from the study. See Section 8.4.1 for End of Study Visit procedures.
2.8.
Section 8  STUDY ACTIVITIES
. . .
During the Double-Blind Treatment Period, all visits will occur at the end of the study month (ie, 
the Month 3 Visit will occur on Day 84 [±7 days]). All scheduled visits should be referenced 
back to Day 1 (first dose of IP)the Baseline Visit.
. . .
2.9.
Section 8.1  Screening Period (Day -3028 to Day 1the Baseline Visit)
2.10.
Section 8.1.1  Screening Visit 1 (Approximately 28 Days Before 
Day 1the Baseline Visit)
2.11.
Section 8.3.  Treatment Period (Day 1 Through Month 24)
Subjects must meet all of the eligibility criteria listed in Section 4.2 and Section 4.3 before being 
randomized and starting IP, study-supplied XOI, and colchicine (as applicable). Subjects will 
receive IP in combination with an XOI for up to 24 months. Subjects who permanently 
discontinue IP early should complete an End of Treatment Visit (Section 8.3.3) as soon as 
possible after discontinuing IP (Section 8.3.3), and a Post-End of Treatment Visit (Section 8.4.1)
1 month after discontinuing IP (Section 8.4.1)the End of Treatment Visit, but should remain 
on the study and follow the protocol-scheduled visits.


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
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2.12.
Section 8.3.3.  Month 24 (±7 Days) and/or End of Treatment Visit
The following procedures and assessments will be performed at Month 24 (for subjects who 
complete the Treatment Period) or as soon as possible after permanently discontinuing IP (for 
subjects who discontinue IP early):

Collect reasons for discontinuing IP, if applicable.

Administer patient-reported outcome assessments.

Review gout flares that occurred since the last study visit.

Take vital signs.

Measure weight.

Assess AEs.

Record concomitant medications.

Assess compliance with IP (lesinurad/placebo).

Assess compliance with XOI.

Measure target tophi.

Collect blood sample for hematology.

Collect blood sample for the following serum chemistry analyses:

Analytes 1.

Analytes 2.

Analytes 3.

Pregnancy test for females of childbearing potential.

Collect blood sample for plasma biomarkers.

Collect urine sample for the following analyses:

Urinalysis.

Protein-creatinine ratio.

Urine biomarkers.

Dispense XOI.
2.13.
Section 8.4.  Follow-Up Period
All subjects who complete the Treatment Period will return to the site for an End of Study Visit 
1 month later (Section 8.4.2).
Subjects who permanently discontinue IP early should return to the site for an End of Treatment 
visit (Section 8.3.3) as soon as possible after discontinuing IP, then a Post-End of Treatment 
(Section 8.4.1) Visit 1 month after discontinuing IP the End of Treatment Visit
(Section 8.3.1) , and then. They should remain on study and follow the protocol schedule (with 


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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the exception of dispensing and taking IP) and have an End of Study Visit (Section 8.4.2) at the 
conclusion of their study period. Alternatively, if the subject does not agree to this option, a 
modified follow-up including, eg, regular telephone contacts or a contact at Month 24, 
should be arranged, if agreed to by the subject and in compliance with local data privacy 
laws/practices. Subjects who do not wish to continue on study after discontinuing IP should 
complete an End of Study Visit 1 month after treatment withdrawal discontinuation
(Section 8.4.1), which can should be performed in place of the Post-End of Treatment Visit.
2.14.
Section 8.4.2  End of Study Visit
All subjects should complete an End of Study Visit. This visit should occur approximately 
28 days after completing the Treatment Period or after permanent treatment 
withdrawaldiscontinuation if the subject is no longer continuing in the study. Subjects should 
return all study supplies to the site. The following procedures and assessments will be 
performed:

Collect reasons for early study discontinuationwithdrawal if applicable.
. . .
2.15.
Section 11.8.2.  Renal Events Adjudication Committee
An independent REAC will routinely evaluate and categorize all serious prospectively-defined 
renal-related and kidney stone AEs. In addition, the REAC chair will review all other SAEs in 
the clinical database and determine whether any additional SAEs should be adjudicated by the 
REAC. The REAC, in a blinded fashion, will assess the likelihood that potential contributing 
factors, including IP, contributed to the event. The committee will operate under a written, 
detailed REAC Charter. See the REAC Charter for details.


