A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving KRYSTEXXA® (Pegloticase) (MIRROR Randomized Controlled Trial [RCT])
Phase: PHASE4
Conditions: Gout
Sponsor: Amgen

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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CLINICAL STUDY PROTOCOL  
FOR KRYSTEXXA 
IND: 010122 
Protocol Number: HZNP-KRY-202 
Version 3.0, Amendment 2, Administrative Change 1 
 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy and 
Safety Study of Methotrexate to Increase Response Rates in Patients with 
Uncontrolled GOut Receiving KRYSTEXXA® (pegloticase) (MIRROR 
Randomized Controlled Trial [RCT]) 
Short Title: MIRROR RCT 
 
Date: 24 August 2021 
 
Sponsor: 
 
Horizon Therapeutics Ireland DAC 
1 Burlington Road 
Connaught House, 1st Floor 
Dublin Ireland D04 C5Y6 
 
 
 
 
This protocol is the confidential information of Horizon Therapeutics Ireland DAC and is intended solely for the guidance of the clinical 
investigation. This protocol may not be disclosed to parties not associated with the clinical investigation or used for any purpose without the 
prior written consent of Horizon Therapeutics Ireland DAC. 
CONFIDENTIAL 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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PROTOCOL 
1 
TITLE PAGE 
Study Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Efficacy and Safety Study of Methotrexate to Increase Response 
Rates in Patients with Uncontrolled GOut Receiving KRYSTEXXA® 
(pegloticase) (MIRROR Randomized Controlled Trial [RCT]) 
Protocol Number: HZNP-KRY-202 
Version: 3.0, Amendment 2, Administrative Change 1  
Investigational 
Products: 
KRYSTEXXA (recombinant modified mammalian urate oxidase 
[uricase]); methotrexate (MTX) 
Indication: Chronic gout in adult patients refractory to conventional therapy 
Sponsor: Horizon Therapeutics Ireland DAC 
1 Burlington Road 
Connaught House, 1st Floor 
Dublin Ireland D04 C5Y6 
Development Phase: 4 
Sponsor’s Responsible 
Medical Officer: 
   
 
Horizon Therapeutics USA, Inc. 
1 Horizon Way 
Deerfield, IL  60015 
Sponsor Signatory: 
 
 
Horizon Therapeutics USA, Inc. 
1 Horizon Way  
Deerfield, IL  60015 
Approval Date: 24 August 2021   
 
CONTACT IN THE EVENT OF AN EMERGENCY 
Any death, life-threatening event, or other serious adverse event experienced by a subject 
during the course of the study, whether or not judged drug-related, must be reported within 
24 hours of knowledge of the event by entering the information into the electronic case 
report form (eCRF). If unable to access the eCRF, the event must be reported by submitting 
the completed Serious Adverse Event Form via email or fax to the contact numbers provided 
below. 
Fax: 
 
Email: 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number:  
HZNP-KRY-202  
Version: 
3.0, Amendment 2, Administrative Change 1 
Protocol Title:  
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy 
and Safety Study of Methotrexate to Increase Response Rates in Patients 
with Uncontrolled GOut Receiving KRYSTEXXA® (pegloticase) 
(MIRROR Randomized Controlled Trial [RCT]) 
Version Date: 
24 August 2021 
I agree to conduct the study according to the protocol named above. I fully understand that any 
changes instituted by the Principal Investigator without previous discussion with the Sponsor 
constitute a violation of the protocol, unless necessary to eliminate an immediate hazard to the 
safety or well-being of a subject. 
I acknowledge that I have read and understand the protocol named above and agree to carry out 
all of its terms in accordance with applicable regulations and laws. 
I assure that the study drug supplied by the Sponsor will be used only as described in the 
protocol named above. 
Signature: 
 
 
 
 
 
 
 Name  
Study Center 
Address 
City State Country 
 
Date 
 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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Page 5 of 145 
 
SUMMARY TABLE OF CHANGES 
 
Protocol Version 1.0, Original (17 April 2019) to 
Protocol Version 2.0, Amendment 1 (20 April 2020) to 
Protocol Version 3.0, Amendment 2 (17 March 2021) 
Protocol Version 3.0, Amendment 2, Administrative Change 1 (24 August 2021) 
 
The Administrative Change includes an update to the Sponsor Signatory.  Administrative and 
typographical updates have also been made. Track changes version of the Protocol Version 
3.0, Amendment 2, Administrative Change 1 can be provided on request. 
 
Text 
Protocol Version 3.0, Amendment 2 
17 March 2021 
Amended Text 
Protocol Version 3.0, Amendment 2, 
Administrative Change 1 
24 August 2021 
Reason for Change 
Title Page 
Sponsor Signatory:  
Paul M. Peloso, MD 
Vice President and Therapeutic Area Head, 
Rheumatology 
Horizon Therapeutics USA, Inc. 
1 Horizon Way  
Deerfield, IL  60015 
Title Page 
Sponsor Signatory:  
Stephen Sainati, MD, PhD   
Senior Medical Director 
Horizon Therapeutics USA, Inc. 
1 Horizon Way 
Deerfield, IL  60015 
An update to the 
Sponsor Signatory was 
made due to staffing 
changes  
Table 6.1:  Central safety laboratory and 
Monitoring 
Covance Central Laboratory Services 
8211 SciCor Drive 
Indianapolis, IN 46214 
Table 6.1:  
LabCorp Central Laboratory Services 
8211 SciCor Drive 
Indianapolis, IN 46214 
Covance updated the 
company name to 
LabCorp 
Removal of Subjects from Study: 
Section 9.3.3.2:   
Paragraph not previously included 
 
Removal of Subjects from Study: 
Section 9.3.3.2:   
Added additional sub-bullet points below 
Lost to Follow up Subjects to include ASG 
Investigations. 
ASG (an external vendor that focuses on 
locating Lost to Follow-up subjects) will 
conduct a search of subjects whose status was 
determined “Lost to Follow-up” during the 
trial.  This search for subjects whose status is 
“Lost to Follow-up” will be conducted 
throughout the study.  See Section 9.5.4.1.2 for 
adverse event reporting if subject’s status 
results in “Death.” 
 
For subjects whose status is 
determined to be deceased, their 
status previously considered to have 
been “Lost to Follow-up” may have 
Updated to add ASG 
Investigations, a vendor 
specializing in locating 
lost to follow up 
subjects to determine 
the alive or death status 
of Lost to Follow up 
subjects 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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the reason for discontinuation 
updated to “Death” if the Investigator 
deems appropriate.  This will be 
considered on a case by case basis. 
 
For subjects whose status is 
determined to be alive:  Subjects 
categorization will remain “Lost to 
Follow-up”.  
Documentation of Adverse Events: 
Section 9.5.4.1.2.:   
Sentence not previously included 
 
Documentation of Adverse Events: 
Section 9.5.4.1.2.:   
ASG will conduct a search of Lost to Follow up 
subjects.  If a subject is confirmed deceased, 
the SAE will be collected if the death occurred 
within 6 months post treatment.   
Updated to specify the 
timeframe for collection 
of the SAE of 6 months 
post treatment if the 
ASG search result is 
Death. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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2 
SYNOPSIS 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy and Safety Study of 
Methotrexate to Increase Response Rates in Patients with Uncontrolled GOut Receiving KRYSTEXXA® 
(pegloticase) (MIRROR Randomized Controlled Trial [RCT]) 
Protocol Number: HZNP-KRY-202 
Phase: 4 
Protocol Version: 3.0, Amendment 2, Administrative Change 1 
 
Test Drugs: pegloticase; methotrexate (MTX), placebo for MTX 
Indication: Chronic gout in adult patients 
refractory to conventional therapy 
Number and Country of Study Sites: Approximately 65 study centers in the United States  
Objectives:  
The overall objective of this study is to assess the potential for pegloticase with MTX to increase the response 
rate seen with pegloticase alone, and to characterize the safety, tolerability and pharmacokinetics (PK) of the 
concomitant use of pegloticase with MTX, by comparing pegloticase co-administered with MTX to pegloticase 
co-administered with placebo for MTX in adults with uncontrolled gout.   
Primary Objective 
The primary objective is to evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on 
the response rate during Month 6 (Weeks 20, 21, 22, 23 and 24), as measured by the sustained normalization of 
serum uric acid (sUA) to <6 mg/dL for at least 80% of the time during Month 6. 
Secondary Objectives (analyzed sequentially) 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the response rate 
during Month 12 (Weeks 48, 50, and 52), as measured by the sustained normalization of sUA to 
<6 mg/dL for at least 80% of the time during Month 12. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the complete 
resolution of ≥ 1 tophi (using digital photography) at Week 52 in subjects with tophi at baseline. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase and placebo for MTX on the mean change 
from baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) Score at Week 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in Health Assessment Questionnaire (HAQ) Pain Score at Week 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in HAQ Health Score at Week 52. 
Exploratory Objectives  
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in urate deposition volume and bone erosions due to gout to Weeks 14, 24, and 52 based 
on dual-energy computed tomography (DECT). 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in bone erosions due to gout to Weeks 24 and 52 based on X-rays of the hands and feet.   
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the complete 
resolution of ≥ 1 tophi (using digital photography) at Weeks 24 and 36 in subjects with tophi at baseline.  
 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in tophus size (long axis measured using digital photography) to Weeks 14, 24, 36 and 52 
in subjects with tophus present at baseline. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the response rate 
during Month 9 (Weeks 32, 34, and 36), as measured by the sustained normalization of sUA to 
<6 mg/dL for at least 80% of the time during Month 9. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the response rate 
during Month 3 (Weeks 10, 12 and 14), as measured by the sustained normalization of sUA to 
<6 mg/dL for at least 80% of the time during Month 3. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the overall 
response rate, as measured by the sustained normalization of sUA to <6 mg/dL for at least 80% of the 
time during Month 3 (Weeks 10, 12, and 14) and Month 6 (Weeks 20, 21, 22, 23, and 24) combined. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on reducing sUA to 
< 5 mg/dL for at least 80% of the time during Months 3, 6, 9 and 12, individually.    
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in sUA at Weeks 14, 24, 36 and 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the time to first 
sUA > 6 mg/dL. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the time to two 
consecutive sUA > 6 mg/dL (sUA stopping rule). 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the percentage of 
non-hyperuricemic (sUA < 6 mg/dL) time during Months 3, 6, 9 and 12. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in HAQ Pain Score at Weeks 14, 24, and 36. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in HAQ Health Score at Weeks 14, 24, and 36. 
 
Evaluate the effect of pegloticase and MTX vs. pegloticase and placebo for MTX on the mean change 
from baseline in HAQ-DI Score at Weeks 14, 24, and 36. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in tender joint count (68-point scale) at Weeks 14, 24, 36 and 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in swollen joint count (66-point scale) at Weeks 14, 24, 36 and 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in number of tender or swollen joints at Weeks 14, 24, 36 and 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in physician global assessment of gout at Weeks 14, 24, 36 and 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the proportion of 
subjects achieving 20%, 50%, or 70% improvement based on gout chronic response criteria at Weeks 
14, 24, 36 and 52. 
 
Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the mean change 
from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) to each visit.   
 
Assess the PK of pegloticase. 
 
Assess the MTX polyglutamate concentrations. 
 
Assess the incidence of anti-PEG and anti-Uricase IgG antibodies. 
Safety and Tolerability Objectives 
 
AE/SAE profile overall for pegloticase and the combination of pegloticase and MTX 
o 
Incidence of AESI: IRs, anaphylaxis, gout flares, cardiovascular events 
 
Laboratory tests 
 
Vital signs and physical examination 
Study Design  
This study is a Phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy and 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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safety study of pegloticase with MTX vs. pegloticase with placebo for MTX in adult subjects with uncontrolled 
gout. 
The study design will include: 1) a Screening Period (screening should be completed within 6 weeks prior to 
Week -6); 2) a 2-week MTX Tolerability Assessment Period consisting of 2 weeks oral MTX for all subjects; 3) 
a Run-In Period consisting of randomization followed by 4 weeks of blinded oral MTX or placebo for MTX; 4) a 
52-week Pegloticase + IMM Period; 5) a Safety Follow-up (Phone/Email/Site Visit) and 6) a 3 and 6 month Post 
Treatment Follow-up.  
All subjects who meet eligibility criteria at Screening will begin 15 mg MTX orally weekly at the Week -6 visit. 
Subjects will also take folic acid 1 mg orally every day beginning during the MTX Tolerability Assessment 
Period (Week -6 to Week -4) and continuing until prior to the Week 52 Visit.  
Subjects must be able to tolerate the weekly dose of MTX 15 mg for 2 weeks to be eligible to be randomized at 
Week -4. Subjects who are unable to tolerate the 15 mg dose of MTX during the 2 weeks preceding the Week -4 
visit will be considered screen failures.  
Subjects who tolerate the weekly 15 mg MTX dose during the 2 weeks preceding Week -4 Visit and continue to 
meet eligibility criteria will be randomized at the Week -4 Visit in a 2:1 ratio (stratified by presence of tophi) to 
receive either blinded oral 15 mg MTX or blinded oral placebo for MTX.  Subjects will continue to take the 
blinded MTX or placebo for MTX from Week -4 to Day 1 (the Run-in period) at the 15 mg MTX or placebo for 
MTX dose. If a subject does not tolerate the 15 mg MTX or placebo for MTX dose after randomization at the 
Week -4 Visit and prior to Day 1, the MTX or placebo for MTX may be dose-reduced or discontinued based on 
pre-specified criteria and after discussion with the Sponsor medical monitor. The subject will be allowed to 
remain in the study.  After Day 1, MTX or placebo for MTX may be re-initiated. The subject will be re-initiated 
to the same treatment they were randomized to at Week -4. The re-initiated MTX or placebo for MTX will 
remain blinded.  
All subjects who complete the Run-In Period will receive the first pegloticase infusion on Day 1. All subsequent 
doses and study visits will be scheduled based on the Day 1 visit date.  
It is required that before a subject begins the pegloticase + IMM Period, he or she has been taking at least one 
protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or non-steroidal anti-inflammatory drugs 
and/or low-dose prednisone ≤10 mg/day) for ≥1 week before the first dose of pegloticase and continues flare 
prophylaxis per American College of Rheumatology guidelines [Khanna D et al. 2012] for the greater of 1) 6 
months, 2) 3 months after achieving target serum urate (sUA < 6 mg/dL) for patients with no tophi detected on 
physical exam, or 3) 6 months after achieving target serum urate (sUA < 5 mg/dL) for patients with one or more 
tophi detected on initial physical exam that have since resolved.  For IR prophylaxis, fexofenadine (180 mg 
orally) will be taken the day before each infusion; fexofenadine (180 mg orally) and acetaminophen 
(1000 mg orally) will be taken the morning of each infusion; and methylprednisolone (125 mg IV) given over an 
infusion duration between 10 - 30 minutes, immediately prior to each infusion.  
During the Pegloticase + IMM Period, pegloticase 8 mg will be administered intravenously (IV) every 2 weeks 
from Day 1 through the Week 50 Visit for a total of 26 infusions; pegloticase will be administered after all pre-
dose study visit assessments have been completed at each visit. The date and start and stop time of infusion will 
be recorded. Serum uric acid stopping rules will be applied: subjects with sUA level >6 mg/dL at 2 consecutive 
study visits beginning with the Week 2 Visit will discontinue treatment, complete the End of Pegloticase Infusion 
Visit procedures within 2 weeks, and continue the subject visits according to the protocol (without treatment). 
During the Pegloticase + IMM Period, subjects will be instructed to take MTX or placebo for MTX weekly on 
the same day each week, within 1 to 3 days prior to each pegloticase infusion and one additional weekly dose 
after the last infusion for subjects who have not stopped pegloticase due to sUA stopping rules; however, if a 
subject does not do so, MTX or placebo for MTX must be taken ≥60 minutes prior to each pegloticase infusion.  
After Day 1, if a subject becomes unable to tolerate MTX or placebo for MTX, the MTX or placebo for MTX 
dose may be reduced and/or discontinued based on pre-defined criteria, and the subject may remain in the study.   

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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The Investigator will review the clinical status and individual subject treatment goals at Screening, Week 24, the 
End of Pegloticase Infusions Visit (if applicable) or the Week 52/End of Study/Early Termination Visit.   
After the Week 52 Visit (or End of Pegloticase Infusion Visit [if applicable]), subjects should resume regular 
care for gout per the judgment of the treating physician, including resumption of ULT upon pegloticase 
discontinuation, if appropriate. Subjects will have a 3 and 6 Month Follow-up visit to assess clinical status, 
including sUA levels. 
Samples for measurement of sUA levels, PK analysis of pegloticase, pegloticase immunogenicity and MTX 
Polyglutamate analysis will be collected at visits indicated in the Schedule of Assessments (Section 2.1). 
Safety assessments, including monitoring and recording of all AEs, whether or not drug-related, measurement of 
vital signs, physical examinations, and monitoring of hematology and blood chemistry, will be performed.  
An external Data Monitoring Committee (DMC) will be convened to review data for safety and efficacy with 
timing and criteria outlined in the DMC Charter, with the possibility of DMC recommendation on study conduct 
modification per criteria also to be outlined in the Charter. 
An independent external adjudication committee will review reported events of infusion reactions, cardiovascular 
events and anaphylaxis.  
An overview of the study design is presented in the schematic below, and details of study activities are provided 
in Section 2.1. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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Study Design (continued): 
 
 

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Subject Population: 
Subjects eligible for this study will have sUA ≥7 mg/dL and gout refractory to conventional therapy 
characterized by failure to normalize serum uric acid despite conventional therapy or contraindication to 
conventional therapy, and ongoing symptoms of gout including one of the following: visible tophi, recurrent gout 
flares, or chronic gouty arthropathy. 
Inclusion Criteria: 
Eligible subjects must meet/provide all of the following criteria: 
1. Willing and able to give informed consent. 
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of 
the study. 
3. Adult men or women ≥18 years of age. 
4. Uncontrolled gout, defined as meeting the following criteria: 
 
Hyperuricemia during the screening period defined as sUA ≥7 mg/dL, and; 
 
Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the maximum 
medically appropriate dose, or with a contraindication to xanthine oxidase inhibitor therapy based 
on medical record review or subject interview, and; 
 
Symptoms of gout including at least 1 of the following: 
o 
Presence of at least one tophus 
o 
Recurrent flares defined as 2 or more flares in the past 12 months prior to screening 
o 
Presence of chronic gouty arthritis 
5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -
6 and remain off when receiving pegloticase infusions.  
6. Women of childbearing potential (including those with an onset of menopause <2 years prior to 
screening, non-therapy-induced amenorrhea for <12 months prior to screening, or not surgically sterile 
[absence of ovaries and/or uterus]) must have negative serum/urine pregnancy tests during Screening 
and Week -6; subjects must agree to use 2 reliable forms of contraception during the study, one of 
which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be 
started ≥1 full cycle prior to Week -6 (start of MTX) and continue for 30 days after the last dose of 
pegloticase, or at least one ovulatory cycle after the last dose of MTX or placebo for MTX (whichever is 
the longest duration after the last dose of pegloticase or MTX or placebo for MTX). Highly effective 
contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include 
implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence, or 
vasectomized partner. 
7. Men who are not vasectomized must agree to use appropriate contraception so as to not impregnate a 
female partner of reproductive potential during the study, beginning with the initiation of MTX at Week 
-6 and continuing and for at least 3 months after the last dose of MTX or placebo for MTX.  
8. Able to tolerate MTX 15 mg orally for 2 weeks (Week -6 through Week -4) prior to randomization. 

HORIZON THERAPEUTICS IRELAND DAC 
 
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Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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Exclusion Criteria: 
Subjects will be ineligible for study participation if they meet any of the following criteria: 
1. Weight >160 kg (352 pounds) at Screening. 
2. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 
2 weeks prior to the Week -6 Visit.  
3. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis. 
4. Current or chronic treatment with systemic immunosuppressive agents such as MTX, azathioprine, or 
mycophenolate mofetil; prednisone ≥10 mg/day or equivalent dose of other corticosteroid on a chronic 
basis (3 months or longer) would also meet exclusion criteria. 
5. History of any transplant surgery requiring maintenance immunosuppressive therapy. 
6. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity. 
7. Known history of hepatitis C virus RNA positivity. 
8. Known history of Human Immunodeficiency Virus (HIV) positivity. 
9. Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit). 
10. Chronic renal impairment defined as estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m2 
or currently on dialysis. 
11. Non-compensated congestive heart failure or hospitalization for congestive heart failure within 
3 months of the Screening Visit, uncontrolled arrhythmia, treatment for acute coronary syndrome 
(myocardial infarction or unstable angina), or uncontrolled blood pressure (>160/100 mmHg) prior to 
Randomization at Week -4. 
12. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate female partner, or not on 
an effective form of birth control, as determined by the Investigator. 
13. Prior treatment with pegloticase, another recombinant uricase (rasburicase), or concomitant therapy with 
a polyethylene glycol-conjugated drug. 
14. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or 
porcine product. 
15. Contraindication to MTX treatment or MTX treatment considered inappropriate. 
16. Known intolerance to MTX. 
17. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to MTX 
administration at Week -6 or plans to take an investigational drug during the study. 
18. Liver transaminase levels (AST or ALT) > upper limit of normal (ULN) or albumin < the lower limit of 
normal (LLN) at the Screening Visit.  
19. Chronic liver disease.  
20. White blood cell count < 4,000/ul, hematocrit < 32 percent, or platelet count <75,000/ul. 
21. Currently receiving systemic or radiologic treatment for ongoing cancer. 
22. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of 
cervix. 
23. Diagnosis of osteomyelitis. 
24. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan 
and Kelley-Seegmiller syndrome. 
25. Unsuitable candidate for the study, based on the opinion of the Investigator (e.g., cognitive impairment), 
such that participation might create undue risk to the subject or interfere with the subject’s ability to 
comply with the protocol requirements or complete the study. 
26. Alcohol use in excess of 3 alcoholic beverages per week. 
27. A known intolerance to all protocol standard gout flare prophylaxis regimens (i.e. subject must be able 
to tolerate at least one: colchicine and/or non-steroidal anti-inflammatory drugs and/or low-dose 
prednisone ≤10 mg/day). 

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28. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis.  If deemed necessary by the 
Investigator, a chest X-ray may be performed during Screening. 
Dose Regimen/Route of Administration: 
MTX or placebo for MTX: 
During the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit), all subjects will take MTX 
15 mg orally weekly.  
At the Week -4 visit, subjects who tolerated MTX will be randomized to receive MTX 15 mg or placebo for 
MTX orally weekly. Subjects will be blinded to MTX or placebo for MTX beginning at Week -4 through the 
remainder of the study. Subjects will continue to take the blinded MTX or placebo for MTX during the Run-in 
Period (from Week -4 to Day 1) at the 15 mg MTX dose or placebo for MTX dose. If a subject does not tolerate 
the 15 mg MTX or placebo for MTX dose after randomization at the Week -4 Visit and prior to Day 1, the MTX 
or placebo for MTX may be dose-reduced or discontinued based on pre-specified criteria and after discussion 
with the Sponsor medical monitor. The subject will be allowed to remain in the study. After Day 1, MTX or 
placebo for MTX may be re-initiated. The subject will be re-initiated to the same treatment they were 
randomized to at Week -4. The re-initiated MTX or placebo for MTX will remain blinded. During the Run-in 
Period, if a dose is missed, it should be taken as soon as it is remembered. If it is within 48 hours of the next 
scheduled dose, the subject will be instructed to skip the missed dose and resume at the next regularly scheduled 
time; thus, subjects will be instructed not to double a dose to make up for a missed dose if within 48 hours of the 
next dose.  
During the Pegloticase + IMM Period, subjects will be instructed to take MTX or placebo for MTX weekly on 
the same day each week, within 1 to 3 days prior to each pegloticase infusion and one additional weekly dose 
after the last infusion for subjects who have not stopped pegloticase due to sUA stopping rules; however, if a 
subject does not do so, MTX or placebo for MTX must be taken ≥60 minutes prior to each pegloticase infusion. 
If a subject becomes unable to tolerate the MTX or placebo for MTX during the Pegloticase + IMM Period, the 
dosage may be decreased. 
Subjects will also take folic acid 1 mg orally every day beginning during the MTX Tolerability assessment 
(Week -6 to Week -4) and continuing until prior to the Week 52 Visit.  
Pegloticase: 
All subjects who meet the inclusion/exclusion criteria and complete the Run-In Period will receive pegloticase at 
a dose of 8 mg administered IV every 2 weeks for a total of 26 infusions from Day 1 through the Week 50 Visit, 
inclusive (Pegloticase + IMM Period). The date and start and stop time of infusion will be recorded. Subjects will 
not be fasting on the day of infusion and will be encouraged to have a snack or normal meal before or after the 
infusion. All subjects will receive standardized prophylactic treatment to reduce the risk of acute gout flares, 
beginning ≥1 week before the first dose of pegloticase and continues flare prophylaxis per American College of 
Rheumatology guidelines [Khanna D et al. 2012] for the greater of 1) 6 months, 2) 3 months after achieving 
target serum urate (sUA < 6 mg/dL) for patients with no tophi detected on physical exam, or 3) 6 months after 
achieving target serum urate (sUA < 5 mg/dL) for patients with one or more tophi detected on initial physical 
exam that have since resolved.  Standardized IR prophylaxis consisting of pre-treatment with antihistamines, 
acetaminophen and corticosteroids will accompany each infusion. 
Dosage Form and Strength Formulation (Pegloticase, MTX and placebo for MTX): 
Pegloticase (KRYSTEXXA) is commercially available in the United States and will be packaged in sterile, 
single-use 2-mL glass vials with a Teflon®-coated (latex-free) rubber injection stopper to deliver pegloticase as 8 
mg of uricase protein in 1 mL volume. Pegloticase will be administered as an admixture of 8 mg in 250 mL of 
0.45% or 0.9% Sodium Chloride Injection, United States Pharmacopeia (USP) for IV infusion by gravity feed or 
infusion pump. Pegloticase will not be administered as an IV push or bolus. 
MTX 2.5 mg tablets for oral administration during the MTX Tolerability Assessment Period (Week -6 through 
Week -4) will be provided to subjects as a commercially available generic. 
MTX 2.5 mg tablets for oral administration during the Run-In Period (Week -4 through Day 1) and the 
Pegloticase + IMM Period (Day 1 through Week 52) will be provided to subjects as a methotrexate 2.5 mg tablet 
over-encapsulated in a size zero Swedish Orange capsule.   

