Clinical trial NCT03994731
Conditions: Gout
Keywords: gout uncontrolled gout
Sponsor: Amgen
Start date: 2019-06-13; Completion date: 2022-04-11
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the potential for pegloticase with methotrexate (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.

Detailed description:
Study acquired from Horizon in 2024.

Arms: arm 1: Following the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit, in which participants take oral MTX 15 mg weekly), participants tolerating MTX are randomized to receive blinded oral MTX 15 mg weekly during the Run-in Period (from Week -4 to Day 1).

During the Pegloticase + Immunomodulator (IMM) Period, in addition to oral 15 mg MTX, participants receive intravenous (IV) pegloticase 8 mg administered every 2 weeks (Q2W) for a total of 26 infusions from Day 1 through the Week 50 Visit.

Per protocol, participants are also required to take folic acid, at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤10 mg/day), and a regimen of fexofenadine, acetaminophen, and methylprednisolone for infusion reaction (IR) prophylaxis. arm 2: Following the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit, in which participants take oral MTX 15 mg weekly), participants tolerating MTX are randomized to receive blinded oral placebo for MTX weekly during the Run-in Period (from Week -4 to Day 1).

During the Pegloticase + IMM Period, in addition to oral placebo for MTX, all participants receive IV pegloticase 8 mg administered Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit.

Per protocol, participants are also required to take folic acid, at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤10 mg/day), and a regimen of fexofenadine, acetaminophen, and methylprednisolone for IR prophylaxis.
Interventions: intervention 1: Pegloticase intervention 2: methotrexate intervention 3: placebo intervention 4: folic acid intervention 5: gout flare prophylaxis regimen intervention 6: fexofenadine intervention 7: acetaminophen intervention 8: methylprednisolone
Intervention descriptions: intervention 1: IV pegloticase 8 mg Q2W intervention 2: Oral MTX 15 mg weekly intervention 3: Oral placebo for MTX intervention 4: Folic acid 1 mg orally every day beginning at Week -6 until prior to the Week 52 Visit. intervention 5: Prior to beginning the Pegloticase + IMM Period, participants must have been taking at least 1 protocol-standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤ 10 mg/day) for ≥ 1 week before the first dose of pegloticase and to continue 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 participants with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA \< 5 mg/dL) for participants with one or more tophi detected on initial physical exam that then resolved. intervention 6: For IR prophylaxis, fexofenadine (180 mg orally) taken the day before each infusion and on the morning of each infusion. intervention 7: For IR prophylaxis, acetaminophen (1000 mg orally) taken the morning of each infusion. intervention 8: For IR prophylaxis, methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to each infusion.

Protocol documents:
Prot_000.pdf: 
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 1 of 145 
 
 
 
 
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 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
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Page 4 of 145 
 
 
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 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
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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 
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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 
 
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Date: 24 August 2021 
 
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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. 


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Date: 24 August 2021 
 
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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 


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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 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
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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 
 
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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. 


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KRYSTEXXA IND: 010122 
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). 


HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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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.   


HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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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 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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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. 


HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
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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 


HORIZON THERAPEUTICS IRELAND DAC 
 
KRYSTEXXA IND: 010122 
Date: 24 August 2021 
 
Protocol: HZNP-KRY-202 
 
 
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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 
Date: 24 August 2021 
 
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 
extended to a minimum of 3 hours. 


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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 


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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 


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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 
 
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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 
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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 
 
KRYSTEXXA IND: 010122 
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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 
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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 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
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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 
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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 
 
 
Version 3.0, Amendment 2, Administrative Change 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 100 of 145 
 
 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 
Page 101 of 145 
 
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). 


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 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 
analysis. 


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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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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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Date: 24 August 2021 
 
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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 
 


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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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17.3 Physician Global Assessment 
 


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SAP_001.pdf: 
Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
 
 
This document is confidential. 
SAP Version: Version 3.0 / 23SEP2021 
 
 
Page 1 of 119 
Statistical Analysis Plan  
 
Sponsor Name: Horizon Therapeutics Ireland DAC 
 
Protocol Number: HZNP-KRY-202 
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 Version and Date:  Version 3.0, Amendment 2 (17Mar2021)  
 
 
 
 
  
 
SAP Version: 3.0 
 
SAP Version Date: 23-SEP-2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Horizon Therapeutics 
Ireland DAC. Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written authorization 
from an official of Horizon Therapeutics Ireland DAC. However, this document may be disclosed 
to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to 
keep it confidential. In the event of an actual or suspected breach of this obligation, 
 
 should be notified promptly. 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 2 of 119 
Revision History 
Version 
# 
Date 
(DD-
Mmm-
YYYY) 
Document 
Owner 
Revision Summary 
2.0 
12-
MAY-
2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Planned analyses revised to remove submission of 6M analysis data and 
unblinding after second DMC review 
 Alpha adjustment updated; response rate during Month 9 moved from 
secondary endpoint to exploratory 
 Clarifications made to rules for handling missing and impacted data due 
to COVID-19 for responder analyses 
 Clarifications added to multiple imputation process 
 Reorganization of primary endpoint analysis sections in 9.2 to match a 
protocol amendment; supplemental analysis section added and 
sensitivity analyses for mITT and PP populations moved to supplemental 
analysis 
 Supplemental analysis of response endpoints using logistic regression in 
imputation model added. 
 Summary of infusion reactions/anaphylactic reactions by ADA status 
added; summary of gout flares by 3 month intervals added; summary of 
AEs occurring on commercial pegloticase or MTX added 
 Changes from protocol were removed since a protocol amendment 
incorporated the changes listed in version 1.0 of the SAP. 
 
3.0 
23-SEP-
2021 
 
 
 Tipping point analysis added as sensitivity to primary endpoint analysis. 
 Supplemental analysis for primary endpoint added looking at response 
when a single sUA > 6 mg/dL stopping rule is applied. 
 Modifications made to the handling of data in subjects impacted by 
COVID-19; imputation for primary endpoint will be used only for subjects 
who have missing data during time of primary endpoint due to site 
closure from COVID-19. 
 Clarifications added for the analysis of tophi data. 
 Compliance calculation for MTX updated. 
 Other minor clarifications and grammatical corrections made. 




Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 4 of 119 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
 
Glossary of Abbreviations ................................................................................................... 8 
 
Purpose ............................................................................................................................ 12 
 
Study Objectives .............................................................................................................. 14 
 
Endpoints ......................................................................................................................... 30 
 
Analysis Populations ........................................................................................................ 33 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 5 of 119 
 
General Aspects for Statistical Analysis ........................................................................... 35 
 
Subject Disposition ........................................................................................................... 49 
 
Demographics, Other Characteristics, and Medication ..................................................... 51 
 
Efficacy ............................................................................................................................ 55 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 6 of 119 
 
Analysis of Anti-Drug Antibodies and Pharmacokinetics ................................................... 79 
 
Safety ............................................................................................................................... 81 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 7 of 119 
 
Changes from Analysis Planned in Protocol ..................................................................... 95 
 
Programming Considerations ........................................................................................... 96 
 
Quality Control ............................................................................................................... 101 
 
Index of Tables ............................................................................................................... 102 
 
Index of Figures.............................................................................................................. 113 
 
Index of Listings ............................................................................................................. 114 
 
References ..................................................................................................................... 116 
 
Appendix – SAS Code .................................................................................................... 117 
 








Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 11 of 119 
 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary 
tables and figures for the HZNP-KRY-202 study that will be produced, and the statistical 
methodologies that will be used, are complete and appropriate to allow valid conclusions 
regarding the study objectives.  
 
Responsibilities 
 will perform the statistical analyses and are responsible for the production and 
quality control of all tables, listings and figures (TLFs) for the HZNP-KRY-202 study, including 
summaries of concentrations for methotrexate (MTX) polyglutamate, pegloticase, and anti-drug 
antibodies (ADA). Additional pharmacokinetic (PK) analysis may be performed by a separate 
vendor and is not covered in the scope of this SAP.  
 will provide summarizations and listings for safety reviews. 
 
Planned Analyses 
 
Interim Analyses 
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of the 
study and perform  review of unblinded, comparative efficacy and safety data in order to protect 
subject welfare and preserve study integrity. The scope of the analysis to be provided to the DMC 
is provided in a mutually agreed upon charter, which defines the DMC membership and meeting 
logistics. 
There are two planned timepoints at which data will be reviewed by the DMC. The first 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 
assist in assessing risk and benefit. Additionally, some data for the secondary endpoints 
(response during Month 12) 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 this analysis. The DMC will recommend to Horizon whether to 
continue the study with or without modification or stop the study due to safety reasons. 
 
 
Final Analysis 
The primary analysis of all endpoints will be performed after all subjects reach Week 52 in which 
the primary and secondary efficacy endpoints will be tested at the 0.0495 significance level in 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 12 of 119 
sequential order. All other efficacy endpoints are exploratory in nature and will be tested using 2-
sided tests at the 5% significance level without multiplicity adjustment. 
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. 
In addition to the above analyses, blinded safety data will be summarized regularly throughout 
the study for safety monitoring by the Sponsor.  
 
Coronavirus Disease 2019 (COVID-19) 
The COVID-19 pandemic outbreak occurred midway through enrollment for this study.  This SAP 
will describe analyses to be performed to assess the impact of COVID-19 on the study and 
methods for handling missing data due to the effects of COVID-19 on study subjects and sites. 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 13 of 119 
 
Study Objectives 
 
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 
 
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 and 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 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 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 14 of 119 
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 Health Assessment Questionnaire (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 Health Assessment Questionnaire – Disability Index 
(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. 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 15 of 119 
 
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-polyethylene glycol (PEG) and anti-uricase immunoglobulin 
(IgG) antibodies. 
 
Safety and Tolerability Objectives 
 
Evaluate the safety and tolerability of pegloticase with MTX vs. pegloticase with placebo 
for MTX by examining the following: 
o Adverse event (AE)/serious adverse event (SAE) profile overall for pegloticase 
and the combination of pegloticase and MTX 
 
And in particular, the Incidence of adverse event of special interest 
(AESI): infusion reactions (IRs), anaphylaxis, gout flares, cardiovascular 
events 
o Mean change in laboratory results 
o Mean change in vital sign parameters  
 
Brief Description 
This is a Phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of pegloticase with MTX vs. pegloticase with placebo 
for MTX in treating adult subjects with uncontrolled gout.  
The study design will include: 1) Screening Period (screening should be completed within 4-6 
weeks prior to Week -6); 2) 2-week MTX Tolerability Assessment Period consisting of 2 weeks 
of open-label oral MTX for all subjects; 3) Run-in Period consisting of randomization followed by 
4 weeks of blinded oral MTX or placebo for MTX; 4) 52-week Pegloticase + IMM Period; 5) 30-
day Safety Follow-up (Phone/Email/Site Visit) and 6) 3 and 6 month Post Treatment Follow-up. 
All subjects who meet eligibility criteria at Screening will begin weekly 15 mg MTX orally  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.  


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
SAP Version: 3.0 / 23SEP2021 
 
 
 
Page 16 of 119 
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 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, initiated 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. 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
This document is confidential. 
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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.   
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. 
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 DMC will be convened to review data for safety and efficacy with the timepoint of 
review and criteria outlined in the DMC Charter, with the possibility of DMC recommendation on 
study cessation or 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. 
 
 
Determination of Sample Size 
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). 
The COVID-19 pandemic outbreak occurred midway through enrollment for the study, which 
has affected some subject enrollment and data acquisition during the trial.  As a result, the 
Sponsor has planned to enroll approximately 10 additional subjects (for a total of 145 
randomized subjects), in order to obtain information equivalent to studying at least 135 subjects 
not impacted by COVID-19. 
 
Treatment Assignment & 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. 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
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Methotrexate 
The Sponsor, Investigator, study site personnel and study subject will remain blinded to each 
subject’s treatment assignment (MTX or placebo for MTX). 
 
 
 will provide access to blinded subject treatment information 
during the study in the case of medical emergency. The study blind 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 study medication. If a subject’s study medication is 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 the interim analyses of 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 in protocol. 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. 
 
Administration of Study Medication 
During the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit), all subjects 
will take weekly open-label MTX 15 mg orally. 
At the Week -4 visit, subjects who tolerated MTX during the tolerability period will be 
randomized to receive MTX 15 mg or matching placebo orally once a week from Week -4 to 
Day 1 (Run-in Period). During the Run-in Period, subjects will take the blinded MTX or placebo  
at the 15 mg 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. 


Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
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Subjects will continue taking MTX or placebo 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.  
 
Study Procedures and Flowchart 
The flowchart copied from the protocol, Section 2.1, is reproduced here. 
 
 














Statistical Analysis Plan  
Sponsor: Horizon Therapeutics Ireland DAC; Protocol No.: HZNP-KRY-202 
 
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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. 
3. 
52-week Pegloticase + MTX or Pegloticase + placebo for MTX Period. 
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, a separate set 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.  