Lesinurad in Subjects With Gout and Moderate Renal Impairment
Ironwood Pharmaceuticals
Protocol:  RDEA594-401
Amendment 2
Confidential
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2.16.
Appendix A.  Schedule of Events
Assessment/Procedure
Screening Period
Double-Blind Treatment Perioda
Follow-Up Period
SV1
SV2
(3 weeks 
[±3 days] after 
SV1)
Baseline Visit 
(4-7 days after 
SV2)
Day 1
(not a 
visit)
M1, 3, 6, 9, 
12, 15, 18, 21
Month 24/
EOT Visit
Post-EOT 
Visit for 
Subjects 
off IPb
Month 25/
EOS Visitc
Obtain informed consent
X
Review eligibility criteria 
X
X
X
Record demographics
X
Record prior ULTs, including 
XOI and dose
X
Assess AEs
X
X
X
Xd
X
X
X
Randomize in IVRS/IWRS
Xe
Complete medical history
X
Record concomitant 
medications
X
X
X
X
X
Administer patient-reported 
outcomes
X
X
(except at 
M1)
X
X
X
Vital signs
X
X
X
X
X
X
X
Physical examination
X
Height and weight (BMI)
X
Weight only
12-lead ECG 
X
Assess gout flaresf
X
X
X
X
X
Measure target tophi
X
M6, 12, 18
X
X
X
Laboratory Assessments
Hematology blood collection
X
M6, 12, 18
X
X
X




Lesinurad in Subjects With Gout and Moderate Renal Impairment
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Protocol:  RDEA594-401
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Note:  A clinical month is considered to be 28 days. All scheduled visits should be referenced to Day 1the Baseline Visit. See Section 6 for more information on 
study procedures and assessments. Additional visits will be required if subjects experience changes in renal function as outlined in Section 6.12.
a The visit window during the Double-Blind Treatment Period is ±7-days beginning with the Month 1 Visit.
b Subjects who permanently discontinue IP early but remain on study should complete a Post-End of Treatment Visit approximately 28 days after the End of 
Treatment Visit.
c All subjects should complete an End of Study Visit approximately 28 days after completing the Treatment Period or withdrawing early from the study.
d For subjects who have permanently discontinued IP, at a minimum AE should be assessed and blood drawn for Analyte panel 1.
e Investigator must confirm eligibility prior to randomization.
f Baseline assessment is an assessment of gout flare history and post-Baseline assessment is an assessment of gout flares since the last visit.
g The estimated creatinine clearance (eCrCl) for each Screening Visit and the average of both Screening Visits (the “Screening eCrCl”) will be calculated by the 
Cockcroft-Gault formula using ideal body weight.
h The follicle-stimulating hormone test (FSH) test will be done at SV2 only, and only for females with 12 months of spontaneous amenorrhea who are not 
surgically sterile.  The human chorionic gonadotropin (HCG) test will be done at SV2 for all females and again at Month 12 for all females except those who are 
surgically sterile or not of childbearing potential as confirmed by the SV2 FSH.
i Includes assessment of protein by dipstick by the central laboratory.
j After a subject permanently discontinues IP, dispensing and compliance are not required.
k Colchicine will be dispensed at Baseline Visit and Month 3 Visit as applicable.
l Prescription XOI compliance will be assessed from Screening to Baseline. Study-supplied XOI compliance will be assessed from Day 1 through 
Month 245/End of Study.
m Corticosteroids for gout flare prophylaxis may be taken through Month 3.