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Placebo for methotrexate 2.5 mg for oral administration during the Run-In Period (Week -4 through Day 1) and 
the Pegloticase + IMM Period (Day 1 through Week 52) will be provided as a size zero Swedish Orange capsule 
with Avicel® filling.   
Duration of Treatment and Follow-up: 
Screening: Completed within 6 weeks prior to the Week -6 visit  
MTX Tolerability Assessment Period (Week -6 through Week -4): 2 weeks of oral MTX for all subjects 
Run-in Period (Week -4 through Day 1): Randomization followed by 4 weeks of blinded oral MTX or 
placebo for MTX. 
Pegloticase + IMM Period (Day 1 through Week 52): MTX or placebo for MTX dosed weekly and 50 weeks 
of pegloticase infusion visits every 2 weeks; Non-infusion visits at Weeks 21, 23 and 52. 
 
End of Pegloticase Infusions Visit (if applicable): If the subject discontinues pegloticase treatment prior to 
infusion Week 50, such as due to the sUA stopping rules, the subject will complete this visit within 
approximately 2 weeks of the last infusion.  Subjects will continue study. 
End of Study/Early Termination Visit: Week 52 or earlier if the subject withdraws consent to participate in 
the study.  
   Safety Follow-up Phone/Email Visit or Visit:  
All subjects will receive a safety follow-up phone call/e-mail approximately 30 days after the last dose of 
pegloticase to assess if any SAE’s have occurred.  Subjects who receive at least one dose of MTX or placebo 
for MTX and are females of childbearing potential, will receive a safety follow-up phone call/e-mail 
approximately 30 days after the last dose of MTX or placebo for MTX to verify at least one ovulatory cycle has 
occurred after the last dose of MTX or placebo for MTX.  If the subject has not ovulated, a urine pregnancy 
test will be performed. Subjects who receive at least one dose of MTX and are non-vasectomized males, a 
phone/e-mail inquiry will be conducted 3 months after MTX discontinuation regarding partner pregnancy 
(inquiry can occur during the 3 month Post Treatment Follow-up). 
3 and 6 Month Post Treatment Follow-up: 
All subjects will be followed for a minimum of 6 months following the last infusion, with follow-up after 
Week 52 as warranted.  
Criteria for Evaluation: 
Efficacy will be assessed by sUA levels, tophus resolution, tophus size, tender and swollen joint counts, 
physician global assessment of gout, and DECT and X-ray of hands and feet. 
Quality of life will be assessed using the HAQ. 
The PK of pegloticase will be assessed prior to and after the pegloticase infusion at specified time points.  
Pegloticase immunogenicity will be assessed by the incidence of anti-PEG and anti-uricase IgG antibodies prior 
to the pegloticase infusion at specified time points.  
Safety assessments will include monitoring and recording of all AEs, whether or not drug-related, measurement 
of vital signs, physical examinations, and monitoring of hematology and blood chemistry. 
Stopping Rules: 
Individual Subject Stopping Rule: 
Subjects with an sUA level >6 mg/dL at 2 consecutive study visits beginning with the Week 2 Visit (not 
including post-infusion samples) will subsequently discontinue treatment and remain in the study. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
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Statistical Analyses: 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of Month 6 (Weeks 20, 21, 22, 23 and 24) responders, defined as 
subjects achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 6.  
Secondary Efficacy Endpoints 
The secondary endpoints will be analyzed sequentially:  
 
The proportion of Month 12 (Weeks 48, 50, and 52) responders, defined as subjects achieving and 
maintaining sUA <6 mg/dL for at least 80% of the time during Month 12. 
 
The proportion of subjects with complete resolution of ≥ 1 tophi (using digital photography) at Week 52 
in subjects with tophi at baseline. 
 
The mean change from baseline in HAQ-DI score at Week 52. 
 
The mean change from baseline in HAQ Pain score at Week 52. 
 
The mean change from baseline in HAQ Health score at Week 52. 
Exploratory Efficacy Endpoints 
 
The mean change from baseline to Weeks 14, 24 and 52 in urate volume and bone erosions due to gout 
based on DECT. 
 
The mean change from baseline to Weeks 24 and 52 in bone erosions due to gout based on X-rays of the 
hands and feet. 
 
The proportion of subjects with complete resolution of ≥ 1 tophi (using digital photography) at Weeks 
24 and 36 in subjects with tophi at baseline. 
 
The mean change from baseline in tophus size (long axis measured using digital photography) to Weeks 
14, 24, 36 and 52 in subjects with tophus present at baseline.   
 
The proportion of Month 9 (Weeks 32, 34, and 36) responders, defined as subjects achieving and 
maintaining sUA <6 mg/dL for at least 80% of the time during Month 9. 
 
The proportion of Month 3 (Weeks 10, 12, and 14) responders, defined as subjects achieving and 
maintaining sUA <6 mg/dL for at least 80% of the time during Month 3. 
 
The proportion of overall responders, defined as subjects achieving and maintaining sUA <6 mg/dL for 
at least 80% of the time during Month 3 (Weeks 10, 12, and 14) and Month 6 (Weeks 20, 21, 22, 23 and 
24) combined. 
 
The proportion of 5 mg/dL responders during each time interval (Month 3, Month 6, Month 9 and 
Month 12), defined as subjects achieving and maintaining sUA <5 mg/dL for at least 80% of the time 
during each time interval. 
 
The mean change from baseline in sUA at Weeks 14, 24, 36 and 52. 
 
The time to first sUA > 6 mg/dL. 
 
The time to two consecutive sUA > 6 mg/dL (stopping rule). 
 
The percentage of non-hyperuricemic (sUA < 6 mg/dL) time during Months 3, 6, 9 and 12. 
 
The mean change from baseline in HAQ Pain score at Weeks 14, 24, and 36. 
 
The mean change from baseline in HAQ Health score at Weeks 14, 24, and 36. 
 
The mean change from baseline in HAQ-DI score at Weeks 14, 24, and 36. 
 
The mean change from baseline in tender joint count (68-point scale) at Weeks 14, 24, 36 and 52. 
 
The mean change from baseline in swollen joint count (66-point scale) at Weeks 14, 24, 36 and 52. 
 
The mean change from baseline in number of tender or swollen joints at Weeks 14, 24, 36 and 52. 
 
The mean change from baseline in physician global assessment of gout at Weeks 14, 24, 36 and 52. 

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KRYSTEXXA IND: 010122 
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Protocol: HZNP-KRY-202 
 
 
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 
The proportion of subjects achieving 20%, 50%, or 70% improvement based on gout chronic response 
criteria at Weeks 14, 24, 36 and 52. 
 
The mean change from baseline in SBP and DBP to each visit. 
Pharmacokinetic and Anti-drug Antibody Endpoints 
 
PK of pegloticase. 
 
MTX polyglutamate concentrations. 
 
The incidence of anti-PEG and anti-Uricase IgG antibodies. 
Safety and Tolerability Objectives 
 
AE/SAE profile overall for pegloticase and the combination of pegloticase and MTX 
o 
Incidence of AESI: IRs, anaphylaxis, gout flares, cardiovascular events  
 
Laboratory tests 
 
Vital signs and physical examination 

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Statistical Analysis on Efficacy Parameters 
The primary analysis will be conducted in the Intent-to-Treat (ITT) population, defined as all randomized 
subjects. The primary efficacy endpoint is the proportion of responders during Month 6. A responder is defined 
as a subject for whom the proportion of time that the sUA-time curve is <6 mg/dL during the analysis interval is 
at least 80%. The proportion of time that the sUA level is below 6 mg/dL is defined as the ratio of the time 
during which the sUA level remains below 6 mg/dL (using linear interpolation, if necessary) to the entire time 
interval during Month 6. A subject will be declared a non-responder if the subject had an sUA level >6 mg/dL at 
2 consecutive study visits beginning with the Week 2 Visit prior to or during Month 6.  
The analysis of the primary responder endpoint will assess risk difference (difference in response proportions) in 
a stratified analysis. The analysis will use Cochran-Mantel-Haenszel (CMH) weighting to estimate the common 
risk difference within strata and to estimate the standard error of the common risk difference. Stratification for 
the analysis will use the same factor as was used to stratify randomization, presence of tophi (yes, no). The 
difference in response rates, comparing pegloticase with MTX vs. pegloticase with placebo for MTX, will be 
estimated along with the corresponding 95% confidence interval (CI) and p-value.  
The proportion of Month 9 responders and Month 12 responders will be analyzed similarly. The difference in the 
proportion of subjects with resolution of ≥ 1 tophi (100% decrease in the area of at least 1 tophus) at Week 52 
between pegloticase and placebo will be tested with a chi-square test, and the difference in rates will be estimated 
along with the corresponding 95% CI and p-value. 
HAQ-DI score, HAQ Pain and Health scores, tophus size (longest axis), urate deposition volume and bone 
erosions due to gout (DECT scans of hands, feet, knees and other anatomical areas), bone erosions due to gout 
using X-ray (hands and feet), swollen/tender joint counts, physician global assessment score, and mean sUA will 
be summarized at baseline and each visit with descriptive statistics. Changes from baseline for these parameters 
to each visit and overall will be analyzed with a mixed model repeated measures (MMRM) analysis of 
covariance (ANCOVA) model with terms for baseline score, tophi presence at baseline (except for analysis of 
tophi size), and factors for treatment group, visit, visit by treatment group interaction and visit by baseline score 
interaction. Baseline is defined as the last observation prior to the first dose of MTX, unless otherwise specified. 
The proportion of subjects achieving 20%, 50%, or 70% improvement based on gout chronic response criteria 
will be analyzed with a CMH test.   
Interim Analysis 
There are two planned timepoints at which data will be reviewed by the DMC. The first unblinded, comparative 
analysis will occur after approximately half of the randomized subjects (i.e. ~78 subjects) have completed 24 
weeks of treatment in the Pegloticase + Immunomodulator (IMM) Period or discontinued therapy (or study) prior 
to that time. The second unblinded, comparative analysis will be performed when all randomized subjects have 
completed 24 weeks of treatment or discontinued treatment (or study) prior to Week 24. The main purpose of the 
analysis by the DMC is to review the safety data. However, limited efficacy data, including the primary efficacy 
endpoint, will be provided to the DMC for review to assess the benefit-risk profile. Additionally, some data for 
the secondary endpoints will be included in the second analysis. Even though there is no plan to make an 
inference of the primary or secondary efficacy endpoints, an alpha adjustment of 0.0005 will be made to account 
for these analyses. 
 
The primary analysis of safety, efficacy, and pharmacokinetics is planned after all subjects complete the final 
visit (Week 52) in the Pegloticase + IMM period or terminate early from the study. A follow-up analysis will be 
performed after all subjects complete the post-treatment follow-up period. The follow-up analysis will only 
include descriptive summaries of the post-treatment efficacy and safety data. 
Sample Size Estimate: 
The response rate during Month 6 on pegloticase 8 mg every 2 weeks was 43% for the phase 3 studies. A sample 
size of 135 subjects (90 subjects randomized to receive pegloticase with MTX, 45 subjects randomized to receive 
pegloticase with placebo for MTX) provides 88% power at the 2-sided alpha=0.05 level to detect a difference of 
28% (71% response rate for pegloticase with MTX vs. 43% for pegloticase with placebo for MTX). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
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Protocol: HZNP-KRY-202 
 
 
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4. 
The Investigator or designee will collect a complete gout history and other relevant medical/surgical/substance use history. 
5. 
Medication history will be collected at Screening. History of all prior gout medications will be collected.  History of non-gout medication use in the year prior to Screening 
will be collected.  
6. 
Subjects that do not have a chest X-ray within 2 years prior to Screening will have an X-ray done during Screening, if deemed necessary by the Investigator. 
7. 
A complete physical examination will be performed at the Screening Visit, including assessment of HEENT, heart, lungs, abdomen, skin, extremities, neurological status and 
musculoskeletal including an assessment for the presence of tophi. A targeted physical examination per investigator judgement will be conducted at Week -6, Day 1, and prior 
to administration of pegloticase at Weeks 4, 8, 12, 16, 20, 24, 36 and the non-infusion End of Pegloticase Infusions Visit (if applicable), Week 52/End of Study/Early 
Termination and 3 and 6 month Post Treatment Follow-up Visits; at a minimum this should include heart, lungs, and abdominal exam. Clinically significant findings from the 
targeted physical examinations will be recorded as AEs.  
8. 
Routine vital signs, including blood pressure, respiratory rate, temperature, and heart rate will be measured at Screening, Week -6, Week -4, Day 1 and Weeks 2, 4, 6, 8, 10, 
12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50 and the End of Pegloticase Infusions Visit (if applicable), Week 52/End of Study/Early Termination 
and 3 and 6 month Post Treatment Follow-up Visits. Heart rate and blood pressure measurements should be taken after the subject has been in a sitting position and in a rested 
and calm state with proper positioning including back support, feet flat on the floor, for at least 5 minutes.  Subjects arm should be supported at heart level; and cuff placed on 
the bare arm.  A large cuff should be used as needed to fit the upper arm and a consistent arm is to be used at each study visit.  The Korotkoff phase V will be used to 
determine diastolic blood pressure.  During the Pegloticase + IMM Period study visits, vitals should be taken before the pegloticase infusion and any time after the end of the 
infusion, but prior to subject’s discharge/release from the site.  At sites who participate and from subjects who consent, optional intensive BP collections will be obtained at 
designated timepoints.  Optional intensive blood pressure measurements will be taken prior to the infusion on Day 1 and at Weeks 6, 12, 18, 24, 30, 36, 42, 48 and at the non-
infusion End of Pegloticase Infusions Visit (if applicable) and Week 52/End of Study/Early Termination Visit. At these intensive blood pressure collections, three blood 
pressure measurements should be performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg prior to pegloticase infusion.  If any of the 3 systolic 
blood pressure measurements differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm Hg, repeat sets of 3 sitting blood pressure 
measurements will be obtained until the difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. All values will be recorded in the eCRF. When 
possible, the same staff member should take all BP measurements for a given subject. Weight should be measured in kilograms or pounds without shoes and recorded at the 
Screening Visit and prior to dosing MTX Week -6 Visit; prior to pegloticase infusion on Day 1 and at the Weeks 8, 16, 24, 36 and at the non-infusion End of Pegloticase 
Infusions Visit (if applicable), Week 52/End of Study/Early Termination and Months 3 and 6 Post Treatment Follow-up Visits. Height will be collected at the Screening Visit 
only. 
9. 
Electrocardiogram should be completed during Screening. The Electrocardiogram is read at the site. When possible, a 12-lead ECG will also be performed at the time the 
AESI of infusion reaction, anaphylaxis and cardiovascular event is suspected. 
10. AEs/SAEs will be collected from the signature of the ICF until the 6 month Post Treatment Follow-up Visit.  For each AE, the Investigator will be asked to record if the event 
was possibly an infusion reaction or anaphylaxis and if so, will be prompted to complete additional eCRFs.  Females of childbearing potential will be asked to confirm if 
ovulation has occurred since the last dose of MTX or placebo for MTX.  If the subject had not ovulated a urine pregnancy test will be required.  
11. For sites with DECT capability and subjects who provide consent, an optional DECT will be obtained at Day 1 and Weeks 14, 24 and the End of Pegloticase Infusions Visit 
(if applicable) and Week 52/End of Study/Early Termination and the 6 month Post Treatment Follow-up Visit for subjects that completed 52 weeks of treatment and consent 
to the additional assessment.  The DECT on Day 1 must be completed prior to the infusion and may be completed within the 14 days prior to Day 1.  The DECT at all other 
scheduled timepoints may be completed within +/- 10 days of the scheduled timepoint. Subjects who end pegloticase infusions prior to Week 52 should follow the scheduled 
timepoints but avoid a repeat DECT scan within 6 weeks of a prior scan (detailed guidance is provided with the imaging manual).  
12. Digital photography will be completed at Week -6, Day 1 and Weeks 14, 24, 36, and the End of Pegloticase Infusions Visit (if applicable) and Week 52/End of Study/Early 
Termination and the 3 and 6 month Post Treatment Follow-up Visits. Digital photography of hands and feet will be performed according to the instructions provided in the 
digital photography manual. Other anatomical sites with large tophi may be photographed in addition to the hands and feet at the Investigator’s discretion.     
13.  For sites with X-ray capability and subjects who provide consent, an optional X-ray of the hands and feet will be obtained at Day 1, Week 24 and End of Pegloticase Infusions 
Visit (if applicable) and Week 52/End of Study/Early Termination Visit. Subjects who end pegloticase infusions prior to Week 52 should follow the scheduled timepoints but 
avoid a repeat X-ray within 3 months of a prior X-ray (detailed guidance is provided with the imaging manual). The X-ray on Day 1 must be completed prior to the infusion 
and may be completed within the 14 days prior to Day 1.  The X-ray at all other scheduled timepoints may be completed within +/- 10 days of the scheduled timepoint. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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14. MTX or placebo for MTX will be dispensed and brought back to check compliance. MTX or placebo for MTX should be taken 1 to 3 days prior to each pegloticase infusion; 
however, if a subject does not do so, MTX or placebo for MTX must be taken ≥60 minutes prior to each pegloticase infusion. 
15. It is required that before a subject begins the pegloticase + IMM Period, he or she has been taking at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine 
and/or non-steroidal anti-inflammatory drugs and/or low-dose prednisone <10 mg/day) for ≥1 week before the first dose of pegloticase and continues flare prophylaxis per 
American College of Rheumatology guidelines [Khanna D et al. 2012] for the greater of 1) 6 months, 2) 3 months after achieving target serum urate (sUA < 6 mg/dL) for 
patients with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA < 5 mg/dL) for patients with one or more tophi detected on initial 
physical exam that have since resolved.  
16. For IR prophylaxis, fexofenadine (180 mg orally) will be taken the day before and the morning of just prior to each infusion.  
17. Subjects will take folic acid 1 mg orally every day beginning at Week -6 (the start of MTX) until prior to the End of Pegloticase Infusions Visit (if applicable) or the Week 
52/End of Study/Early Termination. 
18. Infusion reaction prophylaxis includes fexofenadine (180 mg orally) administered the day before each infusion; fexofenadine (180 mg orally) and acetaminophen (1000 mg 
orally) administered on the morning of each infusion; and methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to 
each infusion. 
19. For all subjects, serum samples for PK analysis will be collected after the end of infusion on Day 1 (prior to discharge); prior to the pegloticase infusion and after the end of 
infusion (prior to discharge) at the Weeks 2, 6, 14, 21, 24, 36, End of Pegloticase Visit and Week 52/End of Study/Early Termination visits. NOTE: Week 21 Visit and the 
End of Pegloticase Infusions Visit (if applicable) and Week 52/End of Study/Early Termination Visits are non infusion visits.  
20. Serum samples for measurement of sUA levels will be collected at the Screening Visit, the Week -6 Visit (prior to the first dose of MTX), the Week -4 Visit (Randomization) 
and the Week -2 Visit during the Run-in Period. On Day 1, a pre-infusion and post infusion sUA will be collected to be shipped to the Central laboratory.  For the remainder 
of study visits beginning at Week 2 during the Pegloticase +IMM period; 2 Serum Uric Acid samples will be collected within 48 hours PRIOR to each pegloticase infusion 
until Week 24 visit. After Week 24, if a subject’s previous visit sUA (local or central laboratory) is less than 6 mg/dl; it will be allowable to draw the local pre-infusion sUA 
sample on the same day and similar time as the sample to send to the central laboratory; however, if the prior visit sUA sample was greater than 6 mg/dl (local or central 
laboratory), a local sUA sample will need to be collected and read out prior to the pegloticase infusion to be certain the subject has not met the stopping rule.   One sample 
will be for testing at the site’s local laboratory for sUA levels and the second sample will be sent to the Central Laboratory. A POST infusion sUA blood sample will 
additionally be collected on Day 1, and at the Weeks 2, 6, 10, 12, 14, 20, 22, 24, 32, 34, 36, 48 and 50 for same day shipment to the Central Laboratory.  Additional serum 
samples for sUA levels will be collected at non-infusion Visits at Weeks 21 and 23 and the End of Pegloticase Infusions Visit (if applicable) and the Week 52/End of 
study/Early Termination Visit and 3 and 6 month Follow-up Visits. Subjects with an sUA level >6 mg/dL at 2 consecutive study visits beginning with the Week 2 Visit will 
discontinue pegloticase and complete the End of Pegloticase Infusions Visit (if applicable) or the Week 52/End of study/Early Termination Visit.  See the Laboratory Manual 
for instructions for alternate scenarios. In the event of an AE suspected to be an infusion reaction, a serum sample will be collected at that time or at the subsequent visit for 
evaluation of pegloticase antibodies.  
21. Serum samples for evaluation of anti-PEG and anti-uricase IgG antibodies will be collected prior to the pegloticase infusion on Day 1 and at the Weeks 2, 6, 14, 22, 24, 36; 
and at the non-infusion End of Pegloticase Infusions Visit (if applicable) or the Week 52/End of Study/Early Termination Visit and Month 3 Post Treatment Follow-up Visits. 
22 For subjects who provide consent, optional blood samples for PBMC, RNA isolation and serum will be collected from each consenting subject prior to the first dose of MTX 
on -6 week, prior to the infusion at Day 1 and Weeks, 6, 14, 24, 36 and the End of Pegloticase Infusions Visit (if applicable) and the Week 52/End-of-Study/Early 
Termination. During visits at Weeks 2, 4, 8, 10 and 12, optional samples will only be collected if subjects are experiencing an acute gout flare on the day of visit.  
23. For women of childbearing potential, a serum pregnancy test will be performed at the Screening Visit.  A urine pregnancy test will be performed 30 days after the last MTX or 
placebo for MTX dose if the subject has not ovulated; at the End of Pegloticase Infusions Visit (if applicable), the Week 52/End of study/Early Termination Visit procedures 
and at the 30 day follow up phone/e-mail visit it is determined that the subject has not ovulated since the last dose of MTX or placebo for MTX; a urine pregnancy test will be 
performed at all other indicated visits. 
24.  The Investigator will review the clinical status and individual subject treatment goals at Screening, Week 24, and the End of Pegloticase Infusions Visit (if applicable) or the 
Week 52/End of study/Early Termination Visit. 
25.    Blood and urine samples (for allantoin) will be collected prior to the pegloticase infusion and after the end of the pegloticase infusion prior to discharge from the site on Day 
1 and at Weeks 14, 24 and 36; Additional blood and urine samples for allantoin will be collected at the End of Pegloticase Infusions Visit (if applicable) and the Week 52/End 

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of study/Early Termination.  If subject consent, subject’s allantoin samples will be retained for potential future analyses which may include biomarkers relevant to gout (e.g. 
inflammatory markers) or gout co-morbidities in response to pegloticase or other potential treatments for gout. The samples will be retained no longer than 15 years after 
study completion or as required by applicable law. The samples will be stored in a secured storage space with adequate measures to protect confidentiality. 
26. Subjects who are non-vasectomized males will be asked 3 months after MTX or placebo for MTX discontinuation regarding partner pregnancy.  This will occur at a 
regulatory scheduled visit or by a separate phone/email visit.  
27. Subjects who end treatment due to the stopping rules or other reasons should complete the End of Pegloticase Treatment Visit within 2 weeks of the last infusion.  Subjects 
should remain on study.  See Section 9.3.3.1.1 for details on visits and procedures.     
28.  All subjects will be followed for a minimum of 6 months following treatment following the end of pegloticase infusions.