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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. 
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 and the End of Pegloticase Infusions Visit (if applicable) 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 


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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 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 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. 
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 in protocol 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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Endpoints 
 
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 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. 
 
 
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 14, 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. 


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 
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 following the first infusion. 
 
The time to two consecutive sUA > 6 mg/dL (stopping rule) following the first infusion. 
 
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. 
 
The mean change from baseline in SBP and DBP to each visit. 
 
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. 
 
Safety and Tolerability Endpoints 
Safety and tolerability endpoints are: 


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 
Incidence of AEs/SAEs overall and potentially attributed to the combination of 
pegloticase and MTX 
o Incidence of AESI: IRs, anaphylaxis, gout flares, cardiovascular events 
 
The mean change from baseline in laboratory test results 
 
The mean change from baseline in vital sign parameters  


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Analysis Populations 
The following analysis populations will be defined for this study:  
 
MTX Population 
The MTX population will include all subjects who take at least one dose of MTX. 
The MTX population will be used for analysis of safety data during the Tolerability Assessment 
Period prior to randomization and the concentrations of MTX polyglutamate. 
 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will include all randomized subjects. 
The ITT population will be used for efficacy analyses; subjects will be analyzed according to 
randomized treatment. It will be considered the primary efficacy analysis population. 
 
Modified Intention-to-Treat Population 
The Modified Intention-to-Treat (mITT) population will include all randomized subjects who 
receive at least 1 dose of pegloticase.  
The mITT population will be used for efficacy analyses; subjects will be analyzed according to 
randomized treatment. 
 
 
Per-protocol Population 
The Per-protocol (PP) population will include all randomized subjects who receive at least 1 
dose of pegloticase, are taking the 15 mg dose of MTX or placebo at the time of first pegloticase 
dose, and have no major protocol deviations that will challenge the validity of their data. The PP 
population will be used for analysis of the primary efficacy endpoint. 
Major protocol deviations will be classified as exclusionary vs. non-exclusionary from the per-
protocol population. Classification of exclusionary protocol deviations will occur prior to the 
unblinding of treatment groups after all subjects complete the Pegloticase + IMM period. Only 
exclusionary deviations that occurred prior to and including Week 24 will be used for 
classification. Exclusionary deviations include: 
 
Enrollment of a subject who did not satisfy the following inclusion/exclusion criteria (see 
Section 9.3 of the protocol): 
o Inclusion criteria #4 and #8 
o Exclusion criteria #13, #15, and #16 
 
 
Subject received treatment other than that to which he or she was randomized 
 
Compliance with MTX or placebo < 80% while receiving pegloticase 
 
Missing >20% of pegloticase infusions unless due to adverse event 


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 
Any other deviation that has the potential to negatively impact the validity of the primary 
or secondary endpoints. 
Compliance will be assessed based on the drug accountability data (per method defined in 
Section 11.1).    
“Missed infusion” is defined as a subject not receiving an infusion at a scheduled visit through 
Week 22 (or not attending a scheduled infusion visit) prior to discontinuation of pegloticase 
treatment unless the reason for not receiving infusion is due to an adverse event. Subjects are 
allowed to discontinue pegloticase treatment for any reason and will not be excluded from the 
Per-Protocol population unless they miss >20% of infusions prior to the End of Pegloticase Visit 
for reasons other than adverse event.   
Subjects with exclusionary deviations specified above that are due to COVID-19 (other than 
those due to suspected or confirmed infection) will be excluded from the PP Population. 
 
Pharmacokinetic Population 
The Pharmacokinetic (PK) Population will include all randomized subjects who receive at least 1 
dose of pegloticase and have a post-pegloticase sample evaluable for PK analysis. 
The PK population will be used for pharmacokinetic analyses of pegloticase. Subjects will be 
analyzed according to the treatment received. In the event a subject receives more than one 
treatment, the subject will be summarized by the treatment received most frequently. 
 
Safety Population 
The safety population will include all randomized subjects who take at least one dose of blinded 
MTX or placebo for MTX. 
The safety population will be used for analysis of safety data and ADA data; subjects will be 
analyzed according to the treatment received. In the event a subject receives more than one 
treatment (i.e. receives treatment other than randomized treatment), the subject will be 
summarized by the treatment received most frequently. 
 
Protocol Deviations 
Protocol deviations are entered into the electronic Case Report Form (eCRF) system. Sites will 
be issued following specific instructions to capture missed visits, out of window visits, treatment 
interruptions and treatment discontinuations due to COVID-19 on the eCRF, including whether 
subject has suspected or confirmed COVID-19 infection, and whether the study site is open or 
closed.  Deviations will be categorized by type and as major or minor. Deviations will be classified 
as occurring in the Screening, MTX Tolerability Assessment Period, Run-in Period, Pegloticase 
+ IMM Period, or Follow-up Period.  
Using the MTX and ITT populations, major deviations will be summarized by type and period of 
occurrence. In addition, deviations related to COVID-19 will be summarized by type and period of 
occurrence.  A listing of all subjects with all deviations related to COVID-19 will be presented. 


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General Aspects for Statistical Analysis 
 
General Methods 
The following conventions will be utilized in the analyses:  
 
In general, descriptive summaries will be provided. Efficacy summaries will be provided 
showing columns for the treatment of Pegloticase + MTX, or Pegloticase + Placebo for 
the ITT, mITT, and PP populations. Safety summaries will be provided for the safety 
population. For safety summaries during the MTX Tolerability Assessment Period, the 
MTX population will be used. Depending on the treatment period, different columns will 
be presented for safety summaries:  
o single column of MTX will be presented for MTX tolerability assessment period;  
o columns of MTX or Placebo will be presented for Run-in Period;  
o columns of Pegloticase + MTX, or Pegloticase + Placebo will be presented for 
Pegloticase + IMM Period. 
 
The following labels will be used for the populations: “ITT Population”, “mITT 
Population”, “PP Population”, “Safety Population”, “MTX Population”, or “PK Population”. 
The following column labels will be used for the treatment groups: MTX, Placebo, 
Pegloticase + MTX, or Pegloticase + Placebo.  
 
Unless otherwise indicated, continuous variables will be summarized using the number 
of observations (n), mean, standard deviation (SD), median, minimum (min), and 
maximum (max). Categorical variables will be summarized using number of observations 
(n), frequency and percentages of subjects. 
 
The same number of decimal places as the raw data will be presented when reporting 
min and max, 1 more decimal place than in the raw data will be presented when 
reporting mean and median, and 2 more decimal places than in the raw data will be 
presented when reporting SD. 
 
Unless otherwise specified, confidence intervals (CI) will be based on 95% confidence 
and two-sided. 
 
If multiple assessments occur at a given post-baseline time point, the latest value will be 
used.  
 
All relevant subject data will be included in listings. All subjects entered into the 
database will be included in subject data listings. 
 
Additional programming considerations are provided in Section 13. 


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Key Definitions 
 
Baseline 
For assessments without a measurement taken prior to the first dose of MTX (DECT, X-ray of 
hands and feet, spot urine collection, and antibody sample), the baseline value will be defined 
as last observation prior to the first dose of pegloticase. For all other assessments, the baseline 
value will be defined as the last measurement taken prior to first dosing of MTX in the MTX 
Tolerability Assessment Period (considering unscheduled visits when available). Change from 
Baseline will be defined as the measurement at each time point minus the Baseline value.  
 
Study Day 
Two different study days will be calculated, the MTX Study Day and the Pegloticase Study Day. 
The MTX Study Day will be determined relative to the first dose of MTX in the MTX Tolerability 
Assessment Period. The Pegloticase Study Day will be determined relative to the first infusion 
of pegloticase. 
For both study day calculations, study days on or after the first dose date the study day will be 
calculated as (assessment date – first dose date) + 1. For study days prior to the first dose date, 
study day will be calculated as assessment date – first dose date. There will be no study day 0.  
 
Age  
Age will be calculated as (informed consent date - date of birth + 1) / 365.25 then truncated to a 
complete year. If the date of birth is only partially available, the first of the month will be imputed 
for any missing days and January will be imputed for any missing months. 
 
Missing Data 
 
Medication Dates 
For prior and concomitant medications with incomplete dates, the following rules will be used to 
impute start and/or stop dates for the purposes of determining if a medication is prior, concomitant 
in the MTX Tolerability Assessment Period, concomitant in the Run-in Period, or concomitant in 
the Pegloticase + IMM Period. Imputed dates will not be presented in the data listings. 
For partial start dates: 
 
If the month and year are provided and day is missing  
o If the month and year match the month and the year of the first pegloticase dose date 
AND match the month and the year of the first MTX dose or placebo in Run-in Period 
(i.e. the MTX or placebo in Run-in Period and pegloticase started in the same month), 
the day of the first dose date of MTX or placebo in Run-in Period will be imputed.  
o Otherwise, if the month and year match the month and the year of the first MTX dose 
date in MTX Tolerability Assessment Period AND match the month and the year of the 
first MTX dose or placebo in Run-in Period (i.e. the MTX in MTX Tolerability 
Assessment Period and MTX or placebo in Run-in Period started in the same month), 


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the day of the first dose date of MTX in MTX Tolerability Assessment Period will be 
imputed.  
o Otherwise, if the month and year match the month and year of the first pegloticase 
dose date, then the first dose date of pegloticase will be imputed.  
o Otherwise, if the month and year match the month and year of the first MTX dose or 
placebo date (either in MTX Tolerability Assessment Period, or Run-in Period), then 
the first dose date of MTX or placebo will be imputed.  
o Otherwise, the first of the month will be used.  
 
If the year is provided and the month and day are missing  
o If the year matches the year of the first pegloticase dose date and the year matches 
the year of the first MTX dose or placebo date, the month and day of the first MTX or 
placebo date will be imputed.  
o Otherwise, if the year matches the year of the first dose of pegloticase, the first dose 
date of pegloticase will be imputed.  
o Otherwise, if the year matches the year of the first MTX or placebo date, then the first 
dose date of MTX or placebo will be imputed.  
o Otherwise, January 1st will be used.  
 
If the start date is completely missing, the start date will not be imputed. If the stop date is 
after first dose date of pegloticase, the medication will be considered to be both prior, 
concomitant in the MTX Tolerability Assessment Period, concomitant in the Run-in Period, 
and concomitant in the Pegloticase + IMM Period. If the stop date is on or after the first 
dose date of MTX in the MTX Tolerability Assessment Period, but prior to the first dose of 
MTX or placebo dose date in the Run-in Period, the medication will be considered to be 
prior and concomitant in the MTX Tolerability Assessment Period. If the stop date is on or 
after the first dose date of MTX or placebo in the Run-in Period, but prior to the first dose 
date of pegloticase, the medication will be considered to be prior and concomitant in the 
MTX Tolerability Assessment Period and Run-in Period. If the stop date is prior to the first 
dose date of MTX in the MTX Tolerability Assessment Period, the medication will be 
considered to be prior only.  
 
If the stop date is complete and the imputed start date is after the actual stop date, then 
the start date will be imputed as the stop date. 
For partial stop dates: 
 
If the month and year of stop are provided, but the day is missing, then the last day of the 
month will be used. 
 
If the year of stop is provided, but the month and day are missing, then December 31st of 
that year will be used.  


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 
If the stop date is completely missing, then the date of last study visit will be used.  
 
Adverse Events 
For adverse events with incomplete dates, the following rules will be used to impute start and/or 
stop dates for the sole purpose of determining if an AE is treatment-emergent in the MTX 
Tolerability Assessment Period, Run-in Period, or Pegloticase + IMM Period. Imputed dates will 
not appear in the data listings. 
For partial start dates: 
 
If the month and year of adverse event onset are provided but day is missing 
o If the month and year match the month and year of the first dose of MTX in the 
MTX Tolerability Assessment Period AND match the month and year of the first 
MTX or placebo in the Run-in Period, the first dose date of MTX in the MTX 
Tolerability Assessment Period will be imputed and the event will be considered 
treatment emergent in the MTX Tolerability Assessment Period, and Run-in 
Period.  
o If the month and year match the month and year of the first dose of MTX or Placebo 
in the Run-in Period AND match the month and year of the first infusion of 
pegloticase in the Pegloticase + IMM Period, the first dose date of MTX or placebo 
in the Run-in Period will be imputed and the event will be considered treatment 
emergent in the Run-in Period and Pegloticase + IMM Period. 
o Otherwise, if the month and year match the month and the year of the first dose 
date of pegloticase, the day of the first infusion date of pegloticase will be imputed 
and the AE will be considered treatment-emergent in the Pegloticase + IMM 
Period.  
o Otherwise, if the month and year match the month and the year of the first dose 
date of MTX in the MTX Tolerability Assessment Period, the day of the first dose 
date of MTX in the MTX Tolerability Assessment Period will be imputed and the 
AE will be considered treatment-emergent in the MTX Tolerability Assessment 
Period. 
o Otherwise, if the month and year match the month and the year of the first dose 
date of MTX or placebo in the Run-in Period, the day of the first dose date of MTX 
or placebo in the Run-in Period will be imputed and the AE will be considered 
treatment-emergent in the Run-in Period. 
o Otherwise, the first of the month will be used and the treatment-emergent status 
will be assessed relative to the first infusion date of pegloticase, the first dose date 
of MTX in the MTX Tolerability Assessment, or the first dose date of MTX or 
placebo in the Run-in Period.  
 