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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 2 
2 
SYNOPSIS .............................................................................................................................. 7 
2.1 
Schedule of Assessments ............................................................................................... 19 
3 
TABLE OF CONTENTS ...................................................................................................... 30 
4 
LIST OF ABBREVIATIONS ............................................................................................... 36 
5 
ETHICS ................................................................................................................................. 38 
5.1 
Institutional Review Board/Independent Ethics Committee .......................................... 38 
5.2 
Ethical Conduct of the Study ......................................................................................... 38 
5.3 
Subject Information and Consent ................................................................................... 38 
5.4 
Compensation for Health Damage of Subjects/Insurance .............................................. 39 
5.5 
Confidentiality ................................................................................................................ 39 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................ 39 
7 
INTRODUCTION ................................................................................................................ 41 
7.1 
Background .................................................................................................................... 41 
7.1.1 
Gout......................................................................................................................... 41 
7.1.2 
Pegloticase .............................................................................................................. 41 
7.1.2.1 Physiochemical Properties .................................................................................. 42 
7.1.2.2 Safety Pharmacology........................................................................................... 43 
7.1.2.3 Non-clinical Pharmacokinetics ........................................................................... 44 
7.1.2.4 Pharmacokinetics ................................................................................................ 44 
7.1.2.5 Risks of Pegloticase ............................................................................................ 45 
7.1.3 
Methotrexate Overview and Risks .......................................................................... 46 
7.2 
Rationale for this Study .................................................................................................. 46 
7.3 
Rationale for Dose Selection .......................................................................................... 47 
8 
STUDY OBJECTIVES ......................................................................................................... 48 
9 
INVESTIGATIONAL PLAN ............................................................................................... 50 
9.1 
Overall Study Design and Plan ...................................................................................... 50 
9.2 
Discussion of Study Design ........................................................................................... 54 
9.3 
Selection of Study Population ........................................................................................ 54 
9.3.1 
Inclusion Criteria .................................................................................................... 54 

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9.3.2 
Exclusion Criteria ................................................................................................... 55 
9.3.3 
Removal of Subjects From Therapy or Study......................................................... 56 
9.3.3.1 Removal of Subjects From Pegloticase Therapy ................................................ 56 
9.3.3.1.1 Study considerations for subjects ending pegloticase infusions prior to 52 
weeks 
57 
9.3.3.2 Removal of Subjects From Study........................................................................ 58 
9.3.4 
Replacement Policy ................................................................................................ 58 
9.3.4.1 Subjects ............................................................................................................... 58 
9.3.4.2 Centers ................................................................................................................. 59 
9.3.4.3 Screen Failures .................................................................................................... 59 
9.4 
Treatments ...................................................................................................................... 59 
9.4.1 
Treatments Administered ........................................................................................ 59 
9.4.1.1 Folic Acid ............................................................................................................ 59 
9.4.1.2 Gout Flare Prophylaxis........................................................................................ 60 
9.4.1.3 Infusion Reaction Prophylaxis ............................................................................ 60 
9.4.2 
Identity of Investigational Products ........................................................................ 60 
9.4.2.1 Pegloticase ........................................................................................................... 60 
9.4.2.2 Methotrexate and Placebo for Methotrexate ....................................................... 61 
9.4.3 
Labeling .................................................................................................................. 61 
9.4.4 
Storage .................................................................................................................... 61 
9.4.5 
Drug Accountability................................................................................................ 62 
9.4.6 
Study Drug Administration and Timing of Dose for each Subject ......................... 62 
9.4.6.1 Description of Clinical Supplies ......................................................................... 62 
9.4.6.2 Determination of Dose Volume .......................................................................... 62 
9.4.6.3 Details Concerning Timing and Dose Administration ........................................ 63 
9.4.6.3.1 Preparation and Administration ..................................................................... 63 
9.4.6.3.2 Dose Modifications, Interruptions, and Delays ............................................. 65 
9.4.7 
Method of Assigning Subjects to Treatment Groups .............................................. 68 
9.4.8 
Blinding................................................................................................................... 68 
9.4.9 
Prior and Concomitant Therapy .............................................................................. 69 
9.4.10 
Restricted Medications............................................................................................ 70 
9.4.11 
Treatment Compliance ............................................................................................ 70 

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9.4.12 
Contraception Requirements ................................................................................... 70 
9.5 
Efficacy, Quality-of-Life, Pharmacokinetic, and Safety Variables ............................... 71 
9.5.1 
Efficacy Variables ................................................................................................... 71 
9.5.1.1 Serum Uric Acid.................................................................................................. 71 
9.5.1.2 Tender and Swollen Joint Counts........................................................................ 72 
9.5.1.3 Physician Global Assessment.............................................................................. 73 
9.5.1.4 Dual-energy Computed Tomography (DECT) ................................................... 73 
9.5.1.5 X-ray of Hands and Feet ..................................................................................... 74 
9.5.1.6 Digital Photography ............................................................................................ 74 
9.5.1.6.1 Assessment of Individual Tophi Response .................................................... 74 
9.5.2 
Quality of Life Assessment ..................................................................................... 75 
9.5.3 
Pharmacokinetic and Anti-drug Antibody Measurements ...................................... 76 
9.5.3.1 Additional Sample Collection for Future Use ..................................................... 76 
9.5.4 
Safety Variables ...................................................................................................... 77 
9.5.4.1 Adverse Events .................................................................................................... 77 
9.5.4.1.1 Definitions ..................................................................................................... 77 
9.5.4.1.2 Documentation of Adverse Events ................................................................ 81 
9.5.4.1.3 Intensity of Adverse Events ........................................................................... 81 
9.5.4.1.4 Relationship to Study Drug ........................................................................... 81 
9.5.4.1.5 Reporting and Documenting SAEs and Product Complaints ........................ 82 
9.5.4.1.6 Follow-up of Adverse Events ........................................................................ 83 
9.5.4.1.7 Medication Error and Overdose .................................................................... 83 
9.5.4.1.8 Review of Adverse Events and Emerging New Safety Information ............. 83 
9.5.4.1.9 Reporting of IND Safety Reports .................................................................. 83 
9.5.4.1.10 Development Safety Update Reports ........................................................ 84 
9.5.4.2 Pregnancy Reporting ........................................................................................... 84 
9.5.4.3 Medical History ................................................................................................... 84 
9.5.4.4 Vital Signs, Height, and Weight.......................................................................... 85 
9.5.4.5 Physical Examinations ........................................................................................ 85 
9.5.4.6 Electrocardiogram ............................................................................................... 86 
9.5.4.7 Clinical Laboratory Safety Tests ......................................................................... 86 

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9.5.4.8 Assessment of Gout Flare ................................................................................... 87 
9.5.5 
Data Monitoring Committee (DMC) ...................................................................... 87 
9.5.6 
Adjudication Committee ......................................................................................... 87 
9.5.7 
Appropriateness of Measurements .......................................................................... 87 
9.5.8 
Study Procedures .................................................................................................... 88 
9.5.8.1 Screening/MTX Tolerability Assessment/Run-in Period ................................... 88 
9.5.8.1.1 Screening Visit (Within 6 Weeks Prior to the First Dose of MTX at Week -6)
 
88 
9.5.8.1.2 Week -6 (MTX Tolerability Assessment Period) .......................................... 89 
9.5.8.1.3 Week -4 (Run-in Period) ............................................................................... 90 
9.5.8.1.4 Week -2 (Run-in Period) ............................................................................... 91 
9.5.8.2 Pegloticase + IMM Period .................................................................................. 91 
9.5.8.2.1 Day 1.............................................................................................................. 91 
9.5.8.2.2 Week 2 ........................................................................................................... 93 
9.5.8.2.3 Week 4 ........................................................................................................... 94 
9.5.8.2.4 Week 6 ........................................................................................................... 95 
9.5.8.2.5 Week 8 ........................................................................................................... 97 
9.5.8.2.6 Week 10 ......................................................................................................... 98 
9.5.8.2.7 Week 12 ......................................................................................................... 99 
9.5.8.2.8 Week 14 ....................................................................................................... 100 
9.5.8.2.9 Week 16 ....................................................................................................... 102 
9.5.8.2.10 Week 18 .................................................................................................. 103 
9.5.8.2.11 Week 20 .................................................................................................. 104 
9.5.8.2.12 Week 21 .................................................................................................. 105 
9.5.8.2.13 Week 22 .................................................................................................. 106 
9.5.8.2.14 Week 23 .................................................................................................. 107 
9.5.8.2.15 Week 24 .................................................................................................. 107 
9.5.8.2.16 Week 26 .................................................................................................. 109 
9.5.8.2.17 Week 28 .................................................................................................. 110 
9.5.8.2.18 Week 30 .................................................................................................. 111 
9.5.8.2.19 Week 32 .................................................................................................. 112 
9.5.8.2.20 Week 34 .................................................................................................. 113 

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9.5.8.2.21 Week 36 .................................................................................................. 114 
9.5.8.2.22 Week 38 .................................................................................................. 116 
9.5.8.2.23 Week 40 .................................................................................................. 117 
9.5.8.2.24 Week 42 .................................................................................................. 118 
9.5.8.2.25 Week 44 .................................................................................................. 119 
9.5.8.2.26 Week 46 .................................................................................................. 120 
9.5.8.2.27 Week 48 .................................................................................................. 121 
9.5.8.2.28 Week 50 .................................................................................................. 123 
9.5.8.3 End of Pegloticase Infusions Visit .................................................................... 124 
9.5.8.4 Week 52/End of Study/Early Termination Visit ............................................... 125 
9.5.8.5 Safety Follow-up Phone/Email Visits ............................................................... 127 
9.5.8.6 MTX Partner Pregnancy Follow-up .................................................................. 127 
9.5.8.7 Post Treatment Follow-up ................................................................................. 127 
9.6 
Statistical Methods and Determination of Sample Size ............................................... 128 
9.6.1 
Endpoints .............................................................................................................. 128 
9.6.1.1 Primary Endpoint .............................................................................................. 128 
9.6.1.2 Secondary Endpoints ......................................................................................... 128 
9.6.1.3 Exploratory Endpoints....................................................................................... 129 
9.6.1.4 Pharmacokinetic and Anti-drug Antibody Endpoints ....................................... 130 
9.6.1.5 Safety and Tolerability Endpoints ..................................................................... 130 
9.6.2 
Populations for Analysis ....................................................................................... 130 
9.6.3 
Demographic Variables ........................................................................................ 131 
9.6.4 
Subject Disposition ............................................................................................... 131 
9.6.5 
Efficacy Endpoint Analysis .................................................................................. 131 
9.6.5.1 Primary and Secondary Endpoint Analysis ....................................................... 131 
9.6.5.2 Exploratory Endpoint Analysis ......................................................................... 132 
9.6.6 
Pharmacokinetic and Anti-drug Antibody Analysis ............................................. 132 
9.6.7 
Safety Analysis ..................................................................................................... 133 
9.6.8 
Interim Analyses ................................................................................................... 134 
9.6.9 
Sample Size and Power Considerations ................................................................ 134 
9.7 
Changes in the Conduct of the Study ........................................................................... 134 

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10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES ..................................... 134 
11 CASE REPORT FORMS ................................................................................................... 135 
12 STUDY MONITORING .................................................................................................... 135 
13 DATA MANAGEMENT .................................................................................................... 136 
14 RETENTION OF RECORDS ............................................................................................. 137 
15 PUBLICATION .................................................................................................................. 137 
16 REFERENCES ................................................................................................................... 137 
17 APPENDICES .................................................................................................................... 140 
17.1 Administrative Appendix ............................................................................................. 140 
17.2 Health Assessment Questionnaire (Disability Index, Pain and Health Scales) ............ 141 
17.3 Physician Global Assessment....................................................................................... 144 
17.4 Investigator Assessment of Clinical Status .................................................................. 145 
LIST OF TABLES 
Table 6.1 
Table of Non-Sponsor Study Responsibilities ........................................................... 40 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Study Design ........................................................................................ 53 
Figure 9.2 Rheumatoid Arthritis 66-68 Tender and Swollen Joint Counts ................................. 73 

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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
CFR 
Code of Federal Regulations 
DECT 
dual-energy computed tomography 
DMC 
data monitoring committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
HAQ 
Health Assessment Questionnaire 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMM 
Immunomodulator 
IND 
Investigational New Drug 
IR 
infusion reaction 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
mITT 
modified intention-to-treat 
MTX 
Methotrexate 
NSAID 
non-steroidal anti-inflammatory drug 
PK 
pharmacokinetic(s) 
PO 
oral  
PBMC 
peripheral blood mononuclear cell 
RNA 
ribonucleic acid 
RTSM 
Randomization and Trial Supply Management 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sUA 
serum uric acid 
ULT 
urate lowering therapy 
USP 
United States Pharmacopeia 

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Note: Abbreviations used only once in a paragraph or in tables or figures are defined within the relevant paragraph, 
table, or figure. 

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5 
ETHICS 
5.1 
Institutional Review Board/Independent Ethics Committee 
The Principal Investigator (Investigator), the Sponsor and/or designee authorized by the Sponsor 
will submit this protocol, any protocol modifications, the informed consent form (ICF), and all 
applicable study documentation to be used in this study to the appropriate Institutional Review 
Board (IRB) for review and approval/favorable opinion. A letter confirming the IRB 
approval/favorable opinion of the protocol, the subject ICF, and applicable study documentation, 
a list of the IRB members involved in the vote, as well as a statement that the IRB is organized 
and operates according to Good Clinical Practice (GCP) and the applicable laws and regulations, 
must be forwarded to the Sponsor or its designee prior to the enrollment of subjects into the 
study. A copy of the approved ICF will also be forwarded to the Sponsor or its designee. 
Appropriate reports on the progress of the study will be made to the IRB and the Sponsor or its 
designee by the Investigator in accordance with applicable governmental regulations and in 
agreement with the policy established by the Sponsor.  
5.2 
Ethical Conduct of the Study 
The Investigators will ensure that this study is conducted in a manner that fully conforms with 
the principles of the Declaration of Helsinki or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. The 
study must fully adhere to the principles outlined by International Council for Harmonisation 
(ICH) Tripartite Guideline for GCP or with local law if it affords greater protection to the 
subject. The Investigator will additionally ensure adherence to the basic principles of GCP, as 
outlined in the current version of 21 Code of Federal Regulations (CFR), subchapter D, part 312, 
“Responsibilities of Sponsors and Investigators,” part 50, “Protection of Human Subjects,” and 
part 56, “Institutional Review Boards.” 
5.3 
Subject Information and Consent 
It is the responsibility of the Investigator or a person designated by the Investigator (if acceptable 
by local regulations) to obtain a signed ICF from each subject prior to participating in this study 
after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study. 
The Investigator or designee must also explain that the subjects are completely free to refuse to 
enter the study or to withdraw from it at any time, for any reason.  
The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the subject 
information and/or the written ICF. The Investigator will inform the subject of changes in a 
timely manner and will ask the subject to confirm his/her participation in the study by signing the 
revised ICF. Any revised written ICF and written information must receive the IRB`s 
approval/favorable opinion in advance of use. 

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All signed ICFs are to remain in the Investigator’s site file or, if locally required, in the subjects’ 
notes/files of the medical institution. 
The electronic case report forms (eCRFs) for this study contain a section for documenting all 
subject ICFs, and this must be completed appropriately. If new safety information results in 
significant changes in the risk/benefit assessment, the ICF should be reviewed and updated, if 
necessary. All subjects (including those already being treated) should be informed of the new 
information, given a copy of the revised ICF, and give their consent to continue in the study. 
5.4 
Compensation for Health Damage of Subjects/Insurance 
The Sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 
5.5 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the Sponsor. Only the subject number will be recorded in 
the eCRF, and if the subject name appears on any other document, it must be obliterated before a 
copy of the document is supplied to the Sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. As part of the informed consent process, the 
subjects will be informed in writing that representatives of the Sponsor, IRB, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects to be identified. 
The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (HIPAA).  
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Sponsor of this study is Horizon Therapeutics Ireland DAC (Horizon). Horizon personnel 
will serve as the Medical Monitor and the Sponsor’s regulatory representative (see Section 17.1 
for details). The Sponsor’s regulatory representative will be responsible for timely reporting of 
serious adverse events (SAEs) to regulatory authorities, as required. The Sponsor will be 
responsible for timely reporting of SAEs and any other new pertinent safety information to all 
Investigators, as required. 

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The study will be conducted at approximately 65 study centers in the United States. Prior to 
initiation of the study, each Investigator will provide the Sponsor or its designee with a fully 
executed and signed Food and Drug Administration (FDA) Form 1572 and a Financial 
Disclosure Form. Financial Disclosure Forms will also be completed by all sub-investigators 
listed on the Form 1572. It is the responsibility of the Investigators or sub-investigators to advise 
the Sponsor of any change in the relevant financial interests that occur during the study and the 
1-year period following its completion. 
Table 6.1 lists organizations that are critical to the conduct of the study, with a brief description 
of their roles: 
Table 6.1 
Table of Non-Sponsor Study Responsibilities 
Study Responsibility 
Organization 
Clinical drug supply and 
distribution 
 
 
 
Central safety laboratory 
 
 
 
Data Management  
  
 
 
 
Statistics 
 
 
 
DMC/Adjudication Committee  
 
 
 
Central imaging vendor 
 
 
 
Monitoring 
 
 
 
Location of Lost to Follow up 
Subjects 
 
 
 
 
 
 

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7 
INTRODUCTION 
7.1 
Background 
7.1.1 Gout 
Gout affects approximately 4% of the United States population, is the most common form of 
inflammatory arthritis in men, and is associated with decreased quality of life [Saag and Choi, 
2006; Singh and Strand, 2008; Zhu et al, 2011; Sattui et al, 2014]. The frequency of gout is 
increasing worldwide, with prevalence rates estimated to be as high as 7% in older men 
[Mikuls et al, 2005; Saag and Choi, 2006; Roddy and Doherty, 2010]. While the exact 
prevalence is unknown, as many as 200,000 persons in the United States experience chronic 
symptoms of gout, which is sometimes referred to as chronic refractory gout, despite trials of 
oral urate-lowering therapy. This is characterized by ongoing symptoms of active disease and a 
failure to control/maintain serum uric acid (sUA) <6 mg/dL with conventional xanthine oxidase 
inhibitors (i.e., allopurinol and febuxostat) and uricosuric agents (i.e., probenecid) 
[AAC Briefing Document 2009; Brook et al, 2010; Wertheimer et al, 2013; Khanna et al, 2016]. 
These patients often have significant, disabling urate deposits in soft tissues and bone known as 
tophi. 
7.1.2 Pegloticase 
 
 
 
 
 
 
Two replicate pivotal phase 3 studies for pegloticase were undertaken to establish the efficacy 
and safety of the product. The primary endpoint was defined as plasma UA (highly correlated to 
serum uric acid) reduction to below 6 mg/dL for 80% of the time in Months 3 and 6 combined. 
The pooled response rate for pegloticase 8 mg every two weeks was 42%, versus a placebo 
response rate of 0%. There was also a greater reduction in complete resolution of ≥ 1 tophus in 
the every 2 weeks dosing group, and favorable effect of pegloticase treatment in the reduction of 
the number of tender and swollen joints. In subsequent open-label extension studies, pegloticase 
led to continued control of pUA, reduction in gout flares, and continued resolution of tophi, 
suggesting continuing benefit with extended pegloticase treatment beyond the initial 6 months of 
therapy, particularly in subjects who met responder criteria in the placebo-controlled trials. 
In the phase 3 pivotal studies, deaths, AEs, SAEs, as well as the laboratory abnormalities were 
generally equally distributed across placebo and pegloticase treatment groups, with the clear 
exception of gout flares and infusion reactions. Pegloticase-treated subjects exhibited a higher 
rate of gout flares during Months 1-3 as uric acid was being acutely lowered, then a decrease in 
gout flares vs. placebo during Months 4-6. Despite use of prophylactic medications against 
hypersensitivity including administration of corticosteroids, antihistamine, and acetaminophen in 
advance of each pegloticase infusion, infusion reactions were seen in 22/85 (26%) of subjects 

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receiving the 8 mg 2 week regimen. There was no specified definition of anaphylaxis in the 
Phase 3 protocols, and there were no investigator-reported events of anaphylaxis in the Phase 3 
studies with pegloticase. However, in a post-hoc review applying the NIAID/FAAN criteria 
(Sampson et al., 2006), it was determined that across the Phase 2 and Phase 3 program, 
anaphylaxis occurred in 6.5% of subjects treated with pegloticase dosed every 2 weeks.  
Anaphylaxis generally occurred within 2 hours after treatment.  Manifestations included 
wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or 
urticaria.  All of these events had relatively rapid resolution with the cessation of infusion.   
In a post-hoc analysis, the apparent role of immunogenicity in both loss of urate lowering effect 
and incidence of infusion reactions was appreciated. Only 2% of subjects with anti pegloticase 
antibody titers exceeding 1:2430 maintained a urate-lowering response to pegloticase compared 
with 63% of subjects who were treated for at least 2 months without developing high-titer 
antibodies (p < 0.001) (Sundy et al., 2011). The incidence of IRs was higher among subjects who 
developed high-titer antibodies compared with those who had titers that did not exceed 1:2430 
(60% vs 19%; p <0.001) (Sundy et al., 2011). In addition, most IRs occurred when sUA levels 
were greater than 6 mg/dL.  Retrospective analyses showed that the loss of urate-lowering 
efficacy, as reflected by sUA of greater than 6 mg/dL, preceded a patient’s first IR, whenever it 
occurred, in 20 (91%) of 22 subjects treated with pegloticase every 2 weeks.  
 
Reducing anti-drug antibodies with concomitant administration of the immunomodulatory agent 
methotrexate (MTX) has been shown to be useful with other infused products that lead to 
immunogenicity, such as adalimumab, in the setting of rheumatoid arthritis treatment [Burmester 
GR, Kivitz AJ, Kupper H, 2015]. This study will test whether the loss of sUA response to 
pegloticase can be prevented or delayed by the pre-treatment and concomitant use of MTX with 
pegloticase compared to pegloticase alone. 
7.1.2.1 Physiochemical Properties 
 
 
 
 
 
 
 

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7.1.2.2 Safety Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 

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7.1.2.3 Non-clinical Pharmacokinetics 
 
 
 
 
 
 
 
 
 
  
 
 
7.1.2.4 Pharmacokinetics 
  
 
 
  

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7.1.2.5 Risks of Pegloticase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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. 
7.1.3 Methotrexate Overview and Risks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 
Rationale for this Study 
Immunogenicity (anti-pegloticase antibodies) in response to pegloticase therapy may lead to loss 
of therapeutic response and/or AEs, including IRs. In the phase 3 studies, IRs occurred more 
commonly in subjects whose sUA values increased above 6 mg/dL, after initially showing 
response following the first 1 or 2 infusions. The titer of the anti-drug antibody was also 
associated with loss of response, with subjects having the highest levels of anti-drug antibodies 
showing the lowest response rates. 
The development of anti-drug antibodies can be influenced by drug and treatment-related factors, 
as well as patient characteristics. A potential prophylactic strategy to manage anti-drug antibody 
response with pegloticase is the co-administration of immunomodulatory therapy. Various 
methods are used to reduce antibody production in other settings, the most common of which is 
the use of traditional rheumatoid arthritis disease-modifying drugs, such as MTX, azathioprine, 

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mycophenolate mofetil, leflunamide, and others, as is commonly implemented with rheumatoid 
arthritis biological therapy (e.g., infliximab and other infusible and subcutaneous antibody 
products) [Strand et al, 2017].  
MTX is the most commonly used non-biological disease modifying agent worldwide and is 
frequently used in combination with other biological therapies [Strand et al, 2017].  
In the current study, MTX will be evaluated for its ability to improve the response rate and 
reduce IRs with pegloticase by reducing drug immunogenicity. Prospective use of sUA stopping 
rules, with pegloticase treatment cessation (but study continuation) when a subject has an sUA 
level > 6 mg/dL on two consecutive study visits, will also help confirm the value of this 
approach to reduce IR risk. 
7.3 
Rationale for Dose Selection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8 
STUDY OBJECTIVES 
The overall objective of the double-blind portion of the study is to assess the potential for 
pegloticase with MTX to increase the response rate seen with pegloticase alone, and to 
characterize the safety, tolerability and pharmacokinetics (PK) of the concomitant use of 
pegloticase with MTX, by comparing pegloticase co-administered with MTX to pegloticase co-
administered with placebo for MTX in adults with uncontrolled gout.   
Primary Objective 
The primary objective is to evaluate the effect of pegloticase with MTX vs. pegloticase with 
placebo for MTX on the response rate during Month 6 (Weeks 20, 21, 22, 23 and 24), as 
measured by the sustained normalization of serum uric acid (sUA) to <6 mg/dL for at least 80% 
of the time during Month 6. 
Secondary Objectives (analyzed sequentially) 
1. Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
response rate during Month 12 (Weeks 48, 50, and 52), as measured by the sustained 
normalization of sUA to <6 mg/dL for at least 80% of the time during Month 12. 
2. Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
complete resolution of ≥ 1 tophi (using digital photography) at Week 52 in subjects with 
tophi at baseline. 
3. Evaluate the effect of pegloticase with MTX vs. pegloticase and placebo for MTX on the 
mean change from baseline in Health Assessment Questionnaire – Disability Index 
(HAQ-DI) Score at Week 52. 
4. Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in Health Assessment Questionnaire (HAQ) Pain Score at 
Week 52. 
5. Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in HAQ Health Score at Week 52. 
Exploratory Objectives  
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in urate volume and bone erosions due to gout to Weeks 14, 
24, and 52 based on DECT. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in bone erosions due to gout to Weeks 24 and 52 based on X-
rays of the hands and feet.   
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
complete resolution of ≥ 1 tophi (using digital photography) at Weeks 24 and 36 in 
subjects with tophi at baseline. 

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 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in tophus size (long axis measured using digital photography) 
to Weeks 14, 24, 36 and 52 in subjects with tophus present at baseline. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
response rate during Month 9 (Weeks 32, 34, and 36), as measured by the sustained 
normalization of sUA to <6 mg/dL for at least 80% of the time during Month 9. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
response rate during Month 3 (Weeks 10, 12 and 14), as measured by the sustained 
normalization of sUA to <6 mg/dL for at least 80% of the time during Month 3. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
overall response rate, as measured by the sustained normalization of sUA to <6 mg/dL 
for at least 80% of the time during Month 3 (Weeks 10, 12, and 14) and Month 6 (Weeks 
20, 21, 22, 23, and 24) combined. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on 
reducing sUA to < 5 mg/dL for at least 80% of the time during Months 3, 6, 9 and 12, 
individually.    
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in sUA at Weeks 14, 24, 36 and 52. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
time to first sUA > 6 mg/dL. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
time to two consecutive sUA > 6 mg/dL (sUA stopping rule). 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
percentage of non-hyperuricemic (sUA < 6 mg/dL) time during Months 3, 6, 9 and 12. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in HAQ Pain Score at Weeks 14, 24, and 36. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in HAQ Health Score at Weeks 14, 24, and 36. 
 Evaluate the effect of pegloticase and MTX vs. pegloticase and placebo for MTX on the 
mean change from baseline in HAQ-DI Score at Weeks 14, 24, and 36. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in tender joint count (68-point scale) at Weeks 14, 24, 36 and 
52. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in swollen joint count (66-point scale) at Weeks 14, 24, 36 
and 52. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in number of tender or swollen joints at Weeks 14, 24, 36 and 
52. 