If the year of adverse event onset is provided, but the month and day are missing 


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o If the year matches the year of the first dose of MTX in the MTX Tolerability 
Assessment Period AND matches the year of the first dose of MTX or placebo in 
the Run-in Period, the first dose date of MTX in the MTX Tolerability Assessment 
Period will be imputed and the event will be considered treatment emergent in 
the MTX Tolerability Assessment Period, and Run-in Period. 
o If the year matches the year of the first dose of MTX or placebo in the Run-in 
Period AND matches the year of the first infusion of pegloticase in the 
Pegloticase + IMM Period, the first dose date of MTX or placebo in the Run-in 
Period will be imputed and the event will be considered treatment emergent in 
the Run-in Period and Pegloticase + IMM Period. 
o Otherwise, if the year matches the year of the first infusion date of pegloticase, the 
month and the day of the first infusion date of pegloticase will be imputed, and the 
AE will be considered treatment-emergent in the Pegloticase + IMM Period.  
o Otherwise, if the year matches the year of the first dose date of MTX in the MTX 
Tolerability Assessment Period, the month and day of the first dose of MTX in the 
MTX Tolerability Assessment Period will be imputed and the AE will be considered 
treatment-emergent in the MTX Tolerability Assessment Period.  
o Otherwise, if the year matches the year of the first dose date of MTX or placebo in 
the Run-in Period, the month and day of the first dose of MTX or placebo in the 
Run-in Period will be imputed and the AE will be considered treatment-emergent 
in the Run-in Period. 
o Otherwise, January 1st will be used and the treatment-emergent status will be 
assessed relative to the dosing start date of pegloticase and the first dose date of 
MTX in the MTX Tolerability Assessment Period. 
 
If the start date is completely missing, the AE will be considered treatment-emergent in 
the Pegloticase + IMM Period, the MTX Tolerability Assessment Period, and the Run-in 
Period, unless the stop date is complete or provides enough partial information to rule out 
a treatment-emergent status in the MTX Tolerability Assessment Period, the Run-in Period 
or in the Pegloticase + IMM Period. This should be a rare occurrence. 
If the stop date is complete and the imputed start date is after the actual stop date, then the start 
date will be imputed as the stop date. 
Events with missing relationship to study drug in the MTX Tolerability Assessment Period will be 
considered “related” to Methotrexate for statistical summaries. Events with missing relationship 
to study drug in the Run-in Period will be considered “related” to Methotrexate or placebo for 
statistical summaries. Events with missing relationship to study drug in the Pegloticase + IMM 
Period will be considered “related” to Methotrexate or placebo and “related” to pegloticase for 
statistical summaries. 
Missing severities will be considered “severe” for statistical summaries. 


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Missing Data due to COVID-19 in sUA Responder Endpoints 
In general, the estimand for this study will use the Treatment Policy Strategy for intercurrent 
events (ICEs), as planned during the design of this study. However, the COVID-19 pandemic was 
not anticipated, and the methodology will be changed for some ICEs. To make the analysis results 
applicable to the post-pandemic situation in which the virus is present in society but site closures 
(due to COVID-19) do not prevent office visits, subjects missing primary and secondary endpoint 
data due to site closure related to COVID-19 will have missing data addressed using the 
Hypothetical Strategy for ICEs. Under this strategy, partial data will be used for more efficient 
estimates of the analysis parameters. 
The protocol deviation eCRF and disposition eCRFs will record reasons for missed visits, 
interruptions in study treatment, and reasons for treatment discontinuation. For deviations related 
to COVID-19, the study team will review before database lock and unblinding and assign a 
category for missing data as defined below. For analyses of response during a timepoint (Month 
3, Month 6, Month 9, and Month 12), the following rules will be applied: 
 
Stopping rule: if a subject meets the sUA stopping rule prior to the analysis timepoint of 
interest and prior to any other COVID-19 impact (from categories below), the subject will 
be considered a non-responder for any timepoint after stopping rule was met.   
 
COVID-19 infection: if a subject is missing results during the timepoint due to confirmed 
or suspected COVID-19 infection prior to this period the subject will be considered a non-
responder.  
 
Site closure: if a subject is ongoing in the study but the site is closed due to COVID-19 
during the analysis timepoint of interest, resulting in missing data for the timepoint, then 
multiple imputation will be used to impute missing sUA values during the timepoint to 
calculate response.  
 
COVID-19 related:  if a subject has missing data for the analysis timepoint of interest due 
to COVID-19 (e.g. had concerns about remaining in study due to pandemic, sheltering in 
place/unable to travel due to COVID-19 restrictions) then the subject will be considered 
a non-responder.   
Details of the multiple imputation process are described in Section 9.2.2 
 
 
Visit Windows 
For all analyses, data will be summarized according to the scheduled visit and time points as 
outlined in the protocol and by the visit denoted on the electronic case report form (eCRF). 
Further, the End of Study/Early Termination (ET) visit and the End of Pegloticase Infusion Visit 
will be windowed to a visit based on the pegloticase study day of occurrence relative to the target 
day of each scheduled visit according to Table 1, Table 2, Table 3, Table 4, Table 5, Table 6,  
Table 7, and Table 8 below. Table 1 shows windows for the gout assessments and sUA 
collections. Table 2 shows windows for vital sign assessments. Table 3 shows the visit windows 
for the clinical laboratory and ADA assessments. Table 4 shows the windows for swollen/tender 
joints, HAQ, and physician global assessment parameters. Table 5 shows the windows for the 
assessment of DECT. Table 6 shows the windows for the assessment of digital photography. 
Table 7 shows the visit windows for the MTX polyglutamate assessments. Unscheduled sUA 
visits, assessed by the central laboratory or local laboratory (see Section 9.1),  will be assigned 


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an analysis window according to the window below. These unscheduled will be used for the 
determination of sUA responder. 
Table 1: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (Gout Assessments and sUA collections) 
Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
Pegloticase + IMM 
Day 1 
1 
1 
 
Week 2 
15 
2 – 22 
 
Week 4 
29 
23 – 36 
 
Week 6 
43 
37 – 50 
 
Week 8 
57 
51 – 64 
 
Week 10 
71 
65 – 78 
 
Week 12 
85 
79 – 92 
 
Week 14 
99 
93 – 106 
 
Week 16 
113 
107 – 120 
 
Week 18 
127 
121 – 134 
 
Week 20 
141 
135 – 144 
 
Week 21 
148 
145 – 151 
 
Week 22 
155 
152 – 158 
 
Week 23 
162 
159 – 165 
 
Week 24 
169 
166 – 176 
 
Week 26 
183 
177 – 190 
 
Week 28 
197 
191 – 204 
 
Week 30 
211 
205 – 218 
 
Week 32 
225 
219 – 232 
 
Week 34 
239 
233 – 246 


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Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
 
Week 36 
253 
247 – 260 
 
Week 38 
267 
261 – 274 
 
Week 40 
281 
275 – 288 
 
Week 42 
295 
289 – 302 
 
Week 44 
309 
303 – 316 
 
Week 46 
323 
317 – 330 
 
Week 48 
337 
331 – 344 
 
Week 50 
351 
345 – 358 
 
Week 52 
365 
≥ 359  
a Study days in the Pegloticase + IMM Period will be calculated relative to the first dose of 
pegloticase. 
 
 


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Table 2: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (Vital Signs) 
Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
Pegloticase + IMM 
Day 1 
1 
1 
 
Week 2 
15 
2 – 22 
 
Week 4 
29 
23 – 36 
 
Week 6 
43 
37 – 50 
 
Week 8 
57 
51 – 64 
 
Week 10 
71 
65 – 78 
 
Week 12 
85 
79 - 92 
 
Week 14 
99 
93 – 106 
 
Week 16 
113 
107 – 120 
 
Week 18 
127 
121 – 134 
 
Week 20 
141 
135 – 148 
 
Week 22 
155 
149 – 162 
 
Week 24 
169 
163 – 176 
 
Week 26 
183 
177 – 190 
 
Week 28 
197 
191 – 204 
 
Week 30 
211 
205 – 218 
 
Week 32 
225 
219 – 232 
 
Week 34 
239 
233 – 246 
 
Week 36 
253 
247 – 260 
 
Week 38 
267 
261 – 274 
 
Week 40 
281 
275 – 288 


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Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
 
Week 42 
295 
289 – 302 
 
Week 44 
309 
303 – 316 
 
Week 46 
323 
317 – 330 
 
Week 48 
337 
331 – 344 
 
Week 50 
351 
345 – 358 
 
Week 52 
365 
≥ 359  
a Study days in the Pegloticase + IMM Period will be calculated relative to the first dose of 
pegloticase. 
Table 3: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (Laboratory and ADA Assessments) 
Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
Pegloticase + IMM 
Day 1 
1 
1 
 
Week 2 
15 
2 – 29 
 
Week 6 
43 
30 – 71 
 
Week 14 
99 
72 – 127 
 
Week 22 
155 
128 -162 
 
Week 24 
169 
163 - 211 
 
Week 36 
253 
212 - 309 
 
Week 52 
365 
≥ 310  
a Study days in the Pegloticase + IMM Period will be calculated relative to the first dose of 
pegloticase. 
 
 


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Table 4: Visit Windows for Assigning ET and End of Pegloticase Visits to a Scheduled Visit 
(Swollen/Tender Joint Counts, HAQ, Physician Global Assessments) 
Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
Pegloticase + IMM 
Day 1 
1 
1 
 
Week 6 
43 
2 – 71 
 
Week 14 
99 
72 – 120 
 
Week 20 
141 
121 -155 
 
Week 24 
169 
156 - 190 
 
Week 30 
211 
191 – 232 
 
Week 36 
253 
233 – 281 
 
Week 44 
309 
282 – 337 
 
Week 52 
365 
≥ 338  
a Study days in the Pegloticase + IMM Period will be calculated relative to the first dose of 
pegloticase. 
Table 5: Visit Windows for Assigning ET and End of Pegloticase Visits to a Scheduled Visit 
(DECT and Urinalysis) 
Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
Pegloticase + IMM 
Day 1 
1 
1 
 
Week 14 
99 
2 – 134 
 
Week 24 
169 
135 – 267 
 
Week 52 
365 
≥ 268 
a Study days in the Pegloticase + IMM Period will be calculated relative to the first dose of 
Pegloticase. 
 
 


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Table 6: Visit Windows for Assigning ET and End of Pegloticase Visits to a Scheduled Visit 
(Digital Photography for Tophi Assessment) 
Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
Pegloticase + IMM 
Day 1 
1 
1 
 
Week 14 
99 
2 – 134 
 
Week 24 
169 
135 – 211 
 
Week 36 
253 
212 – 309 
 
Week 52 
365 
≥ 310  
a Study days in the Pegloticase + IMM Period will be calculated relative to the first dose of 
pegloticase. 
 
 


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Table 7: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (Pre-infusion MTX Polyglutamate Assessments) 
Study Period 
 
Visit 
 
Target Day a  
Window for 
Reassignment to 
Scheduled Visit (days) 
Pegloticase + IMM 
Day 1 
1 
1 
 
Week 14 
99 
2 – 134 
 
Week 24 
169 
135 - 211 
 
Week 36 
253 
≥ 212  
a Study days in the Pegloticase + IMM Period will be calculated relative to the first dose of 
pegloticase. 
In the event that an End of Study/ET or End of Pegloticase visit is reassigned to a visit for which 
the subject has scheduled data collected, the data from the nominal scheduled visit will take 
precedence and the data from the End of Study/ET or End of Pegloticase visit will not be 
summarized. If the End of Study/ET or End of Pegloticase visit maps to a visit where the 
assessment was scheduled to be collected, and a scheduled collection is not available at that 
time point, the End of Study/ET or End of Pegloticase visit data will be summarized in the 
scheduled visit assessment. 
For visit summaries and changes from baseline summaries, scheduled visits and mapped visits 
based on the visit windows will be used for summaries by visit. 
 
Pooling of Centers 
Data from all sites will be summarized together for analyses. 
 
Subgroups 
Subgroup analyses will be repeated for the primary and secondary efficacy analyses for the 
following subgroups: 
1) Age group (<65, ≥ 65 years) 
2) BMI (≤30, >30 kg/m2) 
3) Sex (female, male) 
4) Presence of tophi (yes, no) 
5) Race (white, other) 
6) Randomization group (first 135 randomized, subjects randomized after 135th subject) [only 
to be used for the primary endpoint analysis] 


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Subject Disposition  
A summary of subject disposition will be provided including the number of subjects screened and 
number of screen failures (summarized by those who received open-label MTX vs. those who did 
not), as well as the number of subjects in each analysis population (MTX, ITT, mITT, PP, Safety, 
and PK Populations). In addition, the number and percent of subjects in each of the following 
categories will be provided for the ITT Population by randomized treatment: 
 
 
Randomized and discontinued study prior to receiving randomized MTX or placebo 
 
Entered the Run-in Period (took at least one dose of MTX or placebo) 
o Discontinued from treatment in the Run-in Period 
o Discontinued from study in the Run-in Period along with reason for study 
discontinuation 
 
Entered the Pegloticase + IMM Period  
o Completed pegloticase treatment for the 52 Week Pegloticase + IMM Period 
o  Completed MTX or placebo treatment for the 52 Week Pegloticase + IMM Period 
o Discontinued MTX or placebo treatment in the Pegloticase + IMM Period and 
completed pegloticase treatment 
o Discontinued prematurely from pegloticase treatment in the Pegloticase + IMM 
Period along with reason for treatment discontinuation  
o Discontinuations from pegloticase treatment in the Pegloticase + IMM Period will 
be further broken down by whether they occurred 
 
Prior to Week 14 (Month 3) Time Point  
 
Prior to Week 24 (Month 6) Time Point  
 
Prior to Week 36 (Month 9) Time Point 
 
Prior to Week 52 (Month 12) Time Point 
o Discontinued from pegloticase treatment in the Pegloticase + IMM Period but 
continued in the study 
o Discontinued prematurely from the study during the Pegloticase + IMM Period 
along with reason for study discontinuation  
o Completed study 


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Percentages will be based on the number of subjects in the ITT population. The number of 
subjects who discontinue treatment or study due to COVID-19 will be summarized. A separate 
summary will be provided of the number and percentage of subjects attending each visit using 
the ITT Population. Percentages will be based on the number of subjects in the population and 
randomized treatment as described in Section 6.1. MTX population subjects who are randomized 
are included in the ITT population. ITT population subjects who received an infusion of 
Pegloticase are also included in the mITT population. 
 


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Demographics, Other Characteristics, and Medication  
 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented overall for 
the MTX, ITT, mITT, and safety populations by treatment as described in Section 6.1. In addition, 
the demographic characteristics will be summarized for the ITT population by subgroups of the 
first 135 subjects randomized, and all subjects randomized after the 135th subject. The 
characteristics being summarized include: age, age category (< 65 years, ≥ 65 years), sex, race, 
ethnicity, time since first symptoms of gout (in years), time since first diagnosis of gout (in years), 
presence of uric acid crystals confirming diagnosis, number of acute gout flares in joints over the 
past 12 months, number of acute gout flares in the past 6 months, pattern of flares, typical severity 
of acute flares, chronic gout synovitis/arthropathy, prior occurrence of tophi, occurrences of 
overnight stays in the hospital due to gout, occurrence of surgery for gout (excluding 
arthrocentesis), prior occurrence of kidney stones, number of episodes of renal colic in the past 
year, kidney function affected by gout historically, urate lowering therapy history, tobacco use 
history, current tobacco use status, alcohol use, other substance use, weight, height, body mass 
index (BMI), body surface area (BSA).  
Age, time since first symptoms of gout, time since first diagnosis of gout, number of gout flares 
over the past 12 months, number of acute flares in the past 6 months, number of episodes of 
renal colic in the past year, baseline weight, height, BMI, and BSA will be summarized as 
continuous variables showing number of non-missing values, mean, standard deviation, median, 
minimum and maximum. For number of flares, if the result is ‘>X’ the will qualifier will be dropped 
and the numeric value used in the analysis. 
Age category, sex, race, presence of uric acid crystals confirming diagnosis, number of gout flares 
over the past 12 months (1 flare, 2 flares, 3-5 flares, 6-10 flares and > 10 flares), number of acute 
flares in the past 6 months (1 flare, 2 flares, 3-5 flares, 6-10 flares and > 10 flares), chronic gout 
synovitis/arthropathy, prior occurrence of tophi, occurrences of overnight stays in the hospital due 
to gout, prior occurrence of kidney stones, kidney function affected by gout, tobacco use history, 
current tobacco use status, alcohol use, and other substance use will be summarized using 
categorical values. 
Weight will be converted to kilograms (kg) when reported in pounds (lbs) as follows: Weight (in 
kg) = weight (in lbs) * 0.4536. Height will be converted to meters (m) when reported in inches (in) 
as follows:  Height (in m) = height (in inches) * 0.0254. 
BMI will be calculated as Weight (kg) / [Height (m)]2. 
Time since first gout symptoms will be calculated as: (informed consent date - date of first 
symptoms + 1) / 365.25, rounded to two decimal places. In the event of a partial first symptom 
date, the earliest possible date implied by the data provided will be imputed (e.g. impute January, 
01 if only year is provided, or 01 for day if month and year is provided). 
Time since first gout diagnosis will be calculated as: (informed consent date - date of first 
diagnosis + 1) / 365.25, rounded to two decimal places. In the event of a partial diagnosis date, 
the earliest possible date implied by the data provided will be imputed (e.g. impute January, 01 if 
only year is provided, or 01 for day if month and year is provided). 


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Demographic data and baseline characteristics will be provided in subject listings. 
 
Medical History and Concomitant Diseases 
Medical history information will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.1, summarized and presented overall for the MTX and ITT Populations and 
by treatment as described in Section 6.1. Summaries will be ordered alphabetically by system 
organ class (SOC) and then, within a SOC, alphabetically by preferred term (PT). 
Medical history data will be listed. 
 
Medication 
Medications will be coded using World Health Organization (WHO) Drug Global B3 September 
2018 dictionary. Prior medications, concomitant medications used during the MTX Tolerability 
Assessment Period, concomitant medications used during the Run-in Period, concomitant 
medication used in the Pegloticase + IMM Period, and medications used in the Follow-up Period 
will be summarized by presenting the counts and percentage of subjects using medications 
overall for the MTX, ITT, and mITT (Follow-up Period only) Populations and treatment as 
described in Section 6.1. Summaries will be presented by Anatomical Therapeutic Chemical 
(ATC) Level 4 term and preferred drug name. Medication summaries will be sorted alphabetically 
by ATC Level 4 and by preferred drug name within ATC Level 4.  Subjects will be counted only 
once for each medication class and each preferred drug name.  
Prior and concomitant medications will be listed together with a designation to identify the 
period(s) of usage and sorted by start date. For determination of period(s) of use, missing date 
imputation rules are provided in Section 6.3.1. 
Any medication with a start date prior to the date of first dose of treatment in the MTX Tolerability 
Assessment Period will be considered a prior medication.  
The following medications will be considered concomitant in the MTX Tolerability Assessment 
Period  
 
A medication with a start date on or after the first dose date of MTX in the MTX Tolerability 
Assessment Period but excluding medications with: 
o 
Start date on or after the first MTX or placebo date in the Run-in Period and  
o 
Those started more than 30 days after the last MTX dose, for subjects who did not 
receive MTX or placebo in the Run-in Period and did not receive an infusion of 
pegloticase.  
 
Medications with a partial start date with month and year of start provided and the year of 
start and month of start match the month and year of first MTX date in the MTX Tolerability 
Assessment Period and match the month and year of first MTX or placebo date in the 
Run-in Period will be classified as being used in the MTX Tolerability Assessment Period 
and in the Run-in Period. 


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 
A medication with a start date prior to the first dose date of MTX in the MTX Tolerability 
Assessment Period with a stop date strictly after the first dose date of MTX in the MTX 
Tolerability Assessment Period 
 
A medication with a start date prior to the first dose date of MTX in the MTX Tolerability 
Assessment Period that was ongoing. 
The following medications will be considered concomitant in the Run-in Period  
 
A medication with a start date on or after the first dose date of MTX or placebo in the Run-
in Period but excluding medications with: 
o 
Start date on or after the first infusion date of pegloticase and  
o 
Those started more than 30 days after the last MTX or placebo dose in the Run-in 
Period, for subjects who did not receive an infusion of pegloticase.  
 
Medications with a partial start date with month and year of start provided and the year of 
start and month of start match the month and year of first MTX or placebo date in the Run-
in Period and match the month and year of first Pegloticase infusion will be classified as 
being used in the Run-in Period and in the Pegloticase + IMM Period. 
 
A medication with a start date prior to the first dose date of MTX or placebo in the Run-in 
Period with a stop date strictly after the first dose date of MTX or placebo in the Run-in 
Period 
 
A medication with a start date prior to the first dose date of MTX or placebo in the Run-in 
Period that was ongoing. 
The following medications will be considered concomitant in the Pegloticase + IMM Period  
 
A medication with a start date on or after the first infusion date of pegloticase but excluding 
medications with start date more than 30 days after the date of the end of the last 
pegloticase infusion.  
 
A medication with a start date prior to the first infusion date of pegloticase in the 
Pegloticase + IMM Period with a stop date strictly after the first infusion date of pegloticase 
in the Pegloticase + IMM Period. 
 
A medication with a start date prior to the first infusion date of pegloticase in the 
Pegloticase + IMM Period that was ongoing. 
 
Medications with a partial start date with month and year of start provided and the year of 
start and month of start match the month and year of first MTX or placebo date in the Run-
in Period and match the month and year of first Pegloticase infusion will be classified as 
being used in the Run-in Period and in the Pegloticase + IMM Period. 
The following medications will be considered concomitant during the Follow-up Period 


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 
A medication with start date prior to 30 days after last dose of study medication that 
continued use or had a stop date on or after 30 days after the last dose of study 
medication.  
 
A medication with a start date more than 30 days after the last dose of study medication. 
As such, the same medication may be summarized in one or more of prior, concomitant in the 
MTX Tolerability Assessment Period, concomitant in the Run-in Period, or concomitant in the 
Pegloticase + IMM Period. The summary tables will not be mutually exclusive. Missing date 
imputation rules are provided in Section 6.3.1. 
A summary of medications used for gout treatment taken after the last dose of pegloticase will be 
produced for the mITT Population. 
 
Concomitant Procedures 
A listing will be provided for concomitant procedures the subject underwent during the study. No 
other analysis is planned for concomitant procedures. 


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Efficacy 
 
Handling Rules for sUA Values  
Serum samples for measurement of sUA levels are scheduled for collection 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-dose and post dose 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 are 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. 
 
For the determination of sUA responder endpoints, scheduled assessments of sUA and 
unscheduled assessments of sUA, reported by the central laboratory, will be used. Local 
laboratory-processed pre-infusion sUA results will be used only when the central laboratory-
processed value at a time point is not available, but the local lab-processed pre-infusion value, 
collected value at the same time point, is available.  
 
When the central laboratory or local laboratory reports a value for sUA as being lower than 
the lab assay’s limit of quantification (e.g. “<0.02”), zero will be used as the numeric value for 
the purpose of determining response and for summaries of observed values and the change 
from baseline. 
 
Primary Efficacy Endpoint and Analysis 
This study will compare pegloticase 8 mg co-administered with MTX to pegloticase 8 mg co-
administered with placebo in subjects with uncontrolled gout. 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. The objective is to 
demonstrate superiority of pegloticase given with MTX over pegloticase given with placebo. The 
primary comparison will be made for ITT population, i.e., all randomized subjects, regardless of 
adherence to study treatment. The comparison is between randomized (planned) treatment 
groups of pegloticase given with MTX over pegloticase given with placebo. 
 