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 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in physician global assessment of gout at Weeks 14, 24, 36 
and 52. 
 Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
proportion of subjects achieving 20%, 50%, or 70% improvement based on gout chronic 
response criteria at Weeks 14, 24, 36 and 52. 
  Evaluate the effect of pegloticase with MTX vs. pegloticase with placebo for MTX on the 
mean change from baseline in SBP and DBP to each visit. 
 Assess the PK of pegloticase. 
 Assess the MTX polyglutamate concentrations. 
 Assess the incidence of anti-PEG and anti-Uricase IgG antibodies. 
Safety and Tolerability Objectives 
 AE/SAE profile overall for pegloticase and the combination of pegloticase and MTX 
o Incidence of AESI: IRs, anaphylaxis, gout flares, cardiovascular events 
 Laboratory tests 
 Vital signs and physical examination 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study is a Phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-
group, efficacy and safety study of pegloticase with MTX vs. pegloticase with placebo for MTX 
in adult subjects with uncontrolled gout. 
The study design will include: 1) a Screening Period (screening should be completed within 6 
weeks prior to Week -6); 2) a 2-week MTX Tolerability Assessment Period consisting of 2 
weeks oral MTX for all subjects; 3) a Run-In Period consisting of randomization followed by 4 
weeks of blinded oral MTX or placebo for MTX; 4) a 52-week Pegloticase + IMM Period; 5) a 
Safety Follow-up (Phone/Email/Site Visit) and 6) a 3 and 6 month Post Treatment Follow-up.  
All subjects who meet eligibility criteria at Screening will begin 15 mg MTX orally weekly at 
the Week -6 visit. Subjects will also take folic acid 1 mg orally every day beginning during the 
MTX Tolerability Assessment Period (Week -6 to Week -4) and continuing until prior to the 
Week 52 Visit.  
Subjects must be able to tolerate the weekly dose of MTX 15 mg for 2 weeks to be eligible to be 
randomized at Week -4. Subjects who are unable to tolerate the 15 mg dose of MTX during the 2 
weeks preceding the Week -4 visit during the Run-in Period will be considered screen failures.  
Subjects who tolerate the weekly 15 mg MTX dose during the 2 weeks preceding Week -4 Visit 
and continue to meet eligibility criteria will be randomized at the Week -4 Visit in a 2:1 ratio 
(stratified by presence of tophi) to receive either blinded oral 15 mg MTX or blinded oral 

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placebo for MTX.  Tophi presence (yes, no) will be based on presence of at least one tophus 
identified by the Investigator.  Subjects will continue to take the blinded MTX or placebo for 
MTX from Week -4 to Day 1 (the Run-in period) at the 15 mg MTX or placebo for MTX dose. 
If a subject does not tolerate the 15 mg MTX or placebo for MTX dose after randomization at the 
Week -4 Visit and prior to Day 1, the MTX or placebo for MTX may be dose-reduced or 
discontinued based on pre-specified criteria and after discussion with the Sponsor medical 
monitor. The subject will be allowed to remain in the study.  After Day 1, MTX or placebo for 
MTX may be re-initiated. The subject will be re-initiated to the same treatment they were 
randomized to at Week -4. The re-initiated MTX or placebo for MTX will remain blinded.  
All subjects who complete the Run-In Period will receive the first pegloticase infusion on Day 1. 
All subsequent doses and study visits will be scheduled based on the Day 1 visit date.  
It is required that before a subject begins the pegloticase + IMM Period, he or she has been 
taking at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or non-
steroidal anti-inflammatory drugs and/or low-dose prednisone ≤10 mg/day) for ≥1 week before 
the first dose of pegloticase and continues flare prophylaxis per American College of 
Rheumatology guidelines [Khanna D et al. 2012] for the greater of 1) 6 months, 2) 3 months 
after achieving target serum urate (sUA < 6 mg/dL) for patients with no tophi detected on 
physical exam, or 3) 6 months after achieving target serum urate (sUA < 5 mg/dL) for patients 
with one or more tophi detected on initial physical exam that have since resolved.  For IR 
prophylaxis, fexofenadine (180 mg orally) will be taken the day before each infusion; 
fexofenadine (180 mg orally) and acetaminophen (1000 mg orally) will be taken the morning of 
each infusion; and methylprednisolone (125 mg IV) given over an infusion duration between 10 - 
30 minutes, immediately prior to each infusion.  
During the Pegloticase + IMM Period, pegloticase 8 mg will be administered intravenously (IV) 
every 2 weeks from Day 1 through the Week 50 Visit for a total of 26 infusions; pegloticase will 
be administered after all pre-dose study visit assessments have been completed at each visit. The 
date and start and stop time of infusion will be recorded. Serum uric acid stopping rules will be 
applied: subjects with sUA level >6 mg/dL at 2 consecutive study visits beginning with the 
Week 2 Visit will discontinue treatment, complete the End of Pegloticase Infusion Visit 
procedures within 2 weeks and continue the subject visits according to the protocol (without 
treatment). 
During the Pegloticase + IMM Period, subjects will be instructed to take MTX or placebo for 
MTX weekly on the same day each week, within 1 to 3 days prior to each pegloticase infusion 
and one additional weekly dose after the last infusion for subjects who have not stopped 
pegloticase due to sUA stopping rules; however, if a subject does not do so, MTX or placebo for 
MTX must be taken ≥60 minutes prior to each pegloticase infusion.  
After Day 1, if a subject becomes unable to tolerate MTX or placebo for MTX, the MTX or 
placebo for MTX dose may be reduced and/or discontinued based on pre-defined criteria, and the 
subject may remain in the study.   

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The Investigator will review the clinical status and individual subject treatment goals (Appendix 
17.4) at Screening, Week 24, Week 52 and the End of Pegloticase Infusions Visit (if applicable) 
or the Week 52/End of study/Early Termination Visit.  
After the Week 52 Visit (or End of Pegloticase Infusion Visit [if applicable]), subjects should 
resume regular care for gout per the judgment of the treating physician, including resumption of 
urate lowering therapy (ULT) upon pegloticase discontinuation, if appropriate. Subjects will 
have a 3 and 6 Month Follow-up visit to assess clinical status, including sUA levels. 
Subjects who receive at least one dose of MTX or placebo for MTX and are females of 
childbearing potential will receive a safety follow-up phone call/e-mail approximately 30 days 
after the last dose of MTX or placebo for MTX to verify at least one ovulatory cycle has 
occurred after the last dose of MTX or placebo for MTX.  If the subject has not ovulated, a urine 
pregnancy test will be performed. Subjects who receive at least one dose of MTX or placebo for 
MTX and who are non-vasectomized males, will be asked, 3 months after MTX or placebo for 
MTX discontinuation, regarding partner pregnancy. 
Samples for measurement of sUA levels, PK analysis of pegloticase, pegloticase 
immunogenicity and MTX Polyglutamate analysis will be collected at visits indicated in the 
Schedule for Assessments (Section 2.1). 
Safety assessments, including monitoring and recording of all AEs, whether or not drug-related, 
measurement of vital signs, physical examinations, and monitoring of hematology and blood 
chemistry, will be performed.  
The total blood volume to be collected from each subject during this study is approximately 910 
mL.  
An external Data Monitoring Committee (DMC) will be convened to review data for safety and 
efficacy with timing and criteria outlined in the DMC Charter, with the possibility of DMC 
recommendation on study design modification per criteria also to be outlined in the Charter. 
An independent external adjudication committee will review reported events of infusion 
reactions, cardiovascular events and anaphylaxis. 
An overview of the study design is presented in the schematic below, and details of study 
activities are provided in Section 2.1.

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Figure 9.1 
Schematic of Study Design 
 
 

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9.2 
Discussion of Study Design 
This study is a Phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
efficacy and safety study of pegloticase in combination with MTX or pegloticase in combination 
with placebo for MTX in adult subjects with uncontrolled gout. 
Immunogenicity (anti-pegloticase antibodies) in response to pegloticase therapy may lead to loss of 
therapeutic response and/or AEs, including IRs. A potential prophylactic strategy to manage anti-
drug antibody response with pegloticase is the co-administration of immune-modulating therapy. 
MTX is the most commonly used non-biological disease modifying agent worldwide and is 
frequently used in combination with other biological therapies [Strand et al, 2017]. 
This study will include a 2-week MTX Tolerability Assessment Period, a 4-week Run-in Period 
including 4 weeks of blinded MTX or placebo for MTX, a 52-Week Pegloticase + IMM Period 
including MTX or placebo for MTX dosed weekly and 50 weeks of pegloticase infusion visits 
every 2 weeks and a Post Treatment Follow-up Period.  
9.3 
Selection of Study Population 
9.3.1 Inclusion Criteria 
Eligible subjects must meet/provide all of the following criteria: 
1. Willing and able to give informed consent. 
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the study. 
3. Adult men or women ≥18 years of age. 
4. Uncontrolled gout, defined as meeting the following criteria: 
 Hyperuricemia during the screening period defined as sUA ≥7 mg/dL, and; 
 Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the 
maximum medically appropriate dose, or with a contraindication to xanthine oxidase 
inhibitor therapy based on medical record review or subject interview, and; 
 Symptoms of gout including at least 1 of the following: 
o Presence of at least one tophus 
o Recurrent flares defined as 2 or more flares in the past 12 months prior to 
screening 
o Presence of chronic gouty arthritis 
5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX 
dosing at Week -6 and remain off when receiving pegloticase infusions.  
6. Women of childbearing potential (including those with an onset of menopause <2 years 
prior to screening, non-therapy-induced amenorrhea for <12 months prior to screening, or 
not surgically sterile [absence of ovaries and/or uterus]) must have negative serum/urine 
pregnancy tests during Screening and Week -6; subjects must agree to use 2 reliable forms 
of contraception during the study, one of which is recommended to be hormonal, such as an 

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oral contraceptive. Hormonal contraception must be started ≥1 full cycle prior to Week -6 
(start of MTX) and continue for 30 days after the last dose of pegloticase, or at least one 
ovulatory cycle after the last dose of MTX or placebo for MTX (whichever is the longest 
duration after the last dose of pegloticase or MTX or placebo for MTX). Highly effective 
contraceptive methods (with a failure rate <1% per year), when used consistently and 
correctly, include implants, injectables, combined oral contraceptives, some intrauterine 
devices, sexual abstinence, or vasectomized partner. 
7. Men who are not vasectomized must agree to use appropriate contraception so as to not 
impregnate a female partner of reproductive potential during the study, beginning with the 
initiation of MTX at Week -6 and continuing and for at least 3 months after the last dose of 
MTX or placebo for MTX.  
8. Able to tolerate MTX 15 mg orally for 2 weeks (Week -6 through Week -4) prior to 
randomization. 
9.3.2 Exclusion Criteria 
Subjects will be ineligible for study participation if they meet any of the following criteria: 
1. Weight >160 kg (352 pounds) at Screening. 
2. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics 
at least 2 weeks prior to the Week -6 Visit.  
3. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic 
bronchiectasis. 
4. Current or chronic treatment with systemic immunosuppressive agents such as MTX, 
azathioprine, or mycophenolate mofetil; prednisone ≥10 mg/day or equivalent dose of other 
corticosteroid on a chronic basis (3 months or longer) would also meet exclusion criteria. 
5. History of any transplant surgery requiring maintenance immunosuppressive therapy. 
6. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity. 
7. Known history of hepatitis C virus RNA positivity. 
8. Known history of Human Immunodeficiency Virus (HIV) positivity. 
9. Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit). 
10. Chronic renal impairment defined as estimated glomerular filtration rate (eGFR) 
<40 mL/min/1.73 m2 or currently on dialysis. 
11. Non-compensated congestive heart failure or hospitalization for congestive heart failure 
within 3 months of the Screening Visit, uncontrolled arrhythmia, treatment for acute 

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coronary syndrome (myocardial infarction or unstable angina), or uncontrolled blood 
pressure (>160/100 mmHg) prior to Randomization at Week -4. 
12. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate female 
partner, or not on an effective form of birth control, as determined by the Investigator. 
13. Prior treatment with pegloticase, another recombinant uricase (rasburicase), or concomitant 
therapy with a polyethylene glycol-conjugated drug. 
14. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant 
protein or porcine product. 
15. Contraindication to MTX treatment or MTX treatment considered inappropriate. 
16. Known intolerance to MTX. 
17. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior 
to MTX administration at Week -6 or plans to take an investigational drug during the study. 
18. Liver transaminase levels (AST or ALT) > upper limit of normal (ULN) or albumin < the 
lower limit of normal (LLN) at the Screening Visit).  
19. Chronic liver disease.  
20. White blood cell count < 4,000/ul, hematocrit < 32 percent, or platelet count <75,000/ul. 
21. Currently receiving systemic or radiologic treatment for ongoing cancer. 
22. History of malignancy within 5 years other than non-melanoma skin cancer or in situ 
carcinoma of cervix. 
23. Diagnosis of osteomyelitis. 
24. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as 
Lesch-Nyhan and Kelley-Seegmiller syndrome. 
25. Unsuitable candidate for the study, based on the opinion of the Investigator (e.g., cognitive 
impairment), such that participation might create undue risk to the subject or interfere with 
the subject’s ability to comply with the protocol requirements or complete the study. 
26. Alcohol use in excess of 3 alcoholic beverages per week. 
27. A known intolerance to all protocol standard gout flare prophylaxis regimens (i.e. subject 
must be able to tolerate at least one: colchicine and/or non-steroidal anti-inflammatory drugs 
and/or low-dose prednisone ≤10 mg/day). 
28.  Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis.  If deemed necessary 
by the Investigator, a chest X-ray may be performed during Screening.  
9.3.3 Removal of Subjects From Therapy or Study 
All subjects are free to withdraw from study participation at any time, for any reason, and without 
prejudice to their further medical care. In addition, the Investigator may terminate a subject from 
the study at any time. However, subjects who are removed from pegloticase therapy should remain 
on study barring withdrawal of consent for study participation. 
9.3.3.1 Removal of Subjects From Pegloticase Therapy 
In addition to completion of therapy through Week 52, the reason for discontinuation from the 
therapy should be recorded on the eCRF using 1 of the following categories: 

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 Lost to Follow-up. The subject does not return to the clinic for scheduled assessments, and 
does not respond to the site’s attempts to contact the subject. 
 
Lack of Efficacy. (i.e., sUA level >6 mg/dL at 2 consecutive study visits beginning with the Week 2 
Visit). 
 Adverse Event. The subject experiences an AE that imposes an unacceptable risk to the 
subject’s health (e.g., anaphylactic reaction), or the subject is unwilling to continue therapy 
because of an AE. Subjects who discontinue due to an AE should be followed until 
resolution or stabilization of the AE, or an adequate explanation for the event is obtained. 
 Physician Decision. The Investigator has determined that pegloticase administration poses 
an unacceptable risk to the subject (specify reason).  
 Withdrawal by Subject. Subject refusal of additional therapy (specify reason). 
 Study Terminated by Sponsor. The Sponsor, IRB, or regulatory agency terminates the study.  
 Pregnancy 
 Death 
9.3.3.1.1 Study considerations for subjects ending pegloticase infusions prior to 52 weeks 
 Methotrexate/placebo for MTX, along with folic acid, will be discontinued at the time of 
cessation of pegloticase infusions prior to Week 52.  
 All subjects will complete the End of Pegloticase Infusions Visit and will remain on study 
through Week 52 regardless of whether they stop infusions due to sUA stopping rules or 
other reason (e.g. withdrawal of consent for pegloticase infusions). 
 Subjects are encouraged to continue to participate in all visits through the end of the study. 
Subjects are especially encouraged to complete study visits at the study site during key 
efficacy and safety collections at Weeks 12, 14, 20, 21, 22, 23, 24, 32, 34, 36, 48, 50 and 
52/End of Study/Early Termination, so that sUA labs and other key assessments can be 
completed. During visits between these key efficacy and safety collection visits, in subjects 
who have stopped infusions, subjects may complete study visits in person or via telephone 
to collect AEs, conmeds and gout flare information.   
 Activities related to pre/post infusion monitoring or medication dispensation will not be 
completed once a subject has stopped pegloticase infusions. These activities include:  
o MTX/placebo for MTX compliance/reconciliation 
o Infusion reaction prophylaxis 
o IR prophylaxis compliance 
o Folic acid compliance 
o Pegloticase infusion 
o Pegloticase PK sampling 
o Pre-infusion MTX Polyglutamate sampling  
o MTX drug/dispensation related items 
 Re-introduction of oral ULT’s should not start until after the End of Pegloticase Visit 
laboratory tests are collected.   

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Post Treatment Follow-up: 
The intent is to obtain at least 6 months of follow-up on each subject after cessation of pegloticase 
infusions. If these 6 months occur prior to end of study at Week 52, such as in the case of a subject 
who ends pegloticase infusions on or before Week 24, there will be no follow-up visits after the 
Week 52/End of Study Visit. For subjects who end pegloticase infusions between Weeks 26 and 36, 
there will be at least 3 months of follow-up while the subject remains on-study prior to Week 52, 
and then one follow-up visit after the Week 52/End of Study Visit. For subjects who end 
pegloticase infusions between Weeks 38 and 52, there will be two follow-up visits at intervals of 3 
months apart after the Week 52/End of Study Visit. 
9.3.3.2 Removal of Subjects From Study 
In addition to completion of therapy and designated study visits through Week 52, the reason for 
discontinuation from the study should be recorded on the eCRF using 1 of the following categories: 
 Lost to Follow-up. The subject does not return to the clinic for scheduled assessments, and 
does not respond to the site’s attempts to contact the subject. 
o ASG (an external vendor that focuses on locating Lost to Follow-up subjects) will 
conduct a search of subjects whose status was determined “Lost to Follow-up” 
during the trial.  This search for subjects whose status is “Lost to Follow-up” will be 
conducted throughout the study.  See Section 9.5.4.1.2 for adverse event reporting if 
subject’s status results in “Death.” 
 For subjects whose status is determined to be deceased, their status 
previously considered to have been “Lost to Follow-up” may have the reason 
for discontinuation updated to “Death” if the Investigator deems appropriate.  
This will be considered on a case by case basis. 
 For subjects whose status is determined to be alive:  Subjects categorization 
will remain “Lost to Follow-up”.    
 Withdrawal of Consent. The subject withdraws from the study. The clinical site should 
attempt to determine the underlying reason for the withdrawal and document it on the eCRF; 
(i.e. AE, voluntary withdraw) Specify. 
 Study Terminated by Sponsor. The Sponsor, IRB, or regulatory agency terminates the study. 
 Death  
 
  
 
9.3.4 Replacement Policy 
9.3.4.1 Subjects 
In general, subjects that prematurely discontinue from the study for any reason will not be replaced. 
An exception may be made for subjects who are unevaluable due to the impact of the COVID-19 
pandemic and associated restrictions on movement and work. Subjects unable to receive treatment 
or be evaluated due to restrictions during the COVID-19 pandemic may be replaced, at the 

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discretion of the sponsor. This may result in more subjects than originally planned being enrolled 
into the study to allow for the originally planned number to be evaluable for the primary efficacy 
analysis. 
9.3.4.2 Centers 
A center may be closed and/or replaced for the following administrative reasons:  
 Excessively slow recruitment. 
 Poor protocol adherence. 
9.3.4.3 Screen Failures 
Subjects who do not meet all of the inclusion criteria or meet any of the exclusion criteria between 
Screening and randomization at Week -4 will be considered screen failures. Subjects who do not 
meet all of the inclusion criteria or meet any of the exclusion criteria will be considered screen 
failures. Screen failures may be allowed to rescreen, or retest laboratories for the study if both the 
Investigator and Sponsor are in agreement regarding rescreening/retesting and if the Investigator 
determines that they can satisfy all of the eligibility criteria.  
9.4 
Treatments 
9.4.1 Treatments Administered 
During the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit), all subjects will 
take MTX 15 mg orally weekly. 
At the Week -4 visit, subjects who tolerated MTX will be randomized to receive MTX 15 mg or 
placebo for MTX orally weekly. Subjects will take the blinded MTX or placebo for MTX during 
the Run-in Period (from Week -4 to Day 1) at the 15 mg MTX dose or placebo for MTX dose.  
During the Pegloticase + IMM Period, all subjects will receive pegloticase at a dose of 8 mg 
administered IV every 2 weeks for a total of 26 infusions from Day 1 through the Week 50 Visit. 
Subjects will continue taking MTX or placebo for MTX weekly on the same day each week, within 
1 to 3 days prior to each pegloticase infusion and one additional weekly dose after the last infusion 
for subjects who have not stopped pegloticase due to sUA stopping rules.  
After the Week 52 Visit (or End of Pegloticase Infusion Visit [if applicable]), subjects should 
resume regular care for gout per the judgment of the treating physician, including resumption of 
ULT upon pegloticase discontinuation, if appropriate. Subjects will have a 3 and 6 Month Follow-
up visit to assess clinical status, including sUA levels. 
9.4.1.1 Folic Acid 
Subjects will take folic acid 1 mg orally every day beginning at Week -6 (the start of MTX) until 
prior to the Week 52 Visit. 
If the subject discontinues pegloticase due to the stopping rules or other reason, MTX/placebo for 
MTX should also be discontinued; as such, the subject will discontinue folic acid as well.  

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Prescriptions are to be filled at a local pharmacy, as needed. At study visits, the subject will be 
asked a Yes/No question whether folic acid was taken per protocol. 
9.4.1.2 Gout Flare Prophylaxis 
It is required that before a subject begins the pegloticase + IMM Period, he or she has been taking at 
least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or non-steroidal 
anti-inflammatory drugs and/or low-dose prednisone ≤10 mg/day) for ≥1 week before the first dose 
of pegloticase and continues flare prophylaxis per American College of Rheumatology guidelines 
[Khanna D et al. 2012] for the greater of 1) 6 months, 2) 3 months after achieving target serum 
urate (sUA < 6 mg/dL) for patients with no tophi detected on physical exam, or 3) 6 months after 
achieving target serum urate (sUA < 5 mg/dL) for patients with one or more tophi detected on 
initial physical exam that have since resolved.  
Prescriptions are to be filled at a local pharmacy, as needed. At study visits, the subject will be 
asked a Yes/No question whether gout flare prophylaxis was taken per protocol. 
9.4.1.3 Infusion Reaction Prophylaxis 
Since IRs can occur with pegloticase, all subjects will receive IR prophylaxis prior to each infusion, 
consisting of an antihistamine, acetaminophen, and a corticosteroid. To standardize this regimen, 
subjects will receive fexofenadine (180 mg orally) the day before each infusion; fexofenadine (180 
mg orally) and acetaminophen (1000 mg orally) the morning of each infusion; and 
methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, 
immediately prior to each infusion. Substitution of the corticosteroid is not allowed. The name, 
dose, route, date, and time of administration of each prophylactic medication will be recorded in the 
medical record and in the eCRF. The methylprednisolone used for IR prophylaxis will be supplied 
by the site. Other IR medications administered prior to each infusion may also be supplied by the 
site.  
Prescriptions are to be filled at a local pharmacy, as needed. At study visits, the subject will be 
asked a Yes/No question whether IR prophylaxis was taken per protocol.  
As a precaution, emergency equipment will be readily available to treat a possible hypersensitivity 
reaction, and will include drugs that would be used to treat an anaphylactic reaction. Personnel 
trained in managing IRs and, in the use of the emergency equipment will be readily available 
during, and for 1 hour after, the infusion. As IRs can occur after the completion of the infusion, 
subjects will be observed for 1 hour post-infusion. 
9.4.2 Identity of Investigational Products 
9.4.2.1 Pegloticase 
Pegloticase is a clear, colorless, sterile solution in phosphate-buffered saline intended for IV 
infusion after dilution. Each mL of pegloticase contains 8 mg of uricase protein conjugated to 24 
mg of 10 kDa monomethoxypoly (ethylene glycol). Excipients include disodium hydrogen 
phosphate dihydrate, sodium chloride, sodium dihydrogen phosphate dihydrate, and water for 
injection. 

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9.4.2.2 Methotrexate and Placebo for Methotrexate 
MTX 2.5 mg tablets for oral administration during the MTX Tolerability Assessment Period (Week 
-6 through Week -4) will be provided to subjects as a commercially available generic. 
MTX 2.5 mg tablets for oral administration during the Run-In Period (Week -4 through Day 1) and 
the Pegloticase + IMM Period (Day 1 through Week 52) will be provided to subjects as a 
methotrexate 2.5 mg tablet over-encapsulated in a size zero Swedish Orange capsule.   
Placebo for methotrexate 2.5 mg for oral administration during the Run-In Period (Week -4 through 
Day 1) and the Pegloticase + IMM Period (Day 1 through Week 52) will be provided as a size zero 
Swedish Orange capsule with Avicel® filling. 
A dosing calendar will be provided to subjects at the Week -6 Visit to record each dose of MTX or 
placebo for MTX and the date and time of each dose on each calendar day of MTX or placebo for 
MTX administration. 
See MTX Full Prescribing Information for additional detail.  
9.4.3 Labeling 
Pegloticase (KRYSTEXXA) is commercially available in the United States and will be supplied by 
PCI Pharma Services packaged in sterile, single-use 2-mL glass vials with a Teflon®-coated 
(latex-free) rubber injection stopper to deliver pegloticase as 8 mg of uricase protein in 1 mL 
volume. An ancillary label will be fixed to the vial and carton that identifies the study, allows 
subject information to be entered, and contains the investigational use caution statement according 
to the FDA Title 21 CFR Part 312 requirements. Each vial label will have a unique number. 
MTX for use during the MTX Tolerability Assessment will be provided to sites by PCI Pharma 
Services as tablets in bottles. An ancillary label will be fixed to the bottle that identifies the study, 
allows subject information to be entered, and contains the investigational use caution statement 
according to the FDA Title 21 CFR Part 312 requirements. Each bottle and carton (if applicable) 
label will have a unique number. Bottles will be provided to study subjects at the Week -6 Visit for 
weekly dosing after visit procedures and inclusion/exclusion criteria are confirmed. 
Over-encapsulated MTX or placebo for MTX for use during the Run-in and Pegloticase + IMM 
Period will be provided to sites by PCI Pharma Services as capsules in bottles. A clinical label will 
be fixed to the bottle that identifies the study, allows subject information to be entered, and contains 
the investigational use caution statement according to the FDA Title 21 CFR Part 312 requirements. 
Each bottle label will have a unique number. Bottles will be provided to study subjects after the 
Week -4 Visit for weekly dosing after visit procedures and randomization are confirmed. 
9.4.4 Storage 
Before preparation for use, pegloticase will be stored in the carton, maintained under refrigeration 
between 2ºC and 8ºC (36ºF and 46ºF), protected from light, and will not be shaken or frozen. 
Pegloticase diluted in infusion bags is stable for 4 hours at 2°C to 8°C (36°F to 46°F) and for 4 
hours at room temperature (20°C to 25°C, 68°F to 77°F). 