Calculation of Response  
The sUA concentrations vs. time (collected to the nearest minute in the CRF) curve will be used 
to estimate the proportion of time that the sUA is < 6 mg/dl using the available pre-infusion (or 
values at visit when no infusion performed) and post-infusion samples with non-missing sUA 
values.  
The Month 6 period will include pre-infusion and post-infusion results at Week 20, results at Week 
21, pre-infusion and post-infusion results at Week 22, results at Week 23, and pre-infusion results 
at Week 24, and unscheduled assessments of sUA collected between Week 20 and Week 24 


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processed by the central laboratory. Results from visits where an infusion was not performed (e.g. 
subject discontinued pegloticase but remained in study) will be used when available. Section 9.1 
shows the rules for inclusion of sUA values reported by local laboratories. 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
  
 
Handling of Missing Data and Multiple Imputation Process  
At least two sUA observations from different visits during Month 6 must be available in order for 
a subject to be eligible for consideration as a responder. Subjects with only one sUA observation 
will be considered non-responders, regardless of the value of that single observation; subjects 
with no sUA values will also be considered non-responders. In addition, subjects who meet the 
stopping rule (sUA values > 6 mg/dL at 2 consecutive scheduled visits (excluding post-infusion 
sUA) starting at Week 2 prior to or during Month 6 will be considered to be non-responders.  For 
determination of stopping rule, as specified in Section 9.1, if both central lab and local lab sUA 
results are available at a visit then the central lab value will be used for stopping rule 
determination.  For subjects with missing data due to COVID-19 that is not “Site Closure”, there 
will be no imputation of sUA values due to missing values among those collected between Week 
20 and Week 24. 
For subjects with missing data due to site closure (due to COVID-19 as defined in Section 6.3.3) 
during Month 6 (i.e. have < 2 visits during Month 6 with sUA available), multiple imputation will be 
used to impute missing sUA values . 
The multiple imputation process for imputing missing sUA will involve the following steps: 
1) For subjects who met the stopping rule and have missing data prior to or during Month 6, 
last observation carried forward (LOCF) imputation will be done in order to prevent the 


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multiple imputation algorithm from imputing data inconsistent with known information. For 
example, subjects who meet the sUA stopping rule and have missing sUA after stopping 
rule is met would be expected to continue to have sUA > 6 mg/dL in the absence of other 
treatment, and thus would be expected to be non-responders. LOCF is used to provide 
complete data for stopping rule subjects that may be used to impute missing sUA for “Site 
Closure” subjects. Note that these LOCF values will only be used in the imputation model, 
and will be excluded from all analyses once the imputation model has been used.  
 
2) A regression model will be created using observed data (after imputation specified in step 
#1 performed) from subjects not affected by site closures. A linear regression model will 
be fit for each sUA value comprising Month 6 (i.e., Week 20, Week 21, Week 22, Week 
23, Week 24) as the dependent variable and will include independent variables of 
treatment group, tophi presence, sex, age, baseline weight, race (white, non-white), 
available pre-infusion sUA values from Day 1 up through the timepoint of each dependent 
variable, serious AE (yes or no), severe AE (yes or no), and number of gout flares during 
the Pegloticase + IMM Period up through Month 6.   
 
 
3) Based on the fitted regression model, a new regression model is simulated from the 
posterior predictive distribution of the parameters, and the predictive mean matching 
method is used to impute missing values (Rubin 1987, pp. 166–167, Heitjan and Little 
1991; Schenker and Taylor 1996). The predictive mean matching method imputes a value 
chosen randomly from a set of observed subjects with complete data (K=10) whose 
predicted values are closest to the predicted value for the missing entry from the simulated 
regression model. This will be implemented using the MI procedure in SAS with the fully 
conditional specification (FCS) method. Covariates will be removed from the model if the 
model is unable to converge due to quasi or complete separation. Missing results for 
covariates will be imputed using either linear regression (for continuous variables) or 
logistic regression or discriminant function method (for categorical variables).  
 
4) The imputation model will be used to create 100 datasets with random number generation. 
These 100 datasets will include the data from subjects not impacted by COVID-19 and 
imputed data from subjects with “Site Closure” missing data, resulting in 100 apparently 
complete datasets.  
 
5) Each subject will be classified as a responder or non-responder in each of the 100 
apparently complete datasets, and the proportion of responders will be calculated for each 
of the 100 datasets.  For subjects who meet the ”Site Closure” criteria (as specified in 
Section 6.3.3), the imputed sUA values during Month 6 will be used to classify each subject 
as a responder or non-responder during Month 6. Since date and time of sUA collections 
during Month 6 will be missing, a duration of 7 days (168 hours) will be used for time 
between each visit (i.e. Week 20 to Week 21, etc.). Thus, a total time of 28 days (672 
hours) during Month 6 will be used to calculate proportion of time sUA < 6 mg/dL. For all 
other subjects, the actual data from the study (and no imputed data) will be used to classify 
each subject as a responder or non-responder during Month 6. 
 
SAS code for this analysis can be found in Appendix 19.1. Since the reason for the missing data 
is known to be due to the COVID-19 pandemic (documented via protocol deviation), it is 
reasonable to assume that the missing data is missing at random or missing completely at random 
(MCAR), and therefore multiple imputation is an appropriate method to use.  Predictive mean 


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matching avoids distributional assumptions on the sUA values and avoids imputing values that 
are out of range (e.g., values less than 0, which cannot occur).  Using multiple imputation when 
data are MCAR is more efficient than analyzing observed data only, due to the increased 
information, even though observed data would appropriately control the type I error rate and bias. 
 
 
Analysis of the Primary Endpoint 
The analysis of proportion of responders during Month 6 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 actual 
stratification factor value if the subject is misclassified during the randomization. The difference 
in response rates, comparing pegloticase with MTX vs. pegloticase with placebo, will be 
estimated along with the corresponding 95% CI and p-value.  
If multiple imputation is performed, this analysis will be applied to each of the 100 datasets 
created after the multiple imputation process specified in Section 9.2.2 has been performed.  
Results of the 100 analyses on apparently complete data will be pooled using Rubin’s rule, 
resulting in a single estimate for the proportion of responders in each treatment group with two-
sided 95% confidence interval, as well as the p-value comparing the randomized treatment 
groups and a two-sided 95% confidence interval on the difference in response rates. This will be 
implemented using the MIANALYZE procedure in SAS. 
If multiple imputation is not performed (i.e. there are no subjects with missing data due to site 
closure), the proportion of responders along with a 95% confidence interval for the proportion 
will be summarized based on the observed data (i.e. with no imputation based on COVID-19 
impact), with non-responder imputation used for subjects who meet the stopping rule or have 
missing results during Month 6. The proportion of  sUA < 6 mg/dL responders will be plotted. 
 
 
Supplemental Analysis of the Primary Endpoint 
 
The proportion of time during the period where the sUA was less than 6 mg/dL (based on 
observed sUA) will be summarized using descriptive statistics (i.e. n, mean, standard deviation, 
median, 25th quartile, 75th quartile, minimum, and maximum). The number and proportion of 
subjects in the following categories will also be summarized: data available at Week 24 and 
responders, data available at Week 24 and are non-responders (subcategories for whether or 
not met stopping rule at or prior to Week 24), and non-responders with data not available at 
Week 24 (subcategories for if met stopping rule prior to Week 24, or missing data for other 
reason).  
The primary analysis of the primary endpoint, as well as the summaries described in the previous 
paragraph, will be repeated for the mITT and PP populations.   


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For the primary endpoint analysis, subjects who meet the stopping rule (sUA values > 6 mg/dL at 
2 consecutive scheduled visits excluding post-infusion values) starting at Week 2 are considered 
non-responders during Month 6. In practice, some physicians may choose to discontinue 
pegloticase if subjects have a single sUA value > 6 mg/dL. A supplemental analysis will be 
performed using an alternative stopping rule, in which subjects with a single sUA value > 6 mg/dL, 
excluding post-infusion values, starting at Week 2 will be considered non-responders for Month 
6. This analysis will use the same methods as the primary analysis described in 9.2.1-9.2.3. This 
analysis       
Additionally, the primary analysis will be repeated for the ITT population using a similar imputation 
method as described in Section 9.2.2, but imputing response status for ”Site Closure” subjects 
via logistic regression in the imputation model.  
The multiple imputation process for imputing response (responder or non-responder) will involve 
the following steps: 
1) Response will be calculated for all subjects except those with “Site Closure” missing data 
during Month 6. 
2) A regression model will be created using observed data  from subjects not affected by 
COVID-19. A logistic regression model will be fit for response status at during Month 6 as 
the dependent variable and will include independent variables of treatment group, tophi 
presence, sex, age, baseline weight, race (white, non-white), available pre-infusion sUA 
values from Day 1 up through Week 24, serious AE (yes or no), severe AE (yes or no), 
and number of gout flares during the Pegloticase + IMM Period up through Month 6.   
 
 
3) Based on the fitted regression model, a new regression model is simulated from the 
posterior predictive distribution of the parameters. This will be implemented using the MI 
procedure in SAS with the fully conditional specification method. Covariates removed from 
the primary model (regression model in Section 9.2.2) due to quasi or complete separation 
will be removed from the logistic model. The augmented likelihood method will be used if 
maximum likelihood estimates do not exist. Missing results for covariates will be imputed 
using either linear regression (for continuous variables) or logistic regression or 
discriminant function method (for categorical variables).  
 
4) The imputation model will be used to create 100 datasets with random number generation. 
These 100 datasets will include the data from subjects not impacted by COVID-19 and 
imputed data from subjects impacted by COVID-19, resulting in 100 apparently complete 
datasets.  
 
5) The proportion of responders will be calculated for each of the 100 datasets.  For subjects 
impacted by COVID-19 who meet the site closure criteria  (as specified in Section 6.3.3), 
the imputed response during Month 6 will be used in calculating the proportion of 
responders. For all other subjects, the response based on observed sUA (and no imputed 
data) will be used. 
SAS code for this analysis can be found in Appendix 19.1.  The proportion of responders will be 
analyzed using the same CMH test described in Section 9.2.3. 


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Sensitivity Analysis of the Primary Endpoint 
The following sensitivity analyses of the primary efficacy analysis will be performed for the ITT 
Population:  
1) Include sUA results (if available) in the response calculation following discontinuation of 
treatment for subjects who meet stopping rule and continue on the study (i.e. will not 
automatically assign non-response if stopping rules met). 
2) Exclude sUA results (treat as missing) after the start of the urate lowering therapy taken 
after the first dose of pegloticase if subjects receive urate lowering therapy other than 
pegloticase.   
3) Exclude all subjects from analysis with “COVID-19 Related” or “Site Closure” (per Section 
6.3.3) missing data during Month 6. 
4) Impute non-response for “Site Closure” subjects  in the pegloticase with MTX group and 
impute response for “Site Closure” subjects in the pegloticase with PBO group (i.e. a 
worst-case analysis). 
5) If multiple imputation is performed, a tipping point analysis will be performed to evaluate 
the robustness of the primary analysis to the missing at random (MAR) assumptions.  First, 
all missing data will be imputed by the FCS method described in Section 9.2.2.  Then, a 
small adjustment value will be added to the imputed values during Month 6 for the 
pegloticase + MTX group in each of the 100 datasets.  Response will be calculated based 
on the adjusted imputed sUA values for “Site Closure” subjects and observed sUA values 
for all other subjects, and pooled together using Rubin’s rule to get a p-value. This process 
is repeated with a more stringent adjustment until the p-value > 0.0495. 
Sensitivity analyses 1 and 2 above will be performed with the same statistical method used in 
primary analysis of the primary endpoint, including use of multiple imputation (if performed for 
primary analysis).  Sensitivity analyses 3 and 4 will be performed with the same statistical method 
used in the primary analysis of the primary endpoint but will not apply the multiple imputation 
process.  
As specified in Section 9.2.2, subjects are required to have at least two sUA results from different 
visits during Month 6 in order to be eligible for consideration as a responder. Post-hoc analysis 
may be performed in which this requirement is removed, and in the event that only a single sUA 
result is available during Month 6, response will be determined based on the value of the sUA 
result (e.g. if sUA < 6 mg/dL then the subject is a responder).  
 
Subgroup Analysis of the Primary Endpoint 
The subgroup analyses for proportion of Month 6 responders will be performed using an 
unstratified chi-square test within each subgroup category (Section 6.6) for the ITT population. 
The proportion of responders along with a 95% confidence interval for the proportion will be 
summarized based on the observed data (i.e. with no imputation based on “Site Closure” 
impact), with non-responder imputation used for subjects who meet the stopping rule or have 
missing results during Month 6.  If there are at least 20 subjects in a subgroup category, a 
difference in response rates with a two-sided 95% CI, calculating using normal theory, will be 
reported.   


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Secondary Efficacy Endpoints and Analyses 
 
Proportion of Month 12 Responders 
The proportion of Month 12 (Weeks 48, 50, and 52) responders, will be defined as subjects 
achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 12. 
This endpoint will be analyzed for the ITT and mITT populations.  
This determination will be completed using the same linear interpolation method described for the 
primary efficacy endpoint in Section 9.2.1. The Month 12 period will include pre-infusion and post-
infusion results at Week 48, pre-infusion and post-infusion results at Week 50, pre-infusion results 
at Week 52, and unscheduled assessments of sUA collected between Week 48 and Week 52 
processed by the central laboratory. Section 9.1 shows the rules for inclusion of sUA values 
reported by local laboratories.  
If the subject’s proportion of hours where sUA was less than 6 mg/dL, P, is greater than or equal 
to 80% the subject will be called a responder for the Month 12 responder endpoint. Subjects 
meeting the stopping rule, i.e. has pre-infusion sUA values greater than 6 mg/dL at 2 consecutive 
scheduled visits (starting at Week 2) through Week 52 will be counted as non-responders. A 
subject with the proportion of hours, P, less than 80% will be counted as non-responders.   
There will be no imputation of sUA values due to missing values among those collected 
between Week 48 and Week 52, unless missing data is due to “Site Closure”. At least two sUA 
observations from different visits must be available in order for a subject to be eligible for 
consideration as a responder. Subjects with only one sUA observation will be considered a non-
responder, regardless of the value of that single observation.  For subjects with “Site Closure” 
missing data (as defined in Section 6.3.3) during Month 12, the rules described in Section 6.3.3 
will be applied. The proportion of Month 12 responders will be analyzed using the same multiple 
imputation method and the stratified weighting approach specified for primary analysis of the 
primary endpoint. 
In addition, the proportion of responders along with a 95% confidence interval for the proportion 
will be summarized based on the observed data (i.e. with no imputation based on COVID-19 
impact), with non-responder imputation used for subjects who meet the stopping rule or have 
missing results during Month 12 (this will be the primary analysis method if there are no “Site 
Closure subjects”). 
The proportion of hours during the period where the sUA was less than 6 mg/dL (based on 
observed sUA) will be summarized using descriptive statistics (i.e. n, mean, standard deviation, 
median, 25th quartile, 75th quartile, minimum, and maximum). The number and proportion of 
subjects that discontinued treatment due to the stopping rule will be summarized. The number 
and proportion of responders will be summarized along with a 95% exact (Clopper-Pearson) CI 
for the proportion. In addition, the number and proportion of subjects with data available at 
Week 52 responder, data available at Week 52 non-responder (subcategories of met stopping 
rule at or before Week 52, did not meet stopping rule), and data not available at Week 52 non-
responder (subcategories of met stopping rule at or before Week 52, missing data for other 
reason) will be summarized. 


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The proportion of sUA < 6 mg/dL responders during Month 12 will be plotted. 
The subgroup analyses for proportion of Month 12 responders will be performed using an 
unstratified chi-square test within each subgroup category (Section 6.6) for the ITT population 
using same method as for the subgroup analysis of the primary endpoint. If there are at least 20 
subjects in a subgroup category, a difference in response rates with a two-sided 95% CI, 
calculating using normal theory, will be reported. 
 
Proportion of Subjects Having Tophi at Baseline with Complete Resolution of ≥ 1 
Tophi at Week 52  
Digital photography will be used to assess tophi. 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. 
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 –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). 
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. 


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 
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). 
Each tophus is assessed by 2 readers.  For measurable tophi, the average measurements from 
the two readers will be computed and the response category will be based on the increase or 
decrease in the average area.  For unmeasurable tophi, the worst response between the two 
readers will be used in analysis.   
The overall response for a subject at a visit will be based upon the best response among all 
evaluable tophi (including measurable and unmeasured) for that subject at the visit (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 after Day 1 (as 
identified on the digital photograph in a site previously photographed), the overall response for 
that subject will be Progressive Disease at the visit, regardless of the response of any other 
tophi. In general, the overall response assignment is based on the measured or unmeasured 
tophi category. However, if the best response at a visit for is either “Marked Response” or 
“Partial Response” (for measurable tophi) or “Improved” (for unmeasurable tophi) then the 
corresponding overall response will be “Partial Response”.  
The secondary endpoint is the proportion of subjects with resolution of ≥ 1 tophi at Week 52, 
defined as subjects with an overall tophus response of complete response at the visit (i.e. 
complete response in at least one tophi and no evidence of progressive disease among other 
tophi).   
The difference in the proportion of subjects with resolution of ≥ 1 tophi at Week 52 between 
pegloticase with MTX and pegloticase with 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. The 
difference in the proportion of subjects with complete resolution of ≥ 1 tophi will also be 
summarized at Weeks 14, 24, and 36  
For subjects with missing tophi results (unless missing data is due to site closure) the modified 
non-responder approach will be used for dealing with subjects missing tophi evaluation data at 
Week 52. The imputation, as described below, will be done for overall response and not at the 
individual tophi level. 
Modified non-responder imputation:  
o Completely missing results post-baseline – ‘Progressive Disease’ imputed as 
subjects’ Overall Response. 
o Completely missing result at visit but photography was attempted at a prior visit – 
One-worse than the last evaluable Overall Response is imputed, per Table 9. 
o Photography was attempted at visit, but result was unevaluable: One-worse than 
the last evaluable Overall Response is imputed per Table 9. 
Table 9: Imputation of One-worse than the Last Evaluable Overall Response 


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Last Evaluable Overall Response 
Week 52 Imputed Overall Response 
Complete Response 
Partial Response 
Partial Response 
Stable Disease 
Stable Disease 
Progressive Disease 
Progressive Disease 
Progressive Disease 
No prior post-baseline evaluable 
response available 
Progressive Disease 
 
Subjects with “Site Closure” missing tophus assessments for Week 52 will be excluded from 
analysis (i.e. will not contribute to the numerator or denominator).   
In addition to the imputation methods described above, the proportion of subjects with complete 
response at each visit, and the number and percentage of subjects with each overall response 
status will be summarized as observed. That is, only subjects with evaluable results at the visit 
are analyzed. No imputation is done for missing or “Unable to Evaluate” Overall Response. 
Subjects with a missing result at each visit are not included in the denominator. The p-value for 
this analysis is exploratory. 
For the analyses of the overall response at each visit, each category (CR, PR, SD, or PD) will 
be assigned an ordinal score of 1, 2, 3, or 4. A proportional odds logistic model for ordered 
categorical data with treatment group as the effect will be used to compare pegloticase with 
MTX vs. pegloticase with placebo. This will be performed for both the imputed data and the 
observed data. The estimate of the common odds ratio comparing pegloticase with MTX vs. 
pegloticase with placebo will be provided along with the corresponding 95% CI and p-value. In 
addition, the p-value testing the appropriateness of the proportional odds assumption will be 
provided. 
 
Additionally, the best overall response over ALL visits is defined as the best response among all 
tophi (including measurable and unmeasured) for that subject over all visits, except for Day 1 
visit (e.g., if any one tophus shows complete response at a visit, the best overall response is 
Complete Response, even if at subsequent visits subjects may either not be evaluable or have 
Partial Response or Stable Disease response). If any single tophus shows progression, or if a 
new tophus appears during the study after Day 1 (as noticed per the particular visit evaluation in 
a site previously photographed), the best overall response for that subject will be Progressive 
Disease, regardless of the response of any other tophi. The best overall response will be 
analyzed using the proportional odds logistics model on both the imputed data and observed 
data. 
The analysis described above (proportion of subjects with complete resolution , Overall 
Response, and Best Overall Response) will be performed for the ITT and mITT  populations and 
will be based on available data for subjects who have baseline tophi. 


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Subgroup analyses for the proportion of complete resolution of ≥ 1 tophi at Week 52 will be 
performed for the subgroups identified in Section 6.6 (excluding tophi presence subgroup) using 
an unstratified chi-square test within each subgroup category for the ITT population.  If there are 
at least 20 subjects in a subgroup category, a difference in response rates with a two-sided 95% 
CI, calculating using normal theory, will be reported. 
 
 
Change from Baseline in HAQ-DI, HAQ Pain, and HAQ Health to Week 52 
The HAQ 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. 
The HAQ-DI is a self-reported 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. 
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. In order to convert the 
score to a 0-100 scale, the results (in cm) in database will be divided by 15 then multiplied by 100. 
For the change from baseline to Week 52 in HAQ-DI, HAQ pain score, and HAQ health score, a 
mixed model for repeated measures (MMRM) analysis of covariance (ANCOVA) model will be 
fit to the individual change from baseline value for the parameter of interest, with terms for 
baseline score, tophi presence at baseline, and factors of treatment group, visit, visit by 
treatment group interaction and visit by baseline interaction. The Post Treatment Follow-up 
Month 3 and Month 6 visits will not be included in the MMRM model. The unstructured (UN) 
variance-covariance matrix will be used. In the event that this matrix does not allow for model 
convergence, the following three variance-covariance matrices will be attempted in order until 
one converges: heterogeneous Toeplitz (TOEPH), heterogeneous compound symmetry (CSH), 
Toeplitz (TOEP), and compound symmetry (CS). The p-values for all terms in the model will be 
presented, as well as the treatment group LS means and associated SE, and their difference, 


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SE of the difference, 95% CIs and p-value, overall and for each visit. The p-value for the 
treatment difference between pegloticase with MTX vs. pegloticase with placebo at Week 52 for 
each HAQ parameter will be used in the sequential testing of secondary endpoints.  
If there are subjects without post-baseline values (unless due to Site Closure), a change from 
Baseline value of 0 will be imputed at the first post-baseline visit (in order to avoid exclusion of 
these subjects from the MMRM analysis).  
Subjects with no post-baseline HAQ assessments due to site closure will be excluded from the 
analysis. Otherwise, if at least one post-baseline HAQ assessment is available then “Site Closure” 
subjects will be included in analysis. 
The primary MMRM analysis for HAQ will be performed for the ITT population and repeated in 
the mITT population. Subgroup analysis will be conducted for each HAQ endpoint for the ITT 
population using the MMRM ANCOVA model described above with an additional treatment-by-
subgroup interaction term included in the model. Within each subgroup stratum, the p-values for 
all terms in the model will be presented, as well as the treatment group LS means and 
associated SE, and their difference, SE of the difference, 95% CIs and p-value.  
In addition, observed values and change from baseline in the HAQ-DI, HAQ-Pain, and HAQ-
Health score at each scheduled time point will be summarized using descriptive statistics (i.e. n, 
mean, standard deviation, median, minimum, and maximum) for the ITT population.  
 
 
Exploratory Efficacy Endpoints and Analyses 
All exploratory analyses will be performed on the ITT Population unless otherwise  specified. 
For the exploratory efficacy endpoint analysis of continuous variables, a mixed model repeated 
measures (MMRM) analysis of covariance (ANCOVA) model will be fit to the individual change 
from baseline value for the parameter of interest, with terms for baseline score, tophi presence 
at baseline, and factors of treatment group, visit, visit by treatment group interaction and visit by 
baseline interaction. The Post Treatment Follow-up Month 3 and Month 6 visits will not be 
included in the MMRM model.  The unstructured (UN) variance-covariance matrix will be used. 
In the event that this matrix does not allow for model convergence, the following three variance-
covariance matrices will be attempted in order until one converges: heterogeneous Toeplitz 
(TOEPH), heterogeneous compound symmetry (CSH), and Toeplitz (TOEP). The p-values for 
all terms in the model will be presented, as well as the treatment group LS means and 
associated SE, and their difference, SE of the difference, 95% CIs and p-value, overall and at 
each visit.  
P-values for exploratory endpoints will be provided for descriptive purposes only.   
No imputation of missing data will be performed for the exploratory analysis of continuous 
variables, as the analysis will be performed using MMRM models, which accommodate missing 
data and allow information from every visit to contribute to the analysis of the data. The only 
exception to this is that for any subject in the ITT Population without post-baseline values 
(unless “Site Closure”), a change from Baseline value of 0 will be imputed at the first post-
baseline visit (in order to avoid exclusion from the MMRM analysis). Subjects with no post-


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baseline assessments due to site closure will be excluded from analysis. Otherwise, all 
available data for subjects impacted by COVID-19 will be included. 
For exploratory efficacy endpoint analysis of categorical variables, either CMH or chi-square test 
(for endpoints related to tophi) will be used. 
Observed efficacy endpoints will be summarized by pegloticase treatment status (On 
Treatment, Post-Treatment, and Overall), visit, and treatment group. On Treatment will include 
post-baseline visits on or after pegloticase infusions. Subjects will only be summarized in the On 
Treatment visits for visits that occur (and results available) while still receiving pegloticase 
infusions. End of pegloticase infusion visit (windowed) if occurs, will also be considered On 
Treatment, as well as the Week 52 visit for subjects who complete treatment and study at Week 
52. Post-Treatment visits are any post-baseline visits after the end of pegloticase infusions (or 
Week 52/EOS if subject completes treatment). Overall status will include all visits for all subjects 
regardless of pegloticase treatment status. 
 
Change from Baseline in Urate Deposition Volume and Bone Erosion using 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.  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). 
CT scans of the hands and feet have been used to assess erosive damage in the small joints of 
the hands and feet in rheumatoid arthritis and gout. The DECT images will be used to assess 
erosion change using published semiquantitative scoring systems. Erosion scoring in the hand 
will follow the OMERACT RAMRIS score, which assesses erosive change in 10 locations in each 
hand and 15 locations in each wrist. Erosive damage at each location is scored from 0 to 10, with 
each score representing 10% incremental loss of each carpal bone or the peripheral 1 cm of 
articular bone for long bones (radius, ulna, metacarpals and phalanges). The total erosion score 
can range from 0 to 250 for each hand.  Erosion scoring in the foot will follow the method published 
by Dalbeth et al [4] which was based on the  OMERACT RAMRIS score. Erosive damage at each 
location is scored from 0 to 10, as in the hand. The total erosion score can range from 0 to 70 for 
each foot. 
The observed values and the change from baseline for urate deposition volume and  bone erosion 
scores at each scheduled visit will be summarized using descriptive statistics (i.e. n, mean, 
standard deviation, median, minimum, and maximum). The baseline is defined as the last non-
missing measurement before the first pegloticase infusion. Changes from baseline for urate 
deposition volume and bone erosion score to each visit and overall will be analyzed with MMRM 
ANCOVA model as described in Section 9.4. 