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MTX tablets and capsules and placebo for MTX capsules will be stored between 20°C to 25°C 
(68°F to 77°F) and protected from light. 
9.4.5 Drug Accountability 
Clinical supplies will be dispensed only in accordance with the protocol. Accurate records of the 
clinical supplies received, the amount dispensed for each subject, and the amount remaining at the 
conclusion of the study will be maintained. Each study site will also maintain individual subject 
drug logs/electronic logs to account for MTX tablets (dispensed for the MTX Tolerability 
Assessment Period) and MTX or placebo for MTX capsules (dispensed for the Run-in and 
Pegloticase + IMM Period) and subject compliance will be monitored by the site at each visit (see 
Section 9.4.11). 
Subjects will bring the MTX or placebo for MTX dosing calendar to each study visit for assessment 
of compliance. Subjects will bring the MTX or placebo for MTX bottle to each visit for a 
compliance check by the site. The site will manually count the tablets/capsules and re-dispense the 
bottle to the subject. At the end of the study or if the subject prematurely discontinues the study, the 
subjects will return any unused or partially used study drugs to the site. 
Investigational clinical supplies will be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the Investigator and 
designated assistants have access.  
Please reference the Study Pharmacy Manual for more detailed information on MTX, placebo for 
MTX and pegloticase packaging, labeling, storage, and destruction. 
9.4.6 Study Drug Administration and Timing of Dose for each Subject 
9.4.6.1 Description of Clinical Supplies 
 will supply study drugs (pegloticase, MTX and placebo for MTX) to clinical 
sites. Ancillary supplies for dosing will be provided by the study site (i.e., infusion bags containing 
saline, syringes, needles, alcohol swabs, gauze pads, bandages, and biohazard containers for safe 
storage of used needles and syringes). 
9.4.6.2 Determination of Dose Volume  
Pegloticase will be administered as an admixture of 8 mg in 250 mL of 0.45% or 0.9% Sodium 
Chloride Injection, United States Pharmacopeia (USP) for IV infusion.  
In the event of an IR, the infusion should be slowed, or stopped, and restarted at a slower rate at the 
discretion of the Investigator. Infusions subsequent to an IR in an individual subject may be given 
in a larger volume of diluent, not to exceed 500 mL. In this case, the infusion duration will also be 
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9.4.6.3 Details Concerning Timing and Dose Administration 
9.4.6.3.1 Preparation and Administration 
9.4.6.3.1.1 Preparation 
Vials of pegloticase will be visually inspected for particulate matter and discoloration before 
administration, whenever solution and container permit. Vials will not be used if either is present. 
Using appropriate aseptic technique, 1 mL of pegloticase will be withdrawn from the vial into a 
sterile syringe. Any unused portion of product remaining in the vial will be discarded. Syringe 
contents will be injected into a single 250 mL bag of 0.45% or 0.9% Sodium Chloride Injection, 
USP for IV infusion and will not be mixed or diluted with other drugs. The infusion bag containing 
the dilute pegloticase solution will be inverted a number of times to ensure thorough mixing but will 
not be shaken. In accordance with good pharmacy practice, gloves will be worn during preparation 
of the dose. 
Pegloticase must be started within 4 hours of dilution. Before administration, the diluted solution of 
pegloticase will be allowed to reach room temperature. Pegloticase must never be subjected to 
artificial heating. 
9.4.6.3.1.2 Dose and Administration 
Methotrexate 
During the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit), all subjects will 
take MTX 15 mg orally weekly.  
At the Week -4 visit, subjects who tolerated methotrexate will be randomized to receive MTX 15 
mg or placebo for MTX orally weekly. Subjects will be blinded to MTX or placebo for MTX 
beginning at Week -4 through the remainder of the study. Subjects will continue to take the blinded 
MTX or placebo for MTX during the Run-in Period (from Week -4 to Day 1) at the 15 mg MTX 
dose or placebo for MTX dose. Investigators may choose to have subjects take the weekly dose 
divided over the day (i.e. BID, TID). If a subject does not tolerate the 15 mg MTX or placebo for 
MTX dose after randomization at the Week -4 Visit and prior to Day 1, the MTX or placebo for 
MTX may be dose-reduced or discontinued based on pre-specified criteria and after discussion with 
the Sponsor medical monitor. The subject will be allowed to remain in the study. After Day 1, MTX 
or placebo for MTX may be re-initiated. The subject will be re-initiated to the same treatment they 
were randomized to at Week -4, however the dose may be adjusted (See Section 9.4.6.3.2.2).  The 
re-initiated MTX or placebo for MTX will remain blinded to the subject. During the Run-in Period, 
if a dose is missed, it should be taken as soon as it is remembered. If it is within 48 hours of the next 
scheduled dose, the subject will be instructed to skip the missed dose and resume at the next 
regularly scheduled time; thus, subjects will be instructed not to double a dose to make up for a 
missed dose if within 48 hours of the next dose. 
During the Pegloticase + IMM Period, subjects will be instructed to take MTX or placebo for MTX 
weekly on the same day each week, within 1 to 3 days prior to each pegloticase infusion and one 
additional weekly dose after the last infusion for subjects who have not stopped pegloticase due to 

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sUA stopping rules; however, if a subject does not do so, MTX or placebo for MTX must be taken 
≥60 minutes prior to each pegloticase infusion. Investigators may choose to have subjects take the 
weekly dose divided over the day (i.e. BID, TID). The total MTX or placebo for MTX dose should 
be taken within 24 hours, preferably the same calendar day each week, with the date and time of 
each dose recorded in the dosing calendar. If a subject becomes unable to tolerate the MTX or 
placebo for MTX during the Pegloticase + IMM Period, the dosage may be decreased. 
Refer to Section 9.4.12 for contraception requirements.  
Subjects will take folic acid 1 mg orally every day beginning at Week -6 (the start of MTX) until 
prior to the Week 52 Visit.  
Due to the recent availability of several effective vaccines for COVID-19, study subjects may elect 
to be vaccinated.  The American College of Rheumatology (ACR) has issued guidelines on the use 
of immunomodulatory therapy such as MTX in subjects who receive COVID-19 vaccines [Mikuls 
TR et al., 2020a; 2020b; 2021; ACR COVID-19 Vaccine Clinical Guidance Task Force, 2021].  
This guidance should be referenced and followed for subjects who are vaccinated for COVID-19 
while on study and treated with MTX or placebo for MTX.  Due to the rapidly expanding 
information and evolving evidence related to COVID-19, which may lead to modification of some 
guidance statements over time, updated versions of this guidance will be published, with the version 
number included in the title. Investigators should ensure that they are consulting the most current 
version. 
Pegloticase 
All subjects will receive pegloticase at the same dose of 8 mg administered IV every 2 weeks for a 
total of 26 infusions from Day 1 through the Week 50 Visit (Pegloticase + IMM Period). Subjects 
will not be fasting on the day of infusion and will be encouraged to have a snack or normal meal 
before or after the infusion. Pre-infusion sUA results must be reported by the local or central 
laboratory prior to pegloticase infusion (see Section 9.5.1.1). 
Standardized IR prophylaxis consisting of pre-treatment with antihistamines, acetaminophen, and 
corticosteroids will accompany each infusion (see Section 9.4.1.3). The drug name, dose, and 
timing of these prophylactic medications will be recorded. 
Pegloticase will be administered as an admixture of 8 mg in 250 mL of 0.45% or 0.9% Sodium 
Chloride Injection, USP for IV infusion by gravity feed or infusion pump. Pegloticase will not be 
administered as an IV push or bolus. 
In a patent IV site, using tubing with no in-line filter, the pegloticase preparation will be infused 
over approximately 120 ±15 minutes while the subject is under close observation for any signs of 
distress. If an in-line filter is used, it should be 0.2 µm or larger. At the end of the infusion, the IV 
line will be flushed with 10 mL of normal saline to ensure the full dose is administered. The date 
and time of infusion start and stop (inclusive of the IV flush) will be recorded.  

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9.4.6.3.2 Dose Modifications, Interruptions, and Delays 
9.4.6.3.2.1 Pegloticase Modifications 
Infusion of pegloticase will be immediately held if the subject experiences any significant IR such 
as respiratory distress, agitation, chest or back pain, urticaria, or another clinically significant event 
occurring during infusion. If the AE meets the definition of an SAE for IR, the infusion should not 
be restarted unless the site Investigator determines it is safe to resume the infusion. If the AE does 
not meet the definition of an SAE for IR, the site Investigator may make the decision to re-start the 
infusion depending upon the nature and severity of the AE.  
Infusions subsequent to an IR in an individual subject may be given in a larger volume of diluent, 
not to exceed 500 mL. In this case, the infusion duration will also be extended to a minimum of 3 
hours. The total volume and duration of infusion will be captured in the medical record and eCRF. 
Infusion of pegloticase may be held or delayed if the subject has an ongoing SAE or AE/SAE that 
occurs just prior to the infusion. The status of subjects with skipped infusions will be discussed with 
the Investigator and the Sponsor’s Medical Monitor on a case-by-case basis to determine whether 
the subject should continue to the next scheduled infusion or proceed to the End of Pegloticase 
Visit. 
9.4.6.3.2.2 MTX/Placebo for MTX Dose Titration Algorithm and Intolerance Criteria  
During the MTX Tolerability Assessment Period subjects will be considered a screen failure if any 
of the following new laboratory findings or symptoms reflecting MTX intolerance occur: 
1. Abnormal Hematology findings: 
a. WBC < 3.5 x 109/L 
b. Platelets < 75 x 109/L 
c. Hematocrit < 32% 
2. Abnormal hepatic function findings: 
a. AST/ALT >1.5 x upper limit of reference range and  
b. Albumin < lower limit of reference range 
3. Abnormal renal function: eGFR <30ml/min/1.73 m2 (as estimated with the MDRD 
equation).  
4. New clinically important signs and symptoms, such as the following: 
a. Rash or oral ulceration 
b. Persistent nausea, vomiting and diarrhea  
c. New or increasing dyspnea or dry cough, or unexplained cough with fever  
d. Severe sore throat, abnormal bruising  
e. Severe headaches, fatigue, and problems concentrating  
Note that repeat laboratory tests may be needed to confirm these new findings. In addition, if minor 
clinical symptoms emerge, such as mild stomatitis, mild GI discomfort, etc., the investigator may 
increase folic acid dose (e.g. 2 mg daily) or recommend a divided dose of MTX (e.g. 3 tabs of 2.5 

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mg in the morning and evening on the day of dosing); if symptoms improve, the subject will not be 
considered a screen failure on the basis of that symptom. 
During the Run-In and Pegloticase+IMM Period, MTX or placebo for MTX dose guidance based 
on new laboratory findings or new symptoms is as follows: 
Lab Parameters 
Value 
MTX or placebo for MTX 
Dose Change 
WBC 
3.0 x 109/L ~ 3.5 x 109/L 
Decrease to 10 mg 
< 3.0 x 109/L 
Temporary stop 
Platelets 
< 50 x 109/L 
Temporary stop 
Hematocrit 
< 27% 
Temporary stop 
AST/ALT 
Between 1.5 ~ 2 x ULN 
Decrease to 10 mg 
                    > 2 x ULN  
Temporary stop 
                         eGFR 
< 30 ml/min/1.73 m2 
Temporary stop 
New clinically important 
symptoms/signs* 
Yes 
Temporary stop 
* New clinically important symptoms or important medical events: 
a. Rash or oral ulceration  
b. Persistent nausea, vomiting and diarrhea  
c. New or increasing dyspnea or dry cough, or unexplained cough with fever  
d. Severe sore throat, abnormal bruising  
e. Severe headaches, fatigue, and problems concentrating 
f. Any other important medical events that might increase methotrexate toxicity or pre-
dispose to new or worsening infection (e.g. undergoing surgery, hospitalization, 
being treated with antibiotics, having a clinical infection, developing new clinically 
significant pericardial / pleural effusion or ascites) 
Note that if minor clinical symptoms emerge, such as mild stomatitis, mild GI discomfort, etc., the 
investigator may increase folic acid dose to 2 mg daily or recommend a divided dose of MTX or 
placebo for MTX (e.g. 3 tabs of 2.5 mg in the morning and evening on the day of dosing) and 
monitor for symptom resolution. 
Investigators should discuss the emergence of any one of the following criteria with the medical 
monitor to review the case: 

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1. ALT/AST > 1.5 x ULN on 3 of any 5 consecutive measures  
2. Albumin < 0.8 x LLN on 2 consecutive measures 
3. Any laboratory or clinical symptoms leading to temporary stop on 3 consecutive measures, 
in which case the medical monitor will review to consider re-initiation, a continued 
temporary stop, or a permanent stop in discussion with the PI. 
Guidance for increasing MTX or placebo for MTX back towards 15 mg after dose reduction, based 
on improvement or resolution of abnormal liver enzymes (>2 × upper limit of normal): 
1. When liver enzymes return to values ≤1.5 × upper limit of normal, increase MTX or placebo 
for MTX dose by 2.5 mg and reassess in 2 weeks. 
2. If liver enzymes remain ≤1.5 × upper limit of normal, increase MTX or placebo for MTX 
dose by 2.5 mg and reassess in 2 weeks. 
Improvement of other laboratory abnormalities potentially attributed to MTX or placebo for MTX 
may also warrant titration back up to 15 mg weekly, based on PI judgement and in discussion with 
the Sponsor medical monitor. 
9.4.6.3.2.3 Gout Flare Treatment 
An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, 
including pegloticase. Subjects will be instructed to contact the site within 12 hours of the onset of 
symptoms. Gout flares will be confirmed through questioning or direct observation, as detailed in 
Section 9.5.4.8. All subjects who experience a gout flare during the study will be prescribed anti-
inflammatory treatment (e.g., NSAID, colchicine, corticosteroids and intra-articular steroid 
injections), as is clinically indicated or deemed necessary on an individual basis at the discretion of 
the investigator. Pain medications for gout flare should be administered according to standard of 
care as is clinically indicated or deemed necessary on an individual basis at the discretion of the 
investigator.  All medications should be documented on the concomitant medication eCRF. 
Colchicine will be prescribed in a medically appropriate dose range of 0.6 to 1.8 mg/day, usually 
dosed as 0.6 mg orally twice per day unless reduced dosing is necessitated by renal insufficiency or 
gastrointestinal intolerance. The precise dose and regimen of colchicine will be individualized for 
each subject by the Investigators and documented on the concomitant medication eCRF. 
9.4.6.3.2.4 Infusion Reaction Treatment 
Subjects must be monitored closely for signs and symptoms of IRs. In the event of an IR, the 
infusion should be slowed, or stopped, and restarted at a slower rate at the discretion of the 
Investigator. If a serious IR occurs, the infusion should be discontinued and treatment should be 
provided, as needed.  
If a subject experiences an AE suspected to be an IR:  
 A physical examination will be performed to capture medically relevant details, including, 
but not limited to, a thorough dermatologic examination for detection of erythema, urticaria 
(hives), or peri-oral or lingual edema; a chest examination for breath sounds, stridor or 
wheezing; and a cardiac examination with attention to irregular heartbeat. 

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 Vital signs (sitting or supine blood pressure, heart rate, respiratory rate, and body 
temperature) will be captured at least every 30 minutes until the resolution or stabilization of 
the AE. 
 A serum sample will be collected in a serum-separating tube at that time or at the subsequent 
visit. The sample will be centrifuged, frozen at -20°C or colder, and stored for the batch 
shipment to a Horizon designated laboratory for evaluation of pegloticase antibodies at a 
future date. 
 When possible, a 12-lead ECG will also be performed at the time of infusion reaction.  
If, in the Investigator’s opinion, the subject is experiencing an anaphylactic reaction (see 
Section 9.5.4.1.1.5), pegloticase should be immediately discontinued. Any incidence of anaphylaxis 
should be reported as an SAE. 
The Investigator may administer any medically indicated pharmacologic agent or procedure 
intended to relieve symptoms (CAUTION: no other drugs can be mixed in the pegloticase infusion 
bag). Signs and symptoms of the AE and drugs given for treatment are to be recorded in the medical 
record and in the eCRF. 
After the first incidence of an IR that does not meet the criteria of anaphylaxis (see 
Section 9.5.4.1.1.5) or does not meet serious criteria, the Investigator may elect to initiate the next 
infusion at a slower rate. Additionally, the Investigator may choose to prescribe 20 mg prednisone 
to be taken in the morning of the next infusion. All changes to infusion rate or dilution, and drugs 
given for prophylaxis or treatment, are to be recorded in the medical record and in the eCRF. 
9.4.7 Method of Assigning Subjects to Treatment Groups 
Medidata Randomization and Trial Supply Management (RTSM) will be used to randomly assign 
subjects in a ratio of 2:1 (stratified by presence of tophi) to receive MTX in combination with 
pegloticase or placebo for MTX in combination with pegloticase.   
Specific procedures for randomization through Medidata are contained in the study procedures 
manual.  
9.4.8 Blinding 
Pegloticase 
Because all subjects will receive pegloticase, this study drug will be administered without blinding 
to pegloticase administration, and all subjects, investigators and site personnel will know that all 
subjects are receiving pegloticase. 
Methotrexate 
The Sponsor, Investigator, study site personnel and study subject will remain blinded to each 
subject’s treatment assignment (MTX or placebo for MTX).  RTSM will provide access to blinded 
subject treatment information during the study in the case of medical emergency.  The study blind 

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should be broken only if the safety of a subject is at risk and the treatment plan depends on which 
medication (MTX or placebo for MTX) he or she received. Unless the subject is at immediate risk, 
the Investigator must make diligent attempts to contact the Sponsor or Sponsor’s designee before 
unblinding the subject’s data. If a subject’s data are unblinded without prior knowledge of the 
Sponsor, the Investigator must notify the Sponsor as soon as possible and no later than the next 
business day. All circumstances surrounding the event must be clearly documented.  
The Sponsor’s Pharmacovigilance department or designee will unblind the identity of the study 
medication for an unexpected, drug-related SAE (related to MTX or placebo for MTX only) for 
submission to health authorities and IRB/IEC according to applicable regulatory requirements. 
However, the results will not be shared with other Sponsor representatives or staff at study sites. 
Details of subjects who are unblinded during the study will be included in the Clinical Study 
Report. 
Unblinding for independent pharmacological analysis of biological samples or SAE reporting will 
be performed according to procedures in place to ensure integrity of the data.  
The date and the reason that the blind was broken must be recorded.  
Unblinding of Data for the Data Monitoring Committee (DMC) 
The external DMC will oversee and interpret safety and efficacy data per a pre-defined charter. The 
external statistical vendor will provide unblinded results for the DMC review, while maintaining the 
Sponsor blind. 
All investigative site staff directly involved in this study will remain blinded from randomization 
through analysis of the final data and all site close-out visits, except for emergency unblinding as 
described in Section 9.4.8. The Sponsor and its designees will remain blinded until after the 
database lock for the primary analysis following completion of all subjects in the Pegloticase + 
IMM treatment period unless directed otherwise by the DMC. 
9.4.9 Prior and Concomitant Therapy  
Medication history (i.e., prior medications) will include all prior gout medications, starting at the 
time of diagnosis and up to the Screening Visit, and all other medications taken from 1 year prior to 
the Screening Visit.  
Concomitant medications are defined as drug or biological products other than the study drugs (or 
prior gout medications) taken by a subject from Screening through the Post Treatment Follow-up 
Visits. This includes other prescription medications (including preventive vaccines), over the 
counter medications, herbal medications, vitamins, and food supplements. 
Information about prior and concomitant medications, including those used for any duration to treat 
an AE, will be collected on source documents and the appropriate eCRFs at each visit. The generic 
name of the medication, indication, dose, unit, frequency, route of administration, and start and stop 
dates will be recorded. 

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Subjects will be directed to discontinue current urate-lowering therapy prior to initiation of 
pegloticase therapy as per the current package insert. Other medications used at the time of study 
initiation may be continued at the discretion of the Investigator.  
9.4.10 Restricted Medications 
Subjects should not receive the following medications for at least 7 days prior to MTX dosing at 
Week-6 and remain off when receiving pegloticase infusions:  
 Oral urate-lowering therapies including allopurinol, febuxostat, probenecid, lesinurad, or 
other ULT for gout. Re-introduction of oral ULT’s should not start until after the End of 
Pegloticase Visit (or End of Study) laboratory tests are collected. 
Subjects should not receive the following medications from the time of Screening through the end 
of pegloticase and MTX or placebo for MTX treatment: 
 Any PEG-conjugated drug 
 Any other investigational agent 
 Any methotrexate other than the study approved investigational product, azathioprine, 
mycophenolate mofetil, or other systemic immunosuppressants aside from glucocorticoids 
for gout flare prophylaxis (≤ 10 mg prednisone or equivalent per day) or intermittent gout 
flare treatment 
 If a subject is treated with antibiotics, refer to Section 9.4.6.3.2.2. 
 
9.4.11 Treatment Compliance 
A dosing calendar will be provided to subjects at the Week -6 Visit for recording the dose/s of 
MTX/placebo for MTX and the date and time of each dose on each calendar day of MTX/placebo 
for MTX administration. The dosing calendar and bottle of MTX/placebo for MTX should be 
brought to each study visit for assessment of compliance. Adherence to the MTX/placebo for MTX 
regimen will also be recorded by the study coordinator at study visits in the eCRF by recording the 
date of each MTX/placebo for MTX dose (mg), frequency and time of each dose per calendar day. 
Subjects who have taken at least 80% of the protocol-specified amount of MTX/placebo for MTX 
will be considered compliant. Noncompliant subjects will be re-educated on compliance.  
At study visits, the subject will be asked a Yes/No question whether folic acid, gout flare, and IR 
prophylaxis were administered. 
Pegloticase will be administered at the study site by trained personnel. The date and time of 
infusion start and stop (inclusive of the 10-mL flush) will be recorded. 
9.4.12 Contraception Requirements 
Women of childbearing potential (including those with an onset of menopause <2 years prior to 
screening, non-therapy-induced amenorrhea for <12 months prior to screening, or not surgically 

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sterile [absence of ovaries and/or uterus]) must agree to use 2 reliable forms of contraception during 
the study, one of which is recommended to be hormonal, such as an oral contraceptive.  
Hormonal contraception must be started ≥1 full cycle prior to Week -6 (start of MTX) and continue 
for 30 days after the last dose of pegloticase, or at least one ovulatory cycle after the last dose of 
MTX or placebo for MTX (whichever is the longest duration after the last dose of pegloticase or 
MTX or placebo for MTX). Highly effective contraceptive methods (with a failure rate <1% per 
year), when used consistently and correctly, include implants, injectables, combined oral 
contraceptives, some intrauterine devices, sexual abstinence, or vasectomized partner 
Men who are not vasectomized must agree to use appropriate contraception so as to not impregnate 
their female partner during the study and for at least 3 months after the last dose of MTX or placebo 
for MTX. Men must agree to use appropriate contraception from Week -6 through 3 months post 
the last dose of MTX or placebo for MTX. Appropriate contraception methods include condom use 
and abstinence. 
9.5 
Efficacy, Quality-of-Life, Pharmacokinetic, and Safety Variables 
The Schedule of Assessments is provided in Section 2.1. 
9.5.1 Efficacy Variables 
Efficacy will be assessed based on measurement of sUA levels, tophus resolution, tophus size, 
tender and swollen joint counts, patient and physician global assessments of gout, joint pain, and 
DECT and X-ray of hands and feet. 
9.5.1.1 Serum Uric Acid 
Serum samples for measurement of sUA levels will be collected at the Screening Visit, the Week -6 
Visit (prior to the first dose of MTX), the Week -4 Visit (Randomization) and the Week -2 Visit 
during the Run-in Period. On Day 1, a pre-infusion and post infusion sUA will be collected to be 
shipped to the Central laboratory.  For the remainder of study visits beginning at Week 2 during the 
Pegloticase +IMM period; 2 Serum Uric Acid samples will be collected within 48 hours PRIOR to 
each pegloticase infusion.  One sample will be for testing at the site’s local laboratory for sUA 
levels and the second sample will be sent to the Central Laboratory. A post infusion sUA blood 
sample will additionally be collected on Day 1, and at the Weeks 2, 6, 10, 12, 14, 20, 22, 24, 32, 34, 
36, 48 and 50 for same day shipment to the Central Laboratory.  Additional serum samples for sUA 
levels will be collected at non-infusion Visits at Weeks 21 and 23 and the End of Pegloticase 
Infusions Visit (if applicable) and the Week 52/End of study/Early Termination Visit and 3 and 6 
month Follow-up Visits. Subjects with an sUA level >6 mg/dL at 2 consecutive study visits 
beginning with the Week 2 Visit will discontinue pegloticase and complete the End of Pegloticase 
Infusions Visit (if applicable) or the Week 52/End of study/Early Termination Visit procedures.   
A subject with an sUA level >6 mg/dL (based on the local or central laboratory) at 2 consecutive 
study visits, beginning with the Week 2 Visit, will be discontinued from pegloticase treatment. 

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Samples that result in discordant results between local and central laboratories will be evaluated and 
discussed with the Investigator and the Sponsor’s Medical Monitor on a case-by-case basis to 
determine whether the subject should continue on study or proceed to the End of Pegloticase 
Infusions Visit.  
If a situation arises where a local sUA result cannot be obtained within 48 hours of the infusion 
(beginning at Week 2), the Sponsor medical monitor will be consulted to obtain approval prior to 
proceeding the planned infusion. The pre-infusion sUA sample for the local laboratory should still 
be collected if possible prior to the infusion.   
To Note:  if a subject’s previous visit sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time as the 
sample to send to the central laboratory;  however if the prior visit sUA sample was greater than 6 
mg/dl (local or central laboratory), a local sUA sample will need to be collected and read out prior 
to the pegloticase infusion to be certain the subject has not met the stopping rule.   
9.5.1.2 Tender and Swollen Joint Counts 
Tender and swollen (excludes hip) joint counts will be recorded at the Week -6 Visit (prior to the 
first dose of MTX); prior to pegloticase infusion at the Day 1 and Weeks 6, 14, 20, 24, 30, 36 and 
44 Visits during the pegloticase + IMM Period; and at the End of Pegloticase Infusions Visit (if 
applicable) and the Week 52/End of Study/Early Termination Visit (Section 2.1). 
Tender and swollen joint counts assessed by physical examination and documented using the 
rheumatoid arthritis 66-68 method shown in Figure 9.2 or other site source document.  All 
information will be entered into the appropriate eCRF.  