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Proportion of Month 9 Responders 
The proportion of Month 9 (Weeks 32, 34, and 36) responders, will be defined as subjects 
achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 9. 
This endpoint will be analyzed for the ITT population.  
This determination will be completed using the same linear interpolation method described for the 
primary efficacy endpoint in Section 9.2.1. The Month 9 period will include pre-infusion and post-
infusion results at Week 32, pre-infusion and post-infusion results at Week 34, pre-infusion results 
at Week 36, and unscheduled assessments of sUA collected between Week 32 and Week 36 
processed by the central laboratory. Section 9.1 shows the rules for inclusion of sUA values 
reported by local laboratories.  
If the subject’s proportion of hours where sUA was less than 6 mg/dL, P, is greater than or equal 
to 80% the subject will be called a responder for the Month 9 responder endpoint. Subjects 
meeting the stopping rule, i.e. has pre-infusion sUA values greater than 6 mg/dL at 2 consecutive 
scheduled visits (starting at Week 2) through Week 36 will be counted as non-responders. 
Subjects with the proportion of hours, P, less than 80% will be counted as non-responders.  
There will be no imputation of sUA values due to missing values among those collected between 
Week 32 and Week 36, unless missing data is due to site closure. At least two sUA observations 
from different visits must be available in order for a subject to be eligible for consideration as a 
responder. Subjects with only one sUA observation will be considered a non-responder, 
regardless of the value of that single observation. For subjects with “Site Closure” missing data 
during Month 9, the rules described in Section 6.3.3 will be applied. The proportion of Month 9 
responders will be analyzed using the same multiple imputation method and the stratified 
weighting approach specified for primary analysis of the primary endpoint. 
In addition, the proportion of responders along with a 95% confidence interval for the proportion 
will be summarized based on the observed data (i.e. with no imputation based on COVID-19 
impact), with non-responder imputation used for subjects who meet the stopping rule or have 
missing results during Month 9 (this will be the primary analysis method if there are no “Site 
Closure subjects”).  
The proportion of hours during the period where the sUA was less than 6 mg/dL (based on 
observed sUA) will be summarized using descriptive statistics (i.e. n, mean, standard deviation, 
median, 25 h quartile, 75th quartile, minimum, and maximum). The number and proportion of 
subjects that discontinued treatment due to the stopping rule will be summarized. The number 
and proportion of responders will be summarized along with a 95% exact (Clopper-Pearson) CI 
for the proportion. In addition, the number and proportion of subjects with data available at Week 
36 responder, data available at Week 36 non-responder (subcategories of met stopping rule at or 
before Week 36, did not meet stopping rule), and data not available at Week 36 non-responder 
(subcategories of met stopping rule at or before Week 36, missing data for other reason) will be 
summarized. 
The proportion of sUA < 6 mg/dL responders during Month 9 will be plotted. 
 


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Proportion of Month 3 Responders 
The proportion of Month 3 (Weeks 10, 12, and 14) responders, will be defined as subjects 
achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 3. 
This determination will be completed using the same linear interpolation method described for the 
primary efficacy endpoint in Section 9.2.1. The Month 3 period will include pre-infusion and post-
infusion results at Week 10, pre-infusion and post-infusion results at Week 12, pre-infusion results 
at Week 14, and unscheduled assessments of sUA collected between Week 10 and Week 14 
processed by the central laboratory. Section 9.1 shows the rules for inclusion of sUA values 
reported by local laboratories.  
If the subject’s proportion of hours where sUA was less than 6 mg/dL, P, is greater than or equal 
to 80% the subject will be called a responder for the Month 3 responder endpoint. Subjects 
meeting the stopping rule, i.e. has pre-infusion sUA values greater than 6 mg/dL at 2 consecutive 
scheduled visits (starting at Week 2) through Week 14 will be counted as non-responders. A 
subject with the proportion of hours, P, less than 80% will be counted as non-responders. In 
addition to stopping rule, a subject who withdraws from study treatment for any reason other than 
the stopping rule after randomization and prior to or during Month 3 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.  
There will be no imputation of sUA values due to missed collections among those collected 
between Week 10 and Week 14, unless missing data is due to site closure. At least two sUA 
observations from different visits must be available in order for a subject to be eligible for 
consideration as a responder. Subjects with only one sUA observation will be considered a non-
responder, regardless of the value of that single observation. For subjects with ”Site Closure” 
missing data during Month 3, the rules described in Section 6.3.3 will be applied. The proportion 
of Month 3 responders will be analyzed using the same multiple imputation method and the 
stratified weighting approach specified for primary analysis of the primary endpoint. 
In addition, the proportion of responders along with a 95% confidence interval for the proportion 
will be summarized based on the observed data (i.e. with no imputation based on COVID-19 
impact), with non-responder imputation used for subjects who meet the stopping rule or have 
missing results during Month 3 (this will be the primary analysis method if there are no “Site 
Closure subjects”).  
The proportion of hours during the period where the sUA was less than 6 mg/dL (based on 
observed sUA) will be summarized using descriptive statistics (i.e. n, mean, standard deviation, 
median, 25th quartile, 75th quartile, minimum, and maximum). The number and proportion of 
subjects that discontinued treatment due to the stopping rule will be summarized. In addition, 
the number and proportion of subjects missing all data in analysis period, with only one 
measurement (above cutoff) in analysis period, and with only one measurement (below cutoff) 
in analysis period) will be summarized. The number and proportion of responders and non-
responders will be summarized. In addition, the number and proportion of subjects with data 
available at Week 14 responder, data available at Week 14 non-responder (subcategories of 
met stopping rule at or before Week 14, did not meet stopping rule), and data not available at 


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Week 14 non-responder (subcategories of met stopping rule at or before Week 14, missing data 
for other reason) will be summarized. 
 The proportion of sUA < 6 mg/dL responders during Month 3 will be plotted. 
 
Proportion of Overall Responders Month 3 and Month 6 Combined 
The proportion of overall responders through Month 6 is defined as subjects achieving and 
maintaining sUA < 6 mg/dL for at least 80% of the time during Months 3 and 6 combined. See 
Section 9.2.1 for the sUA results included in Month 6. See Section 9.4.6 for the sUA results 
included in Month 3. Section 9.1 shows the rules for inclusion of sUA values reported by local 
laboratories. 
The definition of overall responders through Month 6 is dependent on the number of available 
sUA results available during Month 3 and during Month 6. 
Case  
Number of sUA 
Values at Month 3 
Number of sUA Values 
at Month 6 
Overall Response 
Determination 
1 
Any Number 
≤1 
Declared Overall Non-responder  
2 
≤1 
Any Number 
Declared Overall Non-responder  
3 
> 1 Record 
> 1 Record 
Overall Response is defined 
based on the weighted proportion 
of hours below the sUA < 6 
mg/dL cutoff.  See the remainder 
of this section. 
Let T1 = the number of elapsed hours between the first and last non-missing sUA concentration 
among those collected between pre-infusion Week 10 and pre-infusion Week 14 collections.  
Let T2 = the number of elapsed hours between the first and last non-missing sUA concentration 
among those collected between pre-infusion Week 20 and pre-infusion Week 24 collections.  
Let W1 = the number of hours among the T1 hours where the sUA concentration was below 6 
mg/dL.  
Let W2 = the number of hours among the T2 hours where the sUA concentration was below 6 
mg/dL.  
The proportion of hours P = 100 ∗
W1+W2
T1+T2  
This is the weighted proportion of hours below 6 mg/dL.  
If the subject’s proportion of hours, P, is greater than or equal to 80% the subject will be called a 
responder for the overall responder endpoint. A subject with the proportion of hours, P, less than 
80% will be counted as non-responders. 


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Subjects meeting the stopping rule, i.e. has pre-infusion sUA values greater than 6 mg/dL at 2 
consecutive scheduled visits (starting at Week 2) through Week 24 will be counted as overall non-
responders.  
The proportion of hours during the period where the sUA was less than 6 mg/dL will be 
summarized using descriptive statistics (i.e. n, mean, standard deviation, median, minimum, and 
maximum). The number and proportion of subjects that discontinued treatment due to the 
stopping rule will be summarized. The proportion of responders during Month 3 and Month 6 
combined will be analyzed using the same multiple imputation method (if performed) and the 
stratified weighting approach specified for primary analysis of the primary endpoint.  
 
Proportion of Responders Achieving and Maintaining a sUA Below 5 mg/dL 
The proportion of responders is defined as subjects achieving and maintaining sUA < 5 mg/dL for 
at least 80% of the time during Month 3, Month 6, Month 9, and Month 12. These will be calculated 
and analyzed using the same method described for the primary efficacy endpoint (Section 9.2), 
secondary endpoint reported in Section 9.3.1, and exploratory endpoints reported in Sections 
9.4.5 and 9.4.6.  
 
Change from Baseline in sUA  
Observed values and change from baseline at each scheduled time point, including pre-infusion 
and post-infusion results for sUA will be summarized using descriptive statistics (i.e. n, mean, 
standard deviation, median, 25th quartile, 75th quartile, minimum, and maximum). Changes from 
baseline for pre-infusion sUA (or available sUA at visits with no infusion, e.g., Weeks 21 and 23) 
to each visit and overall will be analyzed with an MMRM ANCOVA model as described in 
Section 9.4. 
Line plots of the observed mean pre-infusion sUA values with 95% CI at each scheduled visit will 
be presented using the ITT population by pegloticase treatment status (On Treatment and 
Overall) and treatment group. A graphical presentation of the mean pre-infusion sUA values by 
treatment group and Month 6 sUA responders vs. non-responders, based on the primary endpoint 
definition of Month 6 response, will also be produced for the ITT population. 
 
Time to First sUA > 6 mg/dL Following the First Infusion 
The first pegloticase infusion date will be the reference date (REFDATE). Only the scheduled pre-
infusion sUA values starting with Week 2 will be considered for determination of the endpoint. As 
was noted in Section 9.1, the local laboratory’s value may be used if the central laboratory’s value 
at the scheduled time point is unavailable. The days until the sUA > 6 mg/dL will be calculated 
as: 
EVTDAYS = (EVNTDATE – REFDATE) + 1, where EVNTDATE is the date of the earliest post-
reference date where the pre-infusion sUA value (from central lab, or local if central is unavailable) 
is > 6 mg/dL. For subjects who do not have any sUA values > 6 mg/dL, their EVNTDATE will be 
censored at the latest collected sample with non-missing sUA result through Week 52. Kaplan-
Meier (KM) estimates will be provided by treatment group of the 25th percentile, median, and 75th 
percentile. 95% CIs of the median will be provided for the median. Further, a log-rank test stratified 
by presence of tophi (yes, no) will be provided.  
Plots of the time to first sUA > 6 mg/dL will be provided by treatment group using KM curves. 


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Time to Two consecutive sUAs > 6 mg/dL Following the First Infusion 
The first pegloticase infusion date will be the reference date (REFDATE). Only the scheduled pre-
infusion sUA values from the central laboratory starting with Week 2 will be considered for 
determination of the endpoint. As was noted in Section 9.1, the local laboratory’s value  may be 
used if the central laboratory’s value is unavailable. The days until the sUA > 6 mg/dL will be 
calculated as: 
EVTDAYS = (EVNTDATE – REFDATE) + 1, where EVNTDATE is the date of the first of the two 
consecutive post-reference dates where the pre-infusion sUA value (from  central lab, or local if 
central is unavailable) was > 6 mg/dL. For subjects who did not have two consecutive sUA values 
> 6 mg/dL, their EVNTDATE will be censored at the latest collected sample with non-missing sUA 
result through Week 52. Subjects with only a single elevated pre-infusion sUA and no subsequent 
sUA results available will be considered to have the event. Kaplan-Meier estimates will be 
provided by treatment group of the 25th percentile, median, and 75th percentile. 95% CIs of the 
median will be provided. Further, a log-rank test stratified by presence of tophi (yes, no) will be 
provided.  
Plots of the time to two consecutive sUA > 6 mg/dL will be provided by treatment group using KM 
curve. 
 