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Figure 9.2 
Rheumatoid Arthritis 66-68 Tender and Swollen Joint Counts 
 
9.5.1.3 Physician Global Assessment 
The physician global assessment will be collected at the Screening and Week -6 (prior to the first 
dose of MTX) Visits; prior to pegloticase infusion at the Day 1 and Week 6, 14, 20, 24, 30,36 and 
44 Visits during the Pegloticase + IMM Period; and at the End of Pegloticase Infusions Visit (if 
applicable) and the Week 52/End of Study/Early Termination Visit (Section 2.1). The physician 
will respond to the statement, “Considering the subject’s overall health related to gout, rate their 
gout overall” using a numeric rating scale ranging from 0 (excellent) to 10 (very poor) (see 
Appendix 17.3).  
For a given subject, if possible, the same qualified Investigator should perform the assessment at 
each time point. 
9.5.1.4 Dual-energy Computed Tomography (DECT) 
For sites with DECT capability, and subjects who provide consent, an optional DECT (hands, feet, 
knees and other anatomical areas as clinically indicated) will be obtained at Day 1 and Weeks 14, 
24 and at the End of Pegloticase Infusions Visit (if applicable) and the Week 52/End of Study/Early 
Termination Visit and the 6 month Post Treatment Follow-up Visit for subjects that completed 52 
weeks of treatment and consent to the additional assessment.  The DECT on Day 1 must be 
completed prior to the infusion and may be completed within the 14 days prior to Day 1.  The 
DECT at all other scheduled timepoints may be completed within +/- 10 days of the scheduled 
timepoint.   

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Subjects who end pegloticase infusions prior to Week 52 should follow the scheduled timepoints 
but avoid a repeat DECT scan within 6 weeks of a prior scan (detailed guidance is provided with the 
imaging manual).  
The imaging will be performed by a study-specific, qualified radiologist. 
9.5.1.5 X-ray of Hands and Feet 
For sites with X-ray capability, and subjects who provide consent, an optional X-ray of the hands 
and feet will be obtained at Day 1, Week 24 and End of Pegloticase Infusions Visit (if applicable) 
and Week 52/End of Study/Early Termination Visit. The X-ray on Day 1 must be completed prior 
to the infusion and may be completed within the 14 days prior to Day 1.  The X-ray at all other 
scheduled timepoints may be completed within +/- 10 days of the scheduled timepoint.   
Subjects who end pegloticase infusions prior to Week 52 should follow the scheduled timepoints 
but avoid a repeat X-ray within 3 months of a prior X-ray (detailed guidance is provided with the 
imaging manual). 
9.5.1.6 Digital Photography  
Digital photography of the hands and feet will be completed at Week -6, Day 1 and Weeks 14, 24, 
36, and the End of Pegloticase Infusions Visit (if applicable) and Week 52/End of Study/Early 
Termination and the 3 and 6 month Post Treatment Follow-up Visits. Other anatomical sites with 
large tophi may be photographed in addition to the hands and feet at the Investigator’s discretion.    
The sponsor or designee will provide digital photography equipment to each site for photography of 
the hands and feet.   
Details on the digital photography, including source documentation and eCRF requirements will be 
provided in the Study Reference Binder.  
9.5.1.6.1 Assessment of Individual Tophi Response 
 All measurable tophi will be measured bi-dimensionally (using the longest diameter and the longest 
perpendicular to that diameter) and the response of each individual tophus will be categorized 
according to the change from baseline in area of each tophus at each visit as follows: 
 Complete Response (CR) – A 100% decrease in the area of the tophus 
 Marked Response (MR) – At least a 75% decrease in the area of the tophus 
 Partial Response (PR) – At least a 50% decrease in the area of the tophus 
 Stable Disease (SD) – Neither a 50% decrease nor a 25% increase in the area of the tophus 
can be demonstrated 
 Progressive Disease (PD) – A 25% or more increase in the area of the tophus 
 Unable to Evaluate (UE) –The tophus cannot be accurately measured for any reason at any 
given post-baseline time point (e.g., image missing or of poor quality, obvious infection of 
the tophus). 

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Each individual unmeasured tophus will be semi-quantitatively assessed based upon the impression 
of the central reader using the following guideline: 
 Complete Response - the disappearance of the tophus. 
 Improved - An approximate 50% or more reduction from baseline in the size of the tophus. 
 Stable Disease – Neither improvement nor progression from baseline can be determined 
 Progressive Disease - An approximate 50% or more increase from baseline in the area of the 
tophus. 
 Unable to Evaluate - The tophus cannot be assessed for any reason at any given post-
baseline time point (e.g., image missing or of poor quality, or obvious infection of the 
tophus). 
The overall response for a subject will be based upon the best response among all tophi (including 
measurable and unmeasured) for that subject (e.g., if any one tophus shows complete response, the 
overall response is Complete Response). If any single tophus shows progression, or if a new tophus 
appears during the study, the overall response for that subject will be Progressive Disease, 
regardless of the response of any other tophi. 
9.5.2 Quality of Life Assessment 
The HAQ (Appendix 17.2) including the HAQ-DI, pain and health scales, will be administered at 
the Screening and Week -6 (prior to the first dose of MTX) Visits; prior to pegloticase infusion at 
the Day 1 and Weeks 6, 14, 20, 24, 30, 36 and 44 Visits during the Pegloticase + IMM Period; and 
at the End of Pegloticase Infusions Visit (if applicable), Week 52/End of Study/Early Termination 
and 3 and 6 month Post Treatment Follow-up Visits (Section 2.1).  
The HAQ-DI is a self-report functional status instrument that can be filled out by a subject in less 
than 5 minutes and requires 1 minute to score. The index measures disability over the past week by 
asking a total of 20 questions covering 8 domains of function: dressing and grooming, arising, 
eating, walking, hygiene, reach, grip, and usual activities. There are at least 2 questions in each 
domain and the 8 domains represent a comprehensive set of functional activities. The HAQ-DI is 
calculated by scoring the answer to each question in the HAQ from 0 to 3, with 0 representing the 
ability to do without any difficulty, and 3 representing inability to do. Any activity that requires 
assistance from another individual or requires the use of an assistive device raises a 0 or 1 score to a 
2. The highest score for each of the 8 domains is summed (range from 0 to 24) and divided by 8 to 
yield, on a scale with 25 possible values, a Functional Disability Index with a range from 0 to 3. 
The disability index is based on the number of domains answered and is computed only if the 
subject completes answers to at least 6 domains [Bruce and Fries, 2003]. 
The HAQ pain scale consists of a doubly anchored, horizontal visual analog scale (VAS), that is 
scored from 0 (no pain) to 100 (severe pain). Subjects are asked to rate the severity of the pain they 
have had because of illness in the past week by placing a vertical mark on the VAS. 

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The HAQ health scale consists of a doubly anchored, horizontal VAS, that is scored from 0 (very 
well) to 100 (very poor).  Subjects are asked to rate how well they are doing, considering all the 
ways arthritis affects him or her, by placing a vertical mark on the VAS.     
9.5.3 Pharmacokinetic and Anti-drug Antibody Measurements 
Serum samples for PK analysis of pegloticase will be collected after the end of infusion on Day 1 
(prior to discharge); prior to the pegloticase infusion and after the end of infusion (prior to 
discharge) at the Weeks 2, 6, 14, 21, 24, 36, End of Pegloticase Infusions Visit (if applicable) and 
Week 52/End of Study/Early Termination Visits. Note: Week 21, End of Pegloticase Infusions 
Visit and Week 52/End of Study/Early Termination Visits are non infusion visits. 
Serum samples for evaluation of anti-PEG and anti-uricase IgG antibodies will be collected prior to 
the pegloticase infusion on Day 1 and at the Weeks 2, 6, 14, 22, 24, 36, and at the non-infusion End 
of Pegloticase Infusions Visit (if applicable) or the Week 52/End of Study/Early Termination Visit 
and Month 3 Post Treatment Follow-up Visits.  
Blood samples will be collected prior to the pegloticase infusion on Day 1 and at the Weeks 14, 24 
and 36 Visits during the Pegloticase + IMM Period for MTX Polyglutamate analysis. 
Each sample collection date and time will be recorded in source documents and the eCRF. 
Detailed instructions regarding blood sample timing and handling are provided in the Laboratory 
Manual.  
9.5.3.1 Additional Sample Collection for Future Use 
Optional blood samples for PBMC, RNA isolation and serum will be collected from each 
consenting subject prior to the first dose of MTX at Week -6, prior to the infusion on Day 1 and 
Weeks, 6, 14, 24, 36 and the End of Pegloticase Infusions Visit (if applicable) and the Week 
52/End-of-Study/Early Termination. During visits at Weeks 2, 4, 8, 10 and 12, optional samples 
will only be collected if subjects are experiencing an acute gout flare on the day of visit. 
Subjects may still participate in the study even if they decline to provide consent for the optional 
future use blood samples.    
Samples will be retained for potential future analyses which may include biomarkers relevant to 
gout (e.g. inflammatory markers) or gout co-morbidities in response to pegloticase or other 
potential treatments for gout.  
The samples will be retained no longer than 15 years after study completion or as required by 
applicable law. The samples will be stored in a secured storage space with adequate measures to 
protect confidentiality. 
Detailed instructions regarding blood sample timing and handling are provided in the Laboratory 
Manual.  

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9.5.4 Safety Variables 
Safety will be assessed via AE and concomitant medication use monitoring, physical examinations, 
vital signs, clinical safety laboratory evaluations (complete blood count, chemistry, urine 
albumin:creatinine ratio), pregnancy testing (if applicable), electrocardiograms (ECGs), and AEs of 
special interest (i.e., IRs, anaphylaxis, gout flares, and cardiovascular events).  
9.5.4.1 Adverse Events 
9.5.4.1.1 Definitions 
9.5.4.1.1.1 Adverse Event Definition 
As defined by the ICH, an AE is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product, whether or not the event 
is considered related to the study drug. An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of the study drug. This includes any occurrence that is new in onset or 
aggravated in severity or frequency from the baseline condition, or abnormal results of diagnostic 
procedures, including laboratory test abnormalities.  
Examples of an AE include:  
 Conditions newly detected or diagnosed after the signing of the ICF, including conditions 
that may have been present but undetected prior to the start of the study 
 Conditions known to have been present prior to the start of the study that worsen after the 
signing of the ICF 
 Signs, symptoms, or the clinical sequelae of a suspected drug interaction 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational 
product or a concomitant medication (overdose per se should not be reported as an AE) 
Issues that will not be considered an AE include:  
 Conditions present at the start of the study, should be recorded as medical history 
  Medical or surgical procedures (e.g., endoscopy, appendectomy; however, a condition that 
leads to a procedure is an AE if it qualifies according to the definitions above) 
 Situations where an untoward medical occurrence did not occur (e.g., social, diagnostic, 
elective, or convenience admission to a hospital) 
 Fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the 
study that do not represent a clinically significant change from baseline 
 Abnormal laboratory or test findings that are not assessed by the Investigator as a clinically 
significant change from baseline 
AEs are divided into the categories “serious” and “non-serious.” This determines the procedures 
that must be used to report/document the AE. 
 

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9.5.4.1.1.2 Serious Adverse Event Definition 
Based on ICH guidelines, an SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life threatening 
NOTE: The term ‘life threatening’ in the definition of ‘serious’ refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe, prolonged, or untreated. 
 Requires hospitalization or prolongation of existing hospitalization  
NOTE: Hospitalization signifies that the subject has been admitted to the hospital as an 
inpatient for any length of time. Treatment on an emergency, outpatient basis for an event 
not fulfilling any of the definitions of SAEs and not resulting in hospital admission does not 
qualify for this category, but may be appropriately included in category g (see below). 
Complications that occur during hospitalization are usually AEs. If a complication prolongs 
hospitalization or fulfills any other serious criterion, the event will be considered as serious. 
When in doubt as to whether ‘hospitalization’ occurred, consult the Sponsor’s Medical 
Monitor. 
Hospitalization will not be considered an AE in and of itself. It will be considered an 
outcome of an AE. Therefore, if there is no associated AE, there is no SAE. For example, 
hospitalization for elective or pre-planned treatment of a pre-existing condition that did not 
worsen from baseline will not be considered an AE. 
 Results in persistent or significant disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may temporarily interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Is a suspected transmission of any infectious agent via a medicinal product 
 Is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting as serious is appropriate in other situations; specifically, important medical events 
that may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of the 
other outcomes listed in the above definition. These should usually be considered serious. 
Examples of such events are invasive cancers, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. If in doubt as to whether 

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or not an event qualifies as an ‘important medical event,’ consult the Sponsor’s Medical 
Monitor. 
9.5.4.1.1.3 Non-Serious Adverse Event Definition 
AEs that do not result in any of the outcomes listed in Section 0 are considered non-serious. 
9.5.4.1.1.4 Unexpected Adverse Event Definition 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the Reference 
Safety Information section of the Investigator’s Brochure (for pegloticase) or US Prescribing 
Information (for MTX) or is not listed with the specificity or severity that has been observed. 
Unexpected, as used in this definition, also refers to AEs or suspected adverse reactions that are 
mentioned in the Reference Safety Information as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 
9.5.4.1.1.5 Adverse Events of Special Interest 
AEs of special interest include IRs, anaphylaxis, gout flares, and cardiovascular events. An external 
adjudication committee will adjudicate the AESIs of IR, anaphylaxis and cardiovascular events.   
Infusion Reaction 
An IR will be defined as any infusion-related AE or cluster of temporally-related AEs, not 
attributable to another cause, which occur during the pegloticase infusion and for up to 2 hours post 
infusion. Other AEs that occur outside of the 2-hour window following the infusion may also be 
categorized as an IR at the Principal Investigator’s discretion. Signs and symptoms of the IR and 
treatments administered will be documented in the medical record and in the eCRF, and will be 
adjudicated.  
Examples of AEs not considered possible IRs include, but are not limited to: laboratory 
abnormalities that are unlikely to have occurred during or within 1 hour following the infusion (e.g., 
anemia), gout flares, most infectious diseases, or the recurrence or worsening of a known chronic 
medical problem identified in the subject’s medical history. 
 
 

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Anaphylaxis 
Any incidence of anaphylaxis should be reported as an SAE. Anaphylaxis will be defined using the 
National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network 
criteria [Sampson et al, 2006], and will be adjudicated:  
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives; pruritus or flushing; urticaria, and angioedema (of 
lips, tongue, or uvula) and ≥1 of the following: 
a.  Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia)  
b. Reduced blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
subject (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue, uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia) 
c. Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], 
syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy, abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that subject (minutes to several 
hours): systolic blood pressure <90 mmHg or >30% decrease from that subject’s baseline. 
Gout Flares 
It is common for potent urate-lowering therapies to lead to acute attacks of gout. Gout flares will be 
confirmed through questioning or direct observation detailed in Section 9.5.4.8. 
Cardiovascular Events 
Cardiovascular adverse events will be collected as part of the AE collection.  External adjudication 
will be conducted for major adverse cardiovascular events (MACE) and congestive heart failure. 
Refer to the Adjudication Committee Charter for the detailed definition.    

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9.5.4.1.2 Documentation of Adverse Events 
AE monitoring will begin from the signature of the ICF until the 6 month Post Treatment 
Follow-up Visit. 
SAE monitoring will begin from the signature of the ICF until the 6 month Post Treatment 
Follow-up Visit. 
ASG will conduct a search of Lost to Follow up subjects.  If a subject is confirmed deceased, the 
SAE will be collected if the death occurred within 6 months post treatment.   
Subjects will be questioned about AEs at each study visit, using nonspecific questions, such as 
“How have you been feeling since the last study visit?” AEs must be recorded on the AE eCRF 
and documented in the source record after the signing of the ICF. 
9.5.4.1.3 Intensity of Adverse Events 
All AEs, both serious and non-serious, will be assessed for severity using the Rheumatology 
Common Toxicity Criteria v2.0 [Woodworth et al, 2007]. The scale displays Grades 1 through 4 
with unique clinical descriptions of severity for each AE (including abnormal laboratory values) 
based on this general guideline.  
 Grade 1 (mild) – asymptomatic or transient, short duration (<1 week), no change in 
lifestyle, no medication or over-the-counter 
 Grade 2 (moderate) – symptomatic, duration 1 to 2 weeks, alter lifestyle occasionally, 
medications give relief (may be prescription), study drug continued 
 Grade 3 (severe) – prolonged symptoms, reversible, major functional impairment, 
prescription medications/partial relief, hospitalized <24 hours, temporary study drug 
discontinuation or/and dose reduced 
 Grade 4 (includes life-threatening) – at risk of death, substantial disability, especially if 
permanent, hospitalized >24 hours, permanent study drug discontinuation 
9.5.4.1.4 Relationship to Study Drug 
The relationship of each AE to MTX/placebo for MTX and/or pegloticase will be determined by 
the Investigator and the Sponsor based on the following definitions: 
 Not related: There is no plausible temporal relationship or there is another explanation 
that unequivocally provides a more plausible explanation for the event. 
 Related: There is evidence in favor of a causal relationship (i.e., there is a plausible time 
course) and ≥1 of the following criteria apply: 
o There is a reasonable pharmacological relationship (or known class effect). 
o There is no other more plausible explanation. 

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o There is a positive de-challenge (without active treatment of the event). 
o There is a positive re-challenge. 
o There is a distinguishable dose effect. 
The assessment of causality will be based on the information available and may change based 
upon receipt of additional information. 
9.5.4.1.5 Reporting and Documenting SAEs and Product Complaints 
9.5.4.1.5.1 Serious Adverse Events 
Any death, life-threatening event, or other SAE experienced by a subject during the course of the 
study, whether or not judged drug-related, must be reported within 24 hours of knowledge of the 
event by entering the information into the eCRF. If unable to access the eCRF, the event must be 
reported by submitting the completed SAE form via email or fax to the contact numbers 
provided below.   
Fax 
 
E-mail 
 
The event must be documented in source documentation and the eCRF. The following steps will 
be taken to report promptly and document accurately any SAE, whether or not it appears to be 
related to MTX/placebo for MTX and/or pegloticase: 
1. Report the SAE to the Sponsor by entering the information into the eCRF within 24 hours 
after becoming aware that a subject has experienced an SAE. If unable to access the 
eCRF, the event must be reported by submitting the completed SAE form by email to 
 or fax within 24 hours after becoming aware that 
a subject has experienced an SAE. 
2. Perform appropriate diagnostic tests and therapeutic measures, and submit all follow-up 
substantiating data, such as diagnostic test reports, hospital discharge summaries, and 
autopsy report to the Sponsor’s representative. 
3. Respond in a timely manner to any queries from Sponsor regarding the SAE. 
4. Conduct appropriate consultation and follow-up evaluation until the SAE is resolved, 
stabilized, or otherwise explained by the Investigator. 
5. Review each SAE report and evaluate the relationship of the SAE to MTX/placebo for 
MTX and/or pegloticase. 
6. The Investigator must report all AEs or SAEs that meet the criteria for Unanticipated 
Problems Involving Risks to Human Subjects or Others to the IRB. 
After receipt of the initial report, the information will be reviewed and the Investigator may be 
contacted with requests for additional information or for data clarification. 

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Follow-up will be obtained via the eCRF, fax, or e-mail, as necessary, until the event resolves or 
attains a stable outcome. Horizon or designee is responsible for the preparation of 
MedWatch 3500 A/Council for International Organizations of Medical Sciences I forms and 
analysis of similar events for individual occurrences (to be submitted as Investigational New 
Drug [IND] safety letters to the FDA and Investigators according to 21 CFR 312.32 by Horizon). 
9.5.4.1.5.2 Product Complaints 
A product complaint process will be described in the Study Reference Manual. Any product 
complaint must be reported to the Sponsor using this process. 
9.5.4.1.6 Follow-up of Adverse Events 
After the initial recording of an AE, the Investigator should proactively follow the subject. Any 
non-serious AEs that are still ongoing at the 6 month Post Treatment Follow-up visit should be 
reviewed to determine if further follow up is required. The Investigator will document on the AE 
eCRF all ongoing non-serious AEs that will not be followed further after the 6 month Post 
Treatment Follow-up visit. If in doubt, the Investigator should consult the Sponsor’s Medical 
Monitor. 
All SAEs should be followed until resolution, until the condition stabilizes, or until the subject is 
lost to follow-up. Once the SAE is resolved, the corresponding AE eCRF page should be 
updated. 
9.5.4.1.7 Medication Error and Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to, or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
All cases of medication errors and overdose (with or without associated AEs) will be 
documented on the eCRF in order to capture this important safety information consistently in the 
database. AEs associated with an overdose and SAEs of overdose are to be reported according to 
the procedures outlined in Section 9.5.4.1.2 and Section 9.5.4.1.5, respectively. 
In the event of drug overdose, the subject is to be treated as appropriate. 
9.5.4.1.8 Review of Adverse Events and Emerging New Safety Information 
The Sponsor will notify all Investigators involved in the clinical investigation of important safety 
information regarding the study treatment, as required by the applicable regulations. 
Investigators will notify their IRB of all such notifications, as required. 
9.5.4.1.9 Reporting of IND Safety Reports 
The Sponsor will notify the United States FDA and all Investigators on any new serious risks 
associated with the drug. 

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9.5.4.1.10  Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to competent authorities. 
9.5.4.2 Pregnancy Reporting 
Women of childbearing potential (including those with an onset of menopause <2 years prior to 
the screening, non-therapy-induced amenorrhea for <12 months prior to the screening, or not 
surgically sterile [absence of ovaries and/or uterus]) will have a serum pregnancy test at the 
Screening Visit.  Urine pregnancy tests will also be performed at all other time points, as 
indicated in Section 2.1. Pregnancy will not be considered an AE in this study, however, any 
pregnancy complications, including an elective termination for medical reasons, should be 
reported as an AE.  
Information must be obtained and reported if a female subject suspects that she has become 
pregnant during the study (including the MTX Tolerability Assessment and Run-in Periods) up 
to 30 days after the last dose of study treatment (either pegloticase or MTX or placebo for MTX), 
or if a female partner of male subject suspects that she has become pregnant during the study 
(including the MTX Tolerability Assessment and Run-in Periods) up to 3 months (approximately 
90 days) after their male subject partner discontinues MTX or placebo for MTX. The 
Investigator will instruct the female subject to stop taking all study drugs. A serum pregnancy 
test should be performed if any female subject or female partner of a male subject suspects that 
she has become pregnant during the time frame as defined above. If pregnancy is confirmed, 
female subject will be removed from pegloticase therapy and should remain on study barring 
withdrawal of consent for study participation. Pregnancy will be followed up until the outcome 
of pregnancy.  
Complete pregnancy information, including the outcome of the pregnancy, should be collected in 
the source documents on the female subject or partner of a male subject. In the absence of 
complications, follow-up after delivery will be no longer than 8 weeks. Any stillbirths or 
premature terminations of pregnancies, whether elective, therapeutic, or spontaneous, should be 
reported on the pregnancy outcome form. Any pregnancy complications, including an elective 
termination for medical reasons, should be reported as an AE. 
A spontaneous abortion should always be considered an SAE, as should any congenital defects 
in the newborn. Any SAE occurring as a result of a post-study pregnancy and considered 
reasonably related to the investigational product by the Investigator should be reported to the 
Sponsor. 
Women who are breastfeeding are not eligible to participate in the study. 
9.5.4.3 Medical History 
Medical history, including gout history (e.g., time of first diagnosis and history of tophi, 
collected on a gout-specific eCRF) and symptom severity, will be conducted at the Screening 
Visit.  

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9.5.4.4 Vital Signs, Height, and Weight 
Routine vital signs, including blood pressure, respiratory rate, temperature, and heart rate will be 
measured at Screening, Week -6, Week -4, Day 1 and Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 
24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50 and the End of Pegloticase Infusions Visit (if 
applicable), Week 52/End of Study/Early Termination and 3 and 6 month Post Treatment 
Follow-up Visits. Heart rate and blood pressure measurements should be taken after the subject 
has been in a sitting position and in a rested and calm state with proper positioning including 
back support, feet flat on the floor, for at least 5 minutes.  Subject’s arm should be supported at 
heart level; and cuff placed on the bare arm.  A large cuff should be used as needed to fit the 
upper arm and a consistent arm is to be used at each study visit.  The Korotkoff phase V will be 
used to determine diastolic blood pressure.  During the Pegloticase + IMM Period study visits, 
vitals should be taken before the pegloticase infusion and any time after the end of the infusion, 
but prior to subject’s discharge/release from the site.  
At sites who participate and from subjects who consent, optional intensive blood pressure 
measurements will be taken prior to the infusion on Day 1 and at Weeks 6, 12, 18, 24, 30, 36, 42, 
48 and at the non-infusion End of Pegloticase Infusions Visit (if applicable) and Week 52/End of 
Study/Early Termination Visit. At these intensive blood pressure collections, three blood 
pressure measurements should be performed, at least 2 minutes apart, with BP readings 
measured to the nearest mm Hg prior to pegloticase infusion.  If any of the 3 systolic blood 
pressure measurements differed by more than 8 mm Hg or if diastolic measurements differed by 
more than 5 mm Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until 
the difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. All values 
will be recorded in the eCRF. 
When possible, the same staff member should take all BP measurements for a given subject. 
Weight should be measured in kilograms or pounds without shoes and recorded at the Screening 
Visit and prior to dosing MTX Week -6 Visit; prior to pegloticase infusion on Day 1 and at the 
Weeks 8, 16, 24, 36 and at the non-infusion End of Pegloticase Infusions Visit (if applicable), 
Week 52/End of Study/Early Termination and Months 3 and 6 Post Treatment Follow-up Visits. 
Height will be collected at the Screening Visit only. 
Vital sign monitoring during IR is described in Section 9.4.6.3.2.4.  
9.5.4.5 Physical Examinations 
A complete physical examination will be performed at the Screening Visit, including assessment 
of HEENT, heart, lungs, abdomen, skin, extremities, neurological status and musculoskeletal 
including an assessment for the presence of tophi.  
A targeted physical examination per investigator judgement will be conducted at Week -6, Day 
1, and prior to administration of pegloticase at Weeks 4, 8, 12, 16, 20, 24, 36 and the non-
infusion End of Pegloticase Infusions Visit (if applicable), Week 52/End of Study/Early 

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Termination and 3 and 6 month Post Treatment Follow-up Visits; at a minimum this should 
include heart, lungs, and abdominal exam.  
Clinically significant findings from the targeted physical examinations will be recorded as AEs.  
9.5.4.6 Electrocardiogram 
A 12-lead ECG will be performed at Screening and at the discretion of the Investigator 
thereafter. 
When possible, a 12-lead ECG will also be performed at the time the AESI (See Section 
9.5.4.1.1.5) of infusion reaction, anaphylaxis and cardiovascular events is suspected.  
9.5.4.7 Clinical Laboratory Safety Tests 
Blood (for hematology and clinical chemistry) will be collected at the Screening, Week -6 (prior 
to the first dose of MTX), and Week -4 and -2 Visits during the Run-in Period; prior to 
pegloticase infusion on Day 1 and at the Weeks 2, 6, 14, 22, 24, 36 and the non-infusion End of 
Pegloticase Infusions Visit (if applicable), Week 52/End of Study/Early Termination and 3 and 6 
month Post Treatment Follow-up Visits. 
Blood and urine samples (for allantoin) will be collected prior to the pegloticase infusion and after 
the end of each pegloticase infusion prior to discharge from the site on Day 1 and at Weeks 14, 24 
and 36; Additional blood and urine samples for allantoin will be collected at the non-infusion 
End of Pegloticase Infusions Visit (if applicable) and the Week 52/End of study/Early 
Termination Visit.  If subject consent, subject’s allantoin samples will be retained for potential 
future analyses which may include biomarkers relevant to gout (e.g. inflammatory markers) or 
gout co-morbidities in response to pegloticase or other potential treatments for gout. The samples 
will be retained no longer than 15 years after study completion or as required by applicable law. 
The samples will be stored in a secured storage space with adequate measures to protect 
confidentiality. 
Urine (for albumin:creatinine ratio) samples will be collected prior to the pegloticase infusion on 
Day 1 and at the Weeks 14, 24, 36 and the non-infusion End of Pegloticase Infusions Visit (if 
applicable) and Week 52/End of Study/Early Termination Visits. 
Urine (for human chorionic gonadotropin) samples will be collected at all visits except the 
Screening Visit and Weeks 21, 23 and 3 and 6 month Post Treatment Follow-up Visits for all 
female subjects of childbearing potential.  
Safety laboratory assessments will include:  
 Hematology: complete blood count with differential (hemoglobin concentration, 
hematocrit, erythrocyte count, platelet count, leukocyte count, and differential leukocyte 
count) 

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 Chemistry: albumin, transaminases (aspartate aminotransferase, alanine 
aminotransferase), alkaline phosphatase, total bilirubin, creatinine (including calculation 
for eGFR calculated by the MDRD study  equation : 175 x (Scr[mg/dL])-1.154 x (age)-0.203x 
(0.742 if female) x (1.212 if African American) or 175 x (Scr[µmol/L]/88.4)-1.154 x (age)-0.203x 
(0.742 if female) x (1.212 if African American), glucose, sodium, potassium, calcium, 
chloride, total protein, blood urea nitrogen, and human chorionic gonadotropin (at the 
Screening Visit for all female subjects of childbearing potential) 
 Urine: albumin:creatinine ratio,and human chorionic gonadotropin for all female subjects 
of childbearing potential 
Safety laboratory samples will be analyzed by the central laboratory. Samples will be collected 
for analysis at the local laboratory, if needed. 
9.5.4.8 Assessment of Gout Flare 
There is no validated instrument to assess gout flares. Gout flares will be assessed at the time 
points specified in Section 2.1. Investigators will assess gout flares based on subject self-
reporting, with investigator confirmation of flare based on subject questioning and/or direct 
observation. All gout flares will be recorded as adverse events with the required AE reporting 
information. Investigators will also ask the subject a series of questions related to each gout flare, 
to document subject report of swollen joints, joints that are warm to touch, and level of joint pain 
[Gaffo et al, 2012]. 
9.5.5 Data Monitoring Committee (DMC) 
 An external Data Monitoring Committee (DMC) will be convened to review data for safety and 
efficacy, with the possibility of DMC recommendation on study design modification per pre-
defined charter. 
9.5.6 Adjudication Committee 
One clinical adjudication committee will be established for this study to adjudicate the adverse 
events of special interest (AESIs) defined in the protocol (See 9.5.4.1.1.5) which include infusion 
reactions, anaphylaxis and cardiovascular events. The AESI of gout flare will not be adjudicated. 
The committee will be comprised of physicians with experience in immunology, allergic 
reactions, rheumatology, and cardiovascular diseases.  Periodically the adjudication committee 
will review all AESIs. Details outlining the responsibilities of the adjudication committee will be 
included in the adjudication committee charter.  
9.5.7 Appropriateness of Measurements 
The study population is well-defined and is consistent with the expected target population for 
whom pegloticase is indicated (adult subjects with uncontrolled gout and with the ability to 
tolerate MTX or placebo for MTX). 

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9.5.8 Study Procedures 
Subjects who provide informed consent and who meet all the entry criteria for participation in 
this study will be enrolled. 
9.5.8.1 Screening/MTX Tolerability Assessment/Run-in Period 
During the Screening/MTX Tolerability Assessment Period, study candidates will be evaluated 
for study entry according to the stated inclusion and exclusion criteria (Section 9.3). The 
following procedures will be performed during screening to establish each candidate’s eligibility 
for enrollment into the study. 
9.5.8.1.1 Screening Visit (Within 6 Weeks Prior to the First Dose of MTX at Week -6) 
 Obtain signed, written informed consent. Refusal to provide this permission excludes an 
individual from eligibility for study participation. Record date informed consent was 
given and who conducted the process on the appropriate source documentation. 
 Determine study eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3). 
 Obtain demographic information 
 Investigator review of clinical status and subject treatment goals.  
 Collect complete gout history (on gout-specific CRF), other relevant medical/surgical 
history, and medication history, including gout medications starting at the time of 
diagnosis and up to screening (on gout medications-specific CRF), substance use history, 
and all other medications currently being taken at screening (see Section 9.4.10 for 
restrictions regarding medications).  
 Chest X-ray for subjects that do not have a chest X-ray within 2 years prior to Screening 
if deemed necessary by the Investigator. 
 Perform a complete physical examination, including assessment of HEENT, heart, lungs, 
abdomen, skin, extremities, neurological status and musculoskeletal including an 
assessment for the presence of tophi. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate), (see 
Section 9.5.4.4).  
 Record height and weight. 
 Perform 12-lead ECG. 

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 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a serum sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples to evaluate sUA (only 1 sample for central laboratory) and G6PD. 
 Administer HAQ and record physician global assessments. 
 Inquire about AEs and concomitant medication use. 
9.5.8.1.2 Week -6 (MTX Tolerability Assessment Period) 
 Confirm study eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3).  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) (see 
Section 9.5.4.4). 
 Record weight. 
 Document gout flares and intensity. 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Digital photography of hands and feet. 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain a blood sample for measurement of sUA (only 1 sample for central laboratory). 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis. 
 Provide dosing calendar for subjects to record the date and time they take MTX/placebo 
for MTX. (Additional calendar pages may be provided at future visits as needed). 
 Dispense MTX. 

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 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Inquire about AEs and concomitant medication use. 
 Subjects that take MTX during Week -6 or Week -5, and who are females of childbearing 
potential, will receive a safety follow-up phone call/e-mail approximately 30 days after 
the last dose of MTX to verify at least one ovulatory cycle has occurred since the last 
dose of MTX. If the subject has not ovulated, a urine pregnancy test will be performed. 
Subjects who are non-vasectomized males, an inquiry will be conducted approximately 3 
months after MTX discontinuation regarding partner pregnancy. 
9.5.8.1.3 Week -4 (Run-in Period) 
 Confirm study eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3).  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) (see 
Section 9.5.4.4). 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain a blood sample for measurement of sUA (only 1 sample for central laboratory). 
 Assess MTX compliance (from MTX Tolerability Assessment Period)  
 Dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid and gout flare prophylaxis compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Inquire about AEs and concomitant medication use. 
 Randomization in RTMS to MTX or placebo for MTX.  
 Subjects that take MTX/placebo for MTX during Week -4 or Week -3, and who are 
females of childbearing potential, will receive a safety follow-up phone call/e-mail 
approximately 30 days after the last dose of MTX/placebo for MTX to verify at least one 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
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Protocol: HZNP-KRY-202 
 
 
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ovulatory cycle has occurred since the last dose of MTX/placebo for MTX. If the subject 
has not ovulated, a urine pregnancy test will be performed. Subjects who are non-
vasectomized males, an inquiry will be conducted approximately 3 months after 
MTX/placebo for MTX discontinuation regarding partner pregnancy. 
9.5.8.1.4 Week -2 (Run-in Period) 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain a blood sample for measurement of sUA (only 1 sample for central laboratory). 
 Obtain blood samples for hematology and clinical chemistry analysis. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid and gout flare prophylaxis compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Inquire about AEs and concomitant medication use. 
 Subjects that take MTX/placebo for MTX during Week -2 or Week -1, and who are 
females of childbearing potential, will receive a safety follow-up phone call/e-mail 
approximately 30 days after the last dose of MTX/placebo for MTX to verify at least one 
ovulatory cycle has occurred since the last dose of MTX/placebo for MTX. If the subject 
has not ovulated, a urine pregnancy test will be performed. Subjects who are non-
vasectomized males, an inquiry will be conducted approximately 3 months after 
MTX/placebo for MTX discontinuation regarding partner pregnancy. 
9.5.8.2 Pegloticase + IMM Period 
9.5.8.2.1 Day 1 
On Day 1, subjects will return to the clinic for the following assessments and the first dose of 
pegloticase.  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 

HORIZON THERAPEUTICS IRELAND DAC 
 
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Protocol: HZNP-KRY-202 
 
 
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performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Record weight. 
 Digital photography of hands and feet. 
 For sites with X-ray capability, and subjects who provide consent, an optional X-ray of 
the hands and feet will be obtained. The X-ray on Day 1 must be completed prior to the 
infusion and may be completed within the 14 days prior to Day 1. 
 Document gout flares and intensity. 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 For sites with DECT capability, and subjects who provide consent, an optional DECT 
will be obtained. The DECT on Day 1 must be completed prior to the infusion and may 
be completed within the 14 days prior to Day 1. 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood and urine samples for allantoin collection prior to the pegloticase infusion.  
 Obtain 1 blood sample for measurement of sUA prior to the pegloticase infusion for 
shipment to the Central Laboratory.  
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
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Protocol: HZNP-KRY-202 
 
 
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 Obtain blood samples for MTX Polyglutamate analysis prior to the infusion.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies prior to the infusion. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer the first dose of pegloticase and record date, volume, and duration of 
infusion, and start/stop (inclusive of 10-mL flush) times of dosing. 
 Obtain blood samples for pegloticase PK analysis any time after the end of the infusion, 
prior to discharge from the site. 
 Obtain 1 blood sample for measurement of sUA after the end of the pegloticase infusion 
for shipment to the Central Laboratory. 
 Obtain blood and urine samples for allantoin any time after the end of the infusion, prior 
to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.2 Week 2 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.  (see Section 9.5.1.1). 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(see Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies prior to the infusion. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis.  Samples will only be collected at this visit for subjects having an acute gout 
flare during this visit. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion and 
any time after the end of the infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.3 Week 4 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion. (see Section 9.5.1.1). 

HORIZON THERAPEUTICS IRELAND DAC 
 
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Protocol: HZNP-KRY-202 
 
 
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• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis.  Samples will only be collected at this visit for subjects having an acute gout 
flare during this visit. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.4 Week 6 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for hematology and clinical chemistry analysis. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies prior to the infusion. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion and 
any time after the end of the infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.5 Week 8 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Record weight. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis.  Samples will only be collected at this visit for subjects having an acute gout 
flare during this visit. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.6 Week 10 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis.  Samples will only be collected at this visit for subjects having a gout flare 
during this visit. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.7 Week 12 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis.  Samples will only be collected at this visit for subjects having an acute gout 
flare during this visit. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.8   Week 14 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Digital photography of hands and feet. 
 For sites with DECT capability, and subjects who provide consent, an optional DECT 
will be obtained. DECT may be completed within +/- 10 days of the scheduled visit. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain blood and urine samples for allantoin collection prior to the pegloticase infusion. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies prior to the infusion. 
 Obtain blood samples for MTX Polyglutamate analysis prior to the infusion. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 102 of 145 
 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Obtain blood and urine samples for allantoin any time after the end of the infusion, prior 
to discharge from the site. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion and 
any time after the end of the infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.9   Week 16 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 103 of 145 
 
 Record weight.  
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.10   Week 18 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 104 of 145 
 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.11   Week 20 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 105 of 145 
 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed. 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.12   Week 21 
 Obtain a blood sample (1 sample) for measurement of sUA.  
 Obtain blood samples for pegloticase PK analysis. 
 Inquire about AEs and concomitant medication use. 
 Document gout flares and intensity. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 106 of 145 
 
9.5.8.2.13   Week 22 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
  Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed. 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies prior to the infusion. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 107 of 145 
 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
  Inquire about AEs and concomitant medication use. 
9.5.8.2.14   Week 23 
 Obtain a blood sample (1 sample) for measurement of sUA 
 Inquire about AEs and concomitant medication use. 
 Document gout flares and intensity. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
9.5.8.2.15   Week 24 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  The Local 
Laboratory or Central Laboratory pre-infusion sUA results should be reported prior to 
pegloticase infusion. To note:  It is allowable for the Local and Central Laboratory sUA 
samples to be drawn on different days or times so long as both samples are drawn within 
48 hours prior to the infusion and the results of at least one sample are available prior to 
the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Investigator review of clinical status and subject treatment goals.  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 108 of 145 
 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Record weight. 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Digital photography of hands and feet. 
 For sites with DECT capability, and subjects who provide consent, an optional DECT 
will be obtained. DECT may be completed within +/- 10 days of the scheduled visit. 
 For sites with X-ray capability, and subjects who provide consent, an optional X-ray of 
the hands and feet will be obtained. The X-ray may be completed within +/- 10 days of 
the scheduled visit. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain blood and urine samples for allantoin collection prior to the pegloticase infusion. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies prior to the infusion. 
  Obtain blood samples for MTX Polyglutamate analysis prior to the infusion. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 109 of 145 
 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Obtain blood and urine samples for allantoin any time after the end of the infusion, prior 
to discharge from the site. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion and 
any time after the end of the infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.16   Week 26  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.   If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule.  . To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1).   
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 110 of 145 
 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.17   Week 28 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule.   To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 111 of 145 
 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.18   Week 30 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing. If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule. To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion.   (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 112 of 145 
 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.19  Week 32  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule. To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 113 of 145 
 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.20  Week 34 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule.  To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 114 of 145 
 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.21   Week 36 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule To note:  It is allowable for the Local and Central 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 115 of 145 
 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion.. (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Record weight. 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Digital photography of hands and feet. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for hematology and clinical chemistry analysis.  

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 116 of 145 
 
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain blood and urine samples for allantoin collection prior to the pegloticase infusion. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies prior to the infusion. 
  Obtain blood samples for MTX Polyglutamate analysis prior to the infusion. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Obtain blood and urine samples for allantoin any time after the end of the infusion, prior 
to discharge from the site. 
 Obtain blood samples for pegloticase PK analysis prior to the pegloticase infusion and 
any time after the end of the infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.22   Week 38 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing. If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule. To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 117 of 145 
 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.23   Week 40 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule. To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion (see Section 9.5.1.1). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 118 of 145 
 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.24   Week 42 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule.  To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 119 of 145 
 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.25   Week 44 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 120 of 145 
 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule. To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.26   Week 46 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 121 of 145 
 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule. To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.27   Week 48 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 122 of 145 
 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule. To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion. (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). During the pre-infusion blood pressure collection, at sites who 
participate and from subjects who consent, optional intensive BP collections will be 
obtained.  For this optional collection, three blood pressure measurements should be 
performed, at least 2 minutes apart, with BP readings measured to the nearest mm Hg 
prior to pegloticase infusion.  If any of the 3 systolic blood pressure measurements 
differed by more than 8 mm Hg or if diastolic measurements differed by more than 5 mm 
Hg, repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 123 of 145 
 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
9.5.8.2.28   Week 50 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the pegloticase 
infusion at this visit.  One sample will be tested for sUA at the site’s Local Laboratory 
and one sample will be shipped to the Central Laboratory for testing.  If a subject’s 
previous visit pre-infusion sUA (local or central laboratory) is less than 6 mg/dl;  it will 
be allowable to draw the local pre-infusion sUA sample on the same day and similar time 
as the sample to send to the central laboratory;  however if the prior visit pre-infusion 
sUA sample was greater than 6 mg/dl (local or central laboratory), a local sUA sample 
will need to be collected and read out prior to the pegloticase infusion to be certain the 
subject has not met the stopping rule.  To note:  It is allowable for the Local and Central 
Laboratory sUA samples to be drawn on different days or times so long as both samples 
are drawn within 48 hours prior to the infusion (see Section 9.5.1.1). 
• 
Stopping rule: Subjects with an sUA level >6 mg/dL at 2 consecutive study 
visits beginning with the Week 2 Visit (not including post-infusion samples) 
will subsequently discontinue treatment and remain in the study. 
 Administer MTX/placebo for MTX ≥60 minutes prior to pegloticase infusion if subject 
has not taken MTX/placebo for MTX within the previous 1 to 3 days. 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
the pegloticase infusion and any time after the end of the infusion, but prior to discharge. 
(See Section 9.5.4.4). 
 Assess MTX/placebo for MTX compliance and re-dispense MTX/placebo for MTX. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, fexofenadine, acetaminophen, and folic acid prescriptions, as 
needed.  
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 

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 Administer IR prophylaxis (i.e., fexofenadine, acetaminophen, and methylprednisolone) 
(see Section 9.4.1.3). 
 Administer pegloticase and record date, volume, and duration of infusion, and start/stop 
(inclusive of 10-mL flush) times of dosing. 
 Obtain a blood sample (1 sample) for measurement of sUA any time after the end of the 
infusion, prior to discharge from the site. 
 Inquire about AEs and concomitant medication use. 
Note:  MTX will be taken one week following the Week 50 Visit and Folic Acid will be 
taken until just prior to the Week 52 Visit. 
9.5.8.3 End of Pegloticase Infusions Visit 
Subjects who end pegloticase infusions prior to Week 52 will complete the End of Pegloticase 
Infusions Visit procedures following their final infusion. Subjects should continue to participate 
in all visits through the end of the study. Subjects must complete selected study visits at the study 
site during key efficacy and safety collections at Weeks 12, 14, 20, 21, 22, 23, 24, 32, 34, 36, 48, 
50 and 52/End of Study/Early Termination, so that sUA labs and other key assessments can be 
completed. During visits between these key efficacy and safety collection visits, in subjects who 
have stopped infusions, subjects may complete study visits in person or via a telephone visit 
option to collect AEs, conmeds and gout flare information (See 9.3.3.1.1).  
The following procedures will be completed at the End of Pegloticase Visit:  
 Investigator review of clinical status and subject treatment goals.  
 Document gout flares and intensity. 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
discharge. (See Section 9.5.4.4). At sites that participate and from subjects who consent, 
during the BP collection, optional intensive BP collections will be obtained.  For this 
optional collection, three blood pressure measurements should be performed, at least 2 
minutes apart, with BP readings measured to the nearest mm Hg prior to pegloticase 
infusion.  If any of the 3 systolic blood pressure measurements differed by more than 8 
mm Hg or if diastolic measurements differed by more than 5 mm Hg, repeat sets of 3 
sitting blood pressure measurements will be obtained until the difference is less than 8 
mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Record weight. 

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 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Assess MTX/placebo for MTX compliance. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis compliance. 
 Digital photography of hands and feet. 
 For sites with DECT capability, and subjects who provide consent, an optional DECT 
will be obtained. DECT may be completed within +/- 10 days of the scheduled visit. 
Subjects who end pegloticase infusions prior to Week 52 should follow the scheduled 
timepoints but avoid a repeat DECT scan within 6 weeks of a prior scan. 
 For sites with X-ray capability, and subjects who provide consent, an optional X-ray of 
the hands and feet will be obtained. The X-ray may be completed within +/- 10 days of 
the scheduled visit. Subjects who end pegloticase infusions prior to Week 52 should 
follow the scheduled timepoints but avoid a repeat X-ray within 3 months of a prior X-
ray. 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain blood and urine samples for allantoin collection. 
 Obtain blood samples for pegloticase PK analysis.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
analysis. 
 Obtain a blood sample (1 sample) for measurement of sUA. 
 Inquire about AEs and concomitant medication use. 
9.5.8.4 Week 52/End of Study/Early Termination Visit 
 Investigator review of clinical status and subject treatment goals.  
 Document gout flares and intensity. 

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 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
discharge. (See Section 9.5.4.4). At sites that participate and from subjects who consent, 
during the BP collection, optional intensive BP collections will be obtained.  For this 
optional collection, three blood pressure measurements should be performed, at least 2 
minutes apart, with BP readings measured to the nearest mm Hg prior to pegloticase 
infusion.  If any of the 3 systolic blood pressure measurements differed by more than 8 
mm Hg or if diastolic measurements differed by more than 5 mm Hg, repeat sets of 3 
sitting blood pressure measurements will be obtained until the difference is less than 8 
mm Hg for systolic and less than 5 mm Hg for diastolic. 
 Record weight. 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Digital photography of hands and feet. 
 For sites with DECT capability, and subjects who provide consent, an optional DECT 
will be obtained. DECT may be completed within +/- 10 days of the scheduled visit. 
 For sites with X-ray capability, and subjects who provide consent, an optional X-ray of 
the hands and feet will be obtained. The X-ray may be completed within +/- 10 days of 
the scheduled visit. 
 Assess MTX/placebo for MTX compliance. 
 Ask Yes/No question regarding folic acid compliance. 
 Obtain a urine sample from all females of childbearing potential for performance of a 
pregnancy test. 
 Obtain blood samples for hematology and clinical chemistry analysis.  
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain blood and urine samples for allantoin collection. 
 Obtain blood samples for pegloticase PK analysis.  
 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies. 
 Obtain optional whole blood and serum samples from subjects who consent for future 
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 Obtain a blood sample (1 sample) for measurement of sUA. 
 Inquire about AEs and concomitant medication use. 
9.5.8.5 Safety Follow-up Phone/Email Visits 
Thirty (30) days after the last pegloticase infusion, subjects will be contacted by telephone or 
email to inquire about SAEs. Subjects who are females of childbearing potential will be asked to 
confirm that ovulation has occurred. If the subject has not ovulated, the subject will be requested 
to return to the site for a urine pregnancy test.  
9.5.8.6 MTX Partner Pregnancy Follow-up 
Subjects who are non-vasectomized males will be asked 3 months after MTX or placebo for 
MTX discontinuation regarding partner pregnancy.  This will occur at a scheduled visit or by a 
phone/email visit. 
9.5.8.7 Post Treatment Follow-up  
The intent is to obtain at least 6 months of follow-up on each subject after cessation of 
pegloticase infusions. If these 6 months occur prior to end of study at Week 52, such as in the 
case of a subject who ends pegloticase infusions on or before Week 24, there will be no follow-
up visits after the Week 52/End of Study Visit. For subjects who end pegloticase infusions 
between Weeks 26 and 36, there will be at least 3 months of follow-up while the subject remains 
on-study prior to Week 52, and then one follow-up visit after the Week 52/End of Study Visit. 
For subjects who end pegloticase infusions between Weeks 38 and 52, there will be two follow-
up visits at intervals of 3 months apart after the Week 52/End of Study Visit. The following 
procedures will be completed at the 3 and 6 month Post Treatment Follow-up Visits: 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature, and heart rate) prior to 
discharge. (See Section 9.5.4.4). 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Record weight. 
 Collect swollen/tender joint counts; administer HAQ; and record physician global 
assessments. 
 Digital photography of hands and feet. 
 Obtain blood samples for hematology and clinical chemistry analysis. 
 Obtain a blood sample (1 sample) for measurement of sUA. 

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 Obtain blood samples for anti-PEG and anti-uricase IgG antibodies (3 Month Post 
Treatment Follow-up Visit only).  
 Inquire about AEs and concomitant medication use. 
 For subjects that completed 52 weeks of treatment and consent to the additional optional 
DECT assessment, collect a DECT scan at the 6 month Follow-up visit. 
9.6 
Statistical Methods and Determination of Sample Size  
9.6.1 Endpoints 
9.6.1.1 Primary Endpoint 
The primary efficacy endpoint is the proportion of Month 6 (Weeks 20, 21, 22, 23 and 24) 
responders, defined as subjects achieving and maintaining sUA <6 mg/dL for at least 80% of the 
time during Month 6.  
9.6.1.2 Secondary Endpoints 
The secondary efficacy endpoints (analyzed sequentially) are:  
1. The proportion of Month 12 (Weeks 48, 50, and 52) responders, defined as subjects 
achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 12. 
2. The proportion of subjects with complete resolution of ≥ 1 tophi (using digital 
photography) at Week 52 in subjects with tophi at baseline.   
 
3. The mean change from baseline in HAQ-DI score at Week 52. 
4. The mean change from baseline in HAQ Pain score at Week 52. 
5. The mean change from baseline in HAQ Health score at Week 52. 
 
 
 

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9.6.1.3 Exploratory Endpoints 
The exploratory efficacy endpoints are:  
 The mean change from baseline to Weeks 14, 24, and 52 in urate deposition volume and 
bone erosions due to gout based on DECT. 
 The mean change from baseline to Weeks 24 and 52 in bone erosions due to gout based 
on X-rays of the hands and feet. 
 The proportion of subjects with complete resolution of ≥ 1 tophi (using digital 
photography) at Weeks 24 and 36 in subjects with tophi at baseline. 
 The mean change from baseline in tophus size (long axis measured using digital 
photography) to Weeks 14, 24, 36 and 52 in subjects with tophus present at baseline.   
 The proportion of Month 9 (Weeks 32, 34, and 36) responders, defined as subjects 
achieving and maintaining sUA<6 mg/dL for at least 80% of the time during Month 9. 
 The proportion of Month 3 (Weeks 10, 12, and 14) responders, defined as subjects 
achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 3. 
 The proportion of overall responders, defined as subjects achieving and maintaining sUA 
<6 mg/dL for at least 80% of the time during Month 3 (Weeks 10, 12, and 14) and Month 
6 (Weeks 20, 21, 22, 23 and 24) combined. 
 The proportion of 5 mg/dL responders during each time interval (Month 3, Month 6, 
Month 9 and Month 12), defined as subjects achieving and maintaining sUA <5 mg/dL 
for at least 80% of the time during each time interval. 
 The mean change from baseline in sUA at Weeks 14, 24, 36 and 52. 
 The time to first sUA > 6 mg/dL. 
 The time to two consecutive sUA > 6 mg/dL (stopping rule). 
 The percentage of non-hyperuricemic (sUA < 6 mg/dL) time during Months 3, 6, 9 and 
12. 
 The mean change from baseline in HAQ Pain score at Weeks 14, 24, and 36. 
 The mean change from baseline in HAQ Health score at Weeks 14, 24, and 36. 
 The mean change from baseline in HAQ-DI score at Weeks 14, 24, and 36. 
 The mean change from baseline in tender joint count (68-point scale) at Weeks 14, 24, 36 
and 52. 
 The mean change from baseline in swollen joint count (66-point scale) at Weeks 14, 24, 
36 and 52. 
 The mean change from baseline in number of tender or swollen joints at Weeks 14, 24, 
36 and 52. 
 The mean change from baseline in physician global assessment of gout at Weeks 14, 24, 
36 and 52. 
 The proportion of subjects achieving 20%, 50%, or 70% improvement based on gout 
chronic response criteria at Weeks 14, 24, 36 and 52. 

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 The mean change from baseline in SBP and DBP to each visit. 
 
9.6.1.4  Pharmacokinetic and Anti-drug Antibody Endpoints 
The PK and anti-drug antibody endpoints are:  
 PK of pegloticase. 
 MTX polyglutamate concentrations. 
 The incidence of anti-PEG and anti-Uricase IgG antibodies. 
9.6.1.5 Safety and Tolerability Endpoints 
Safety and tolerability objectives are: 
 AE/SAE profile overall and potentially attributed to the combination of pegloticase and 
MTX 
o Incidence of AESI: IRs, anaphylaxis, gout flares, cardiovascular events 
 Laboratory tests 
 Vital signs and physical examination 
9.6.2 Populations for Analysis 
The following analysis populations will be defined for this study:  
 Intent-to-treat population (ITT): all randomized subjects 
 Modified intention-to-treat (mITT) population: all randomized subjects who receive at 
least 1 dose of pegloticase 
 Per-protocol population (PP): all randomized subjects who receive at least 1 dose of 
pegloticase, are taking the 15 mg dose of MTX or placebo for MTX at the time of first 
pegloticase dose, and have no major protocol deviations that would challenge the validity 
of the data  
 Pharmacokinetic (PK) population: all randomized subjects who receive at least one dose 
of pegloticase and have a post-pegloticase sample evaluable for PK analysis 
 Safety population: all randomized subjects who take at least one dose of blinded MTX or 
placebo for MTX 
 MTX population: all subjects who take at least one dose of MTX  
The ITT and mITT populations will be used for analysis of efficacy data; subjects will be 
analyzed according to the treatment to which they were randomized. The PP population will be 
used for analysis of select efficacy endpoints; subjects will be analyzed according to the 
treatment received. The safety population will be used for analysis of safety data; subjects will be 
analyzed according to the treatment received. The MTX population will be used for analysis of 
safety data during the Run-In period prior to randomization. 

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9.6.3 Demographic Variables 
Demographic data, including age, race, and gender, medical history, and other disease 
characteristics, will be summarized using descriptive statistics. Listings will include all screened 
subjects. 
9.6.4 Subject Disposition 
The number of subjects in each population and the number and percentage of subjects who 
completed the study and who discontinued the study prematurely, and who completed 
pegloticase treatment and who discontinued treatment prematurely, along with the reasons for 
discontinuation will be summarized for each study period. 
9.6.5 Efficacy Endpoint Analysis 
Efficacy analyses will be performed using the ITT and mITT populations, with select endpoints 
analyzed using the PP population. Continuous variables will be summarized using descriptive 
statistics (number of subjects, mean, median, standard deviation, minimum, and maximum). 
Categorical variables will be summarized using frequencies and percentages. Unless otherwise 
specified, baseline is defined as the last non-missing observation prior to the first dose of MTX.  
9.6.5.1 Primary and Secondary Endpoint Analysis 
The primary analysis will be conducted in the ITT population. The primary efficacy endpoint is 
the proportion of responders during Month 6. A responder is defined as a subject for whom the 
proportion of time that the sUA-time curve is <6 mg/dL during the analysis interval is at least 
80%. The proportion of time that the sUA level is below 6 mg/dL is defined as the ratio of the 
time during which the sUA level remains below 6 mg/dL (using linear interpolation, if 
necessary) to the entire time interval during Month 6. A subject will be declared a non-responder 
if the subject had 2 sUA levels >6 mg/dL at 2 consecutive study visits beginning with the Week 
2 Visit prior to or during Month 6. Additionally, a subject who withdraws from study treatment 
for any reason other than the stopping rule after randomization and prior to or during Month 6 
(for the primary endpoint) or Months 12 (for the secondary endpoint) will be considered a non-
responder at the time of withdrawal (and for all subsequent time points) if sUA values are not 
collected at the planned time points. Sensitivity analyses of the primary and secondary endpoints 
will include data (if available) for subjects who discontinue treatment due to stopping rule and 
remain on study. Special consideration may be given to subjects who discontinue the study or 
miss visits due to reasons related to the COVID-19 pandemic. 
The analysis of the primary endpoint and the secondary responder endpoints will assess risk 
difference (difference in response proportions) in a stratified analysis. The analysis will use 
Cochran-Mantel-Haenszel (CMH) weighting to estimate the common risk difference within 
strata and to estimate the standard error of the common risk difference. Stratification for the 
analysis will use the same factor as was used to stratify randomization, presence of tophi (yes, 
no). The difference in response rates, comparing pegloticase with MTX vs. pegloticase with 
placebo for MTX, will be estimated along with the corresponding 95% confidence interval (CI) 
and p-value.  

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Subjects with resolution of ≥ 1 tophi are subjects with an overall tophus response of complete 
response (i.e. complete response in at least one tophi and no evidence of progressive disease, see 
Section 9.5.1.6.1).  The difference in the proportion of subjects with resolution of ≥ 1 tophi at 
Week 52 between pegloticase with MTX and pegloticase with placebo for MTX will be tested 
with a chi-square test, and the difference in rates will be estimated along with the corresponding 
95% confidence interval (CI) and p-value. 
The change from baseline to Week 52 for HAQ-DI, HAQ pain score, and HAQ health score to 
each visit and overall will be analyzed with a mixed model repeated measures (MMRM) analysis 
of covariance (ANCOVA) model with a term for baseline score, tophi presence at baseline 
(except for analyses of tophi size), and factors for treatment group, visit, visit by treatment group 
interaction and visit by baseline-score interaction. 
To control the overall Type 1 error rate of the study, taking into consideration the one primary 
and 5 secondary endpoints, the endpoints will be tested sequentially. For each endpoint, 
pegloticase with MTX will be tested against pegloticase with placebo for MTX at the 0.0495 
level only if pegloticase with MTX was statistically significant for the endpoint preceding it in 
the prespecified order and 5 secondary endpoints, the endpoints will be tested sequentially. For 
each endpoint, pegloticase with MTX will be tested against pegloticase with placebo for MTX at 
either the 0.0495 level only if pegloticase with MTX was statistically significant for the endpoint 
preceding it in the prespecified order. 
 
9.6.5.2 Exploratory Endpoint Analysis 
HAQ-DI score, HAQ pain and health scores, tophus size (longest axis), urate deposition volume 
and bone erosions due to gout (DECT scans of hands, feet, knees and other anatomical areas), 
bone erosions due to gout using X-ray (hands and feet), swollen/tender joint counts, physician 
global assessment score, and mean sUA will be summarized at baseline and each visit with 
descriptive statistics. Changes from baseline for these parameters to each visit and overall will be 
analyzed with a mixed model repeated measures (MMRM) analysis of covariance (ANCOVA) 
model with a term for baseline score, tophi presence at baseline (except for analyses of tophi 
size), and factors for treatment group, visit, visit by treatment group interaction and visit by 
baseline score interaction.  
The proportion of subjects achieving 20%, 50%, or 70% improvement based on gout chronic 
response criteria is defined as 20/50/70% improvement in 3 of the 4 components (TJC, SJC, 
HAQ pain and HAQ health). The proportion of subjects with improvement will be summarized 
and the difference between treatment groups analyzed with a CMH test. P-values for exploratory 
endpoints will be provided for descriptive purposes only, and treatment effects with 
corresponding two-sided 95% confidence intervals will be provided.  
9.6.6 Pharmacokinetic and Anti-drug Antibody Analysis 
Concentrations for pegloticase and MTX polyglutamate (as appropriate) will be summarized 
using descriptive statistics for the PK population. Details will be provided in a separate PK 
analysis plan. 

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Incidence of anti-drug antibodies and titer levels will be summarized. 
9.6.7 Safety Analysis 
Treatment-emergent AEs (TEAEs) during the MTX Tolerability Assessment Period and Run-In 
Period are defined as events with an onset date on or after the first dose of MTX through the first 
pegloticase infusion, or 30 days after the last dose of MTX for subjects who do not receive 
pegloticase. TEAEs during the Pegloticase + IMM Period are defined as events that occur after 
the start of the first pegloticase infusion through 30 days after the last dose of pegloticase and/or 
MTX or placebo for MTX (whichever is later). TEAEs that occur during the MTX Tolerability 
Assessment Period prior to randomization (Weeks -6 to -4) will be summarized separately for the 
MTX population. TEAEs will be summarized for the safety population separately for the Run-In 
Period (after randomization at Week -4 to Day 1) by treatment group (MTX and placebo for 
MTX) and the Pegloticase + IMM Period by treatment group (pegloticase with MTX and 
pegloticase with placebo for MTX), and overall (after randomization through 30 days after the 
last dose of treatment) by treatment group (MTX and placebo for MTX). AEs that occur more 
than 30 days after the last dose of pegloticase and/or MTX or placebo for MTX through the 6 
month follow-up visit will also be summarized.  
The number and percentage of subjects experiencing AEs will be summarized by system organ 
class and preferred term. Summaries by maximum severity and relationship to MTX and/or 
pegloticase will also be provided. SAEs and AEs leading to discontinuation of MTX and/or 
pegloticase will be presented by system organ class and preferred term. 
The proportion of subjects with SAEs and each AESI will be summarized by treatment group.  A 
Fisher’s exact test will be performed to evaluate the difference in proportions between 
pegloticase with MTX vs. pegloticase with placebo for MTX. The proportion of subjects 
experiencing an SAE and each AESI will be summarized for each treatment group, along with 
the treatment difference in proportions, corresponding 95% CI for the treatment difference and p-
value. 
Laboratory test results, including urine albumin:creatinine ratio, will be summarized by study 
visit and change from baseline. Shift tables for laboratory parameters by Common Terminology 
Criteria for Adverse Events grade will be presented. Laboratory test results will also be classified 
relative to the normal reference range (normal, low, or high). 
Vital signs, including blood pressure, respiratory rate, temperature, and heart rate, will be 
summarized by study visit and change from baseline.  
Prior and concomitant medications will be summarized and/or included in the data listings. 
Data for the MTX Tolerability Assessment Period, Run-in Period and Pegloticase + IMM Period 
will be summarized separately, and for the Run-in and Pegloticase + IMM periods combined, 
where applicable. 

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9.6.8 Interim Analyses 
There are two planned timepoints at which data will be reviewed by the DMC. The first 
unblinded, comparative analysis will occur after approximately half of the randomized subjects 
(i.e. ~78 subjects) have completed 24 weeks of treatment in the Pegloticase + Immunomodulator 
(IMM) Period or discontinued therapy (or study) prior to that time. The second unblinded, 
comparative analysis will be performed when all randomized subjects have completed 24 weeks 
of treatment or discontinued treatment (or study) prior to Week 24. The main purpose of the 
analysis by the DMC is to review the safety data. However, limited efficacy data, including the 
primary efficacy endpoint, will be provided to the DMC for review to assess the benefit-risk 
profile. Additionally, some data for the secondary endpoints will be included in the second 
analysis. Even though there is no plan to make an inference of the primary or secondary efficacy 
endpoints, an alpha adjustment of 0.0005 will be made to account for these analyses. 
 
The primary analysis of safety, efficacy, and pharmacokinetics is planned after all subjects 
complete the final visit (Week 52) in the Pegloticase + IMM period or terminate early from the 
study. A follow-up analysis will be performed after all subjects complete the post-treatment 
follow-up period. The follow-up analysis will only include descriptive summaries of the post-
treatment efficacy and safety data. 
 
9.6.9 Sample Size and Power Considerations 
The response rate during Month 6 on pegloticase 8 mg every 2 weeks was 43% for the phase 3 
studies. A sample size of 135 subjects (90 subjects randomized to receive pegloticase with MTX, 
45 subjects randomized to receive pegloticase with placebo for MTX) provides 88% power at the 
2-sided alpha=0.05 level to detect a difference of 28% (71% response rate for pegloticase with 
MTX vs. 43% for pegloticase with placebo for MTX). 
9.7 
Changes in the Conduct of the Study 
If any modifications in the experimental design, dosages, parameters, subject selection, or any 
other sections of the protocol are indicated or required, the Investigator will consult with the 
Sponsor before any such changes are instituted. Modifications will be accomplished through 
formal amendments to this protocol by the Sponsor and approved from the appropriate IRB. 
All protocol deviations and the reasons for such deviations must be documented in the eCRF.  
The Sponsor has a legal responsibility to report fully to regulatory authorities all results of 
administration of investigational drugs to humans. No investigational procedures other than those 
described in this protocol will be undertaken on the enrolled subjects without the agreement of 
the IRB and Sponsor. 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
The Investigator must maintain adequate and accurate records to document fully the conduct of 
the study and to ensure that study data can be subsequently verified. These documents should be 

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classified in 2 separate categories: (1) Investigator study file and (2) subject clinical source 
documents that corroborate data collected in the eCRFs. Subject clinical source documents 
would include, as applicable, original hospital/clinic subject records; physicians’ and nurses’ 
notes; appointment book; original laboratory, ECG, electroencephalogram, radiology, pathology, 
and special assessment reports; dispensing records; signed ICFs; consultant letters; and subject 
screening and enrollment logs. 
In order to comply with regulatory requirements, it is the policy of the Sponsor that, at a 
minimum, the following be documented in source documents at the study center: 
 Medical history/physical condition and diagnosis of the subject before involvement in the 
study sufficient to verify that the subject meets protocol entry criteria.  
 Study number, assigned subject number, and verification that written informed consent 
was obtained (each recorded in dated and signed progress notes). 
 Progress notes for each subject visit (each dated and signed). 
 Records of each study visit including each study assessment and the identity of the staff 
member performing the assessment. 
 Study drug dispensing and return. 
 Review by the Investigator or qualified personnel on the 1572 of laboratory test results. 
 AEs (start and stop date, description, action taken, and resolution). 
 Investigator or sub-investigator’s signed assessment of AEs. 
 Concomitant medications (start and stop dates, reason for use). 
 Condition of subject upon completion of, or premature withdrawal from, the study. 
11 CASE REPORT FORMS 
An eCRF is required for every subject who signs the ICF. Required data must be entered on the 
eCRF within the required time period, which will be outlined within each site agreement, after 
data collection or the availability of test results. Separate source records are required to support 
all eCRF entries. Data captured on the eCRF, and requested anonymized copies of supporting 
documents, will be transferred to the Sponsor at study completion. 
The Investigator will ensure that the eCRFs are accurate, complete, legible, and timely, and will 
review and provide an electronic signature for the eCRF according to the standard operating 
procedure of the Data Management System. Final eCRFs will be provided to the Investigator and 
Sponsor by Data Management. 
12 STUDY MONITORING 
The Investigator will ensure that the study is conducted in accordance with all regulations 
governing the protection of human subjects. The Investigator will adhere to the basic principles 
of GCP as outlined in Title 21 of the CFR, Part 312, Subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, Part 50, “Protection of Human Subjects”; 21 CFR, Part 56, 
“Institutional Review Boards”; 21 CFR, Part 54 “Financial Disclosure by Clinical Investigators”; 
and the ICH guideline entitled “Good Clinical Practice: Consolidated Guidance.” Additionally, 

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this study will be conducted in compliance with the Declaration of Helsinki and with all local 
laws and regulations. 
The Investigator will ensure that all work and services described in, or associated with, this 
protocol are conducted in accordance with the investigational plan, applicable regulations, and 
the highest standards of medical and clinical research practice. The Investigator will provide 
copies of the study protocol and Investigator’s Brochure to all Sub-Investigators, pharmacists, 
and other staff responsible for study conduct. 
All aspects of the study will be monitored by qualified individuals designated by the Sponsor. 
The Sponsor will ensure that the study is monitored adequately in accordance with GCP 
guidelines. 
Prior to initiation of the study, the Sponsor’s representatives will review with study center 
personnel information regarding the investigational drug, protocol requirements, monitoring 
requirements, and reporting of SAEs. 
At intervals during the study, as well as after the completion of subject enrollment, the study 
center will be monitored by the Sponsor or designee for compliance. During these visits, the 
monitor will discuss study progress, verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on the eCRF (source data verification); 
oversee the resolution of outstanding data discrepancies, and check on various aspects of study 
conduct (e.g., drug accountability, sample storage). The Investigator agrees to allow monitors 
access to the clinical supplies, dispensing and storage areas, and clinical records of the study 
subjects, and, if requested, agrees to assist the monitors. The Investigator must cooperate with 
the monitors to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
A secondary audit may be conducted by Quality Assurance designated by the Sponsor. The 
Investigator will be informed if this is to take place and advised as to the nature of the audit. 
Representatives of the United States FDA and/or representatives of other regulatory authorities 
may also conduct an inspection of the study at the investigative site. If informed of such an 
inspection, the Investigator should notify the Sponsor immediately. 
Every effort will be made to maintain the anonymity and confidentiality of subjects participating 
in this clinical study. However, because of the investigational nature of this treatment, the 
Investigator agrees to allow representatives of the Sponsor, its designated agents, and authorized 
employees of the appropriate regulatory agencies to inspect the facilities used in this study and to 
have direct access to inspect, for purposes of verification, the hospital or clinical records of all 
subjects enrolled in this study. A statement to this effect should be included in the ICF. 
13 DATA MANAGEMENT 
Data will be entered into a clinical database, as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Data will be reviewed and checked for omissions, apparent errors, and values 

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KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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requiring further clarification using computerized and manual procedures. Data queries requiring 
clarification will be communicated to the investigational site for resolution. Only authorized 
personnel will make corrections to the clinical database, and all corrections will be documented 
in an audit trail. 
The coding of an AE, medical history and concomitant medication terms will be performed by 
the Sponsor or designated vendor and reviewed and approved by the Sponsor. Concomitant 
medications will be coded using the World Health Organization Drug Dictionary (WHODrug) 
and AE/medical history/surgery/non drug therapy terms will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
14 RETENTION OF RECORDS 
No study documents at the study site should be destroyed without prior written agreement 
between the Sponsor and the Investigator. All subjects’ medical records, the Investigator’s copy 
of the eCRF, other supporting data, records of drug dispensing and accountability, signed ICFs, 
IRB correspondence, and correspondence with the Sponsor must be kept by the Investigator for 
at least 2 years and/or as required by the local law following the date of the last approval of a 
marketing application in an ICH region (including the United States) and until there are no 
pending or contemplated marketing applications in any other ICH region. If an application is not 
filed or not approved for the indication under study, all study-related files must be retained for at 
least 2 years and for a period in compliance with all federal, state, and local regulations. The 
Sponsor must be notified prior to the disposal of any study-related files. If the Investigator leaves 
the practice or institution during the required retention period, it is important that arrangements 
be made for continued record retention. In that event, the records generally will be retained at the 
institution at which the study was conducted. 
15 PUBLICATION 
To avoid disclosures that could jeopardize proprietary rights, the institution and/or the 
Investigator agree to certain restrictions on publications (e.g., abstracts, speeches, posters, 
manuscripts, and electronic communications), as detailed in the Clinical Trial Agreement. 
16 REFERENCES 
ACR COVID-19 Vaccine Clinical Guidance Task Force. COVID-19 Vaccine Clinical Guidance 
Summary for Patients with Rheumatic and Musculoskeletal Diseases. Draft summary approved 
by ACR Board of Directors, February 8, 2021 
Bressolle F, Bologna C, Kinowski JM, Sany J, Combe B. Effects of moderate renal insufficiency 
on pharmacokinetics of methotrexate in rheumatoid arthritis patients. Ann Rheum Dis. 1998 
Feb;57(2):110-3. 
Brook RA, Forsythe A, Smeeding JE, Lawrence Edwards N. Chronic gout: epidemiology, 
disease progression, treatment and disease burden. Curr Med Res Opin. 2010;26(12):2813‐21. 

HORIZON THERAPEUTICS IRELAND DAC 
 
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Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: dimensions and practical 
applications. Health Qual Life Outcomes. 2003;1:20. 
Burmester GR, Kivitz AJ, Kupper H, et al.  Efficacy and safety of ascending methotrexate dose 
in combination with adalimumab: the randomised CONCERTO trial. Ann Rheum Dis. 2015 
Jun;74(6):1037-44. 
Ceponis A, Kavanaugh A. Use of methotrexate in patients with psoriatic arthritis. Clin Exp 
Rheumatol. 2010 Sep-Oct;28(5 Suppl 61):S132-7. 
Food and Drug Administration. Center for Drug Evaluation and Research, Division of 
Anesthesia, Analgesia, and Rheumatology Products. AAC Briefing Document Krystexxa 
(Pegloticase). 2009. 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Arthri
tisDrugsAdvisoryCommittee/UCM165714.pdf. [Accessed 2018 May 31]. 
Gaffo AL, Schumacher RH, Saag KG, et al. Developing a provisional definition of flare in 
patients with established gout. Arthritis Rheum. 2012;65(5):1508-17. 
Khanna D et al. 2012 ACR guidelines for management of gout; part 2. ACR Vol 64, No 10, Oct 
2012, p1447-1461. 
Khanna P, Khanna D, Storgard C, Baumgartner S, Morlock R. A world of hurt: failure to achieve 
treatment goals in patients with gout requires a paradigm shift. Postgrad Med. 
2016;128(1):34-40. 
Mease P. Methotrexate in psoriatic arthritis. Bull Hosp Jt Dis. 2013;71 Suppl 1:S41-5. 
Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher HR, Saag KG. Gout epidemiology: 
results from the UK General Practice Research Database, 1990 1999. Ann Rheum Dis. 
2005;64(2):267‐72. 
Mikuls TR, Johnson SR, Fraenkel L et al. American College of Rheumatology Guidance for the 
management of rheumatic disease in adult patients during the COVID-19 pandemic: Version 1. 
Arthritis Rheumatol. 2020a;72(8):1241–1251 
Mikuls TR, Johnson SR, Fraenkel L et al. American College of Rheumatology Guidance for the 
management of rheumatic disease in adult patients during the COVID-19 pandemic: Version 2. 
Arthritis Rheumatol. 2020b;72(9):e1–e12 
Mikuls TR, Johnson SR, Fraenkel L et al. American College of Rheumatology Guidance for the 
management of rheumatic disease in adult patients during the COVID-19 pandemic: Version 3. 
Arthritis Rheumatol. 2021;73(2):e1–e12 
Mouterde G, Baillet A, Gaujoux-Viala C, et al. Optimizing methotrexate therapy in rheumatoid 
arthritis: a systematic literature review. Joint Bone Spine. 2011 Dec;78(6):587-92. 

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KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. 2010;12(6):223. 
Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res 
Ther. 2006;8 Suppl 1:S2. 
Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology. American College of 
Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying 
antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008 Jun 15;59(6):762-84. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report–second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 
2006;117(2):391-7. 
Sattui SE, Singh JA, Gaffo AL. Comorbidities in patients with crystal diseases and 
hyperuricemia. Rheum Dis Clin North Am. 2014;40(2):251‐78. 
Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial 
Transplant. 2005;20 Suppl 6:vi3‐9. 
Singh JA, Strand V. Gout is associated with more comorbidities, poorer health related quality of 
life and higher healthcare utilisation in US veterans. Ann Rheum Dis. 2008;67(9):1310‐6. 
Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of biologics in chronic inflammatory 
diseases: a systematic review. BioDrugs. 2017:31(4):299-316. 
Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of 
chronic gout in patients refractory to conventional treatment: two randomized controlled trials. 
JAMA. 2011;306(7):711‐20. 
Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in 
rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009 Jul;68(7):1094-
9. 
Wertheimer A, Morlock R, Becker A. A revised estimate of the burden of illness of gout. Curr 
Ther Res Clin Exp. 2013;75:1‐4. 
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 v2.0. 
J Rheumatol. 2007;34(6):1401-14. 
Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general 
population: the National Health and Nutrition Examination Survey 2007‐2008. Arthritis Rheum. 
2011;63(10):3136‐41. 
 

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17 APPENDICES 
17.1 Administrative Appendix 
This appendix provides names and contact information for the study administrative structure. 
The IRB must be notified of changes that are made to this section, but IRB review or approval of 
these changes is not required. Changes made in this section will be dated but will not be assigned 
a protocol amendment number. 
Medical Monitor 
 
                                                            
  
                                                            Rheumatology Clinical Development 
                                                            Horizon Therapeutics USA, Inc. 
                                                            1 Horizon Way 
                                                            Deerfield, IL  60015 
 
Mobile telephone number: 
  
 
Office telephone number: 
 
 
 Fax number: 
 
 
Email: 
  
 
Sponsor 
 
Representative 
 
 
Horizon Therapeutics USA, Inc. 
 
1 Horizon Way 
 
Deerfield, IL  60015 
 
Mobile telephone number: 
 
 
Fax number: 
 
 Email: 
 
 
Sponsor Contact for 
 
Serious Adverse Event Reporting 
 Fax number: 
 
 
Email:
 
 
24-hour Phone Contact for 
 
Safety Coverage 
 

HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
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Protocol: HZNP-KRY-202 
 
 
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17.2 Health Assessment Questionnaire (Disability Index, Pain and Health Scales) 
Example HAQ below. This page not for subject use. Horizon will supply the site with copies for 
subject use. 

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Protocol: HZNP-KRY-202 
 
 
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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HORIZON THERAPEUTICS IRELAND DAC 
 
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17.3 Physician Global Assessment 
 

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