Percentage of Non-Hyperuricemic (sUA < 6 mg/dL) Time during Months 3, 6, 9 and 
12  
The proportion or percentage of time 𝑃= 100 ∗
𝑊1
𝑇1 of non-hyperuricemic (sUA < 6 mg.dL) during 
Months 3, 6, 9, and 12 are defined in Section 9.4.5, Section 9.2, Section 9.3.1, and Section 9.3.2.  
The proportion or percentage of time during the month where the sUA was less than 6 mg/dL will 
be summarized using descriptive statistics (i.e. n, mean, standard deviation, median, minimum, 
and maximum). The proportion or percentage of hours will be analyzed with an MMRM ANCOVA 
model as described in Section 9.4. 
 
Change from Baseline in HAQ-DI, HAQ Pain, and HAQ Health to Weeks 24 and 36 
The analysis of the change from baseline in HAQ scores to Weeks 24 and 36 are described in 
Section 9.3.3. 
 
Change from Baseline in Tender Joint Count and Swollen Joint Count 
Tender and swollen (excludes hip) joint counts will be recorded at the Week -6 (prior to the first 
dose of MTX); prior to pegloticase infusion at the Day 1 and Weeks 6, 14, 20, 24, 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, Post Treatment Follow-up 
Month 3, and Post-treatment Follow-up Month 6. 
Tender and swollen joint counts will be assessed using the rheumatoid arthritis 66-68 joints 
shown in the Figure 1 below. All information will be entered into the appropriate eCRF. 
Figure 1 Rheumatoid Arthritis 66-68 Tender and Swollen Joint Counts 


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For tender joint count, 68 joints are assessed as tender or non-tender (1=tender, 0=non-tender), 
and the tender joint count is the sum of 0s and 1s over all 68 joints for each subject. For swollen 
joint count, 66 joints are assessed as either swollen or non-swollen (1=swollen, 0=non-swollen) 
and the swollen joint count is the sum over all 66 for each subject. 
Observed values, change from baseline in the tender and swollen joint counts at each 
scheduled time point will be summarized using descriptive statistics (i.e. n, mean, standard 
deviation, median, minimum, and maximum). Changes from baseline for these parameters to 
each visit and overall will be analyzed with an MMRM ANCOVA model as described in Section 
9.4. 
 
Change from Baseline in Number of Tender Joints or Swollen Joints 
The number of joints (via Tender and Swollen Joint Counts assessment eCRF) are scheduled to 
be assessed at Screening, Weeks 6, 14, 20, 24, 36, 44 and Week 52/End of Study/Early 
Termination Visit, Post-treatment Follow-up Month 3, and Post-treatment Follow-up Month 6.  
Observed values and change from baseline in the number of joints identified as tender or swollen 
at each scheduled visit will be summarized using descriptive statistics (i.e. n, mean, standard 
deviation, median, minimum, and maximum). Changes from baseline for the number of joints to 
each visit and overall will be analyzed with an MMRM ANCOVA model as described in Section 
9.4. 
 
Change from Baseline in Physician Global Assessment of Gout 
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 Weeks 6, 14, 20, 24, 30, 36, 
and 44 Visits during the Pegloticase + IMM Period; at the End of Pegloticase Infusions Visit (if 


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applicable), and the Week 52/End of Study/Early Termination Visit. The global assessment asks 
the physician to 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). 
Observed values, change from baseline in the physician global assessment at selected scheduled 
time point will be summarized using descriptive statistics (i.e. n, mean, standard deviation, 
median, minimum, and maximum). Changes from baseline for the physician global assessment 
to each visit and overall will be analyzed with an MMRM ANCOVA model as described in Section 
9.4.  
 
Gout Chronic Response 
Gout chronic response (GCR) criteria will be used to define subjects who achieve 20%, 50%, or 
70% improvement in 3 of the 4 following measures at a scheduled time point:  
 
swollen joint count 
 
tender joint count 
 
HAQ health score 
 
HAQ pain score  
The GCR response will be determined at Week 14, Week 24, Week 36, End of Pegloticase 
Infusion Visits, Week 52/End of Study/Early Termination Visit, Post Treatment Follow-up Month 
3, and Post-treatment Follow-up Month 6. 
A subject will be defined as a GCR20 (GCR50, GCR70) responder at a post-baseline assessment 
if they have at least a 20% (50%, 70%) reduction from the baseline in 3 or more of the measures 
noted above. If a subject has 3 of the 4 measures and all 3 meet the reduction goal, the subject 
will be a responder. In addition, if a subject has value of zero at baseline and also value of zero 
at the given post baseline for any tests above, the subject is considered to have at least 20%, 
50%, and 70% reduction from the baseline for that assessment. 
In the other cases, including subjects with fewer than 4 of the criteria completed at the scheduled 
assessment, and subjects with all 4 criteria completed at the scheduled assessment who do not 
meet the 20% (50%, 70%) reduction criteria, subjects will be declared non-responders at the 
scheduled assessment.  
GCR20, GCR50, and GCR70 responses, and the number/percentage of subjects who achieved 
a 20%, 50%, and 70% reduction in each component endpoint in the GCR response, will be 
summarized and the difference between treatment groups will be analyzed using the same 
stratified weighting approach specified for primary analysis.  
Considering some subjects also have tophus area at baseline, another analysis with the same 
CMH test is proposed. A subject will be defined as a GCR20 (GCR50, GCR70) responder at a 
post-baseline assessment if they have at least a 20% (50%, 70%) reduction from baseline 
(including subjects who have zero value at baseline and zero at the given post baseline in 4 or 
more of the measures noted above including tophus area). 




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Analysis of Anti-Drug Antibodies and Pharmacokinetics 
 
Anti-Drug Antibodies 
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.  
Using the Safety Population for anti-PEG IgG antibodies, the number and percentage of subjects 
ADA positive and ADA negative at baseline will be summarized.  Additionally, the number and 
percentage of subjects who meet the following criteria will be summarized by scheduled timepoint 
and treatment group: 
 
ADA positive in subjects ADA negative at baseline or with increase in titer from baseline, 
 
ADA positive in subjects ADA negative at baseline, and  
 
ADA positive in subjects with increase in titer from baseline 
For anti-uricase IgG antibodies, the number and percentage of subjects ADA positive at baseline 
and post-baseline will be summarized by scheduled timepoint and treatment group. 
Kaplan-Meier estimates of the time to positive anti-PEG response (for subjects who were negative 
at baseline) or increase in anti-PEG titer (for subjects who were positive at baseline), and the time 
to anti-uricase response with 25th percentile, median, 75th percentile, and 95% CI, along with a 
Kaplan-Meier curve will be produced by treatment group. Subjects who never have a positive anti-
PEG response or increase in titer will be censored at the date of their last visit (Week 52/End of 
Study/ET visit, or, if the subject did not attend this visit, then whatever last visit they have on 
record).  
Anti-PEG and anti-uricase titer will be summarized descriptively with mean and CV% by study 
visit. 
 
 
Pegloticase and MTX PK 
For all subjects, 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 Visit and the 
End of Pegloticase Infusions Visit (if applicable) and Week 52/End of Study/Early Termination 
Visits are non-infusion visits. 
Blood samples for MTX polyglutamate analysis 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 . 
The following presentations of subject pegloticase and MTX polyglutamate concentration data 
covered in this SAP will be provided: 




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Safety 
Safety analyses will be based on the safety population and the MTX population, depending on 
the treatment period. The MTX population will be used for analysis of safety data during the MTX 
Tolerability period prior to randomization and the safety population will be used for analysis 
thereafter. For summaries by study period, the number of subjects included in the Safety 
Population for each period will be the number of subjects with data in that period (e.g. for the 
Pegloticase + IMM Period, subjects must have received pegloticase). 
Safety will be assessed via AEs including AEs of special interest (AESI [i.e., IRs, anaphylaxis, 
gout flares, and cardiovascular events]), concomitant medication use (refer to Section 8.3), 
physical examinations, vital signs, clinical safety laboratory evaluations (complete blood count, 
chemistry, 
urine 
albumin:creatinine 
ratio), 
pregnancy 
testing 
(if 
applicable), 
and 
electrocardiograms (ECGs). 
All safety information will be provided in subject listings. 
 
Extent of Exposure 
Study drug exposure will be summarized from the MTX and placebo dosing calendar using the 
duration of treatment (in days), number of infusions, total dosage (mg) received for MTX or 
placebo and pegloticase, average dose (mg) received for MTX during MTX Tolerability, Run-in, 
and Pegloticase + IMM Period, average dose (mg) for placebo during Run-in and Pegloticase + 
IMM Period, and total dosage (mg) per dose overall. The MTX (or placebo) is supposed to be 
taken once weekly. The sequential dose number of MTX or placebo is defined by weekly. Any 
split doses taken within 48 hours are considered as one single dose, and the sum of the split 
doses is considered as the dosage for that dose number. The usage of folic acid, IR prophylaxis 
of fexofenadine in the evening prior to pegloticase infusion, IR prophylaxis of fexofenadine in the 
morning prior to the pegloticase infusion, acetaminophen, and methylprednisolone on the morning 
prior to pegloticase infusion will be summarized by number of subjects and percentage with 
compliance < 80% and ≥ 80%, in addition to being provided in listings. Interruptions in pegloticase 
infusions will be summarized. Reasons for infusion interruptions will be provided in the listings.  
For the MTX Tolerability Assessment Period, the following will be summarized for the MTX 
population:  
 
Duration of treatment defined as (the last dose of MTX prior to the Week -4 visit date – 
first dose date of MTX in the MTX Tolerability Assessment Period) + 1 (summarized with 
descriptive statistics of mean, SD, median, minimum, and maximum) 
 
Total MTX dosage taken between the first and last dose dates in the MTX Tolerability 
Assessment Period, inclusive (in mg) (summarized with descriptive statistics of mean, SD, 
median, minimum, and maximum) 
 
Average MTX dose (mg) (total dosage for MTX Tolerability Period divided by number of 
doses taken during MTX Tolerability Period) (summarized with descriptive statistics of 
mean, SD, median, minimum, and maximum) 
 
 


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For the Run-in Period, the following will be summarized by treatment group for the Safety 
population:  
 
Duration of treatment defined as [the last dose of MTX or placebo prior to the Day 1 visit 
date – first dose date of MTX or placebo in the Run-in Period (Week -4)] + 1 (summarized 
with descriptive statistics of mean, SD, median, minimum, and maximum) 
 
Total MTX or placebo dosage taken between the first and last dose dates in the Run-in 
Period, inclusive (in mg) (summarized with descriptive statistics of mean, SD, median, 
minimum, and maximum) 
 
Average MTX or placebo dose (mg) (total dosage for Run-in Period divided by number of 
doses taken during Run-in Period) (summarized with descriptive statistics of mean, SD, 
median, minimum, and maximum) 
 
Number of subjects with dosage reductions (reduction in planned dose for reason of AE, 
abnormal labs, or titration down) from planned 15 mg/week. 
For the Pegloticase + IMM Period, the following will be summarized by treatment group for the 
Safety Population: 
 
Pegloticase 
o Number of pegloticase infusions received overall per subject (summarized with 
frequency summary along with descriptive statistics of mean, SD, median, 
minimum, and maximum) 
o Duration in days between first and last pegloticase infusion, defined as (last 
infusion date – first infusion date) + 1 (summarized with descriptive statistics of 
mean, SD, median, minimum and maximum) 
o Number of incomplete infusions received (summarized with frequency summary 
along with descriptive statistics of mean, SD, median, minimum and maximum) 
o Number of interrupted infusions summarized with frequency summary along with 
descriptive statistics of mean, SD, median, minimum and maximum) 
 
At each scheduled Pegloticase infusion visit 
o Number of subjects not receiving MTX or placebo between previous infusion and 
current infusion (for subjects infused at current visit) 
o Number of subjects receiving a complete infusion (i.e. full dose administered) 
o Number of infusions administered without interruption 
o Number of subjects with an interrupted infusion 
 
MTX or placebo 


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o Duration of MTX or placebo dosing during the Pegloticase + IMM Period, defined 
as [the last MTX or placebo date – first MTX or placebo dosing date (on or after 
the date of the Day 1 visit)] + 1 
o Cumulative MTX or placebo dosage (in mg) received during the Pegloticase + IMM 
period  
o Average MTX or placebo dose (mg) (total dosage for Pegloticase + IMM Period 
divided by number of doses taken during Pegloticase + IMM Period) (summarized 
with descriptive statistics of mean, SD, median, minimum, and maximum) 
o Number of subjects with dosage reductions (reduction in planned dose for reason 
of AE, abnormal labs, or titration down) from planned 15 mg/week. 
For the overall study, the following will be summarized by treatment group: 
 
MTX 
o Duration of MTX dosing, defined as [the last MTX date – first MTX dosing date (on 
or after the date of the Day 1 visit)] + 1 
o Cumulative MTX dosage (in mg) received 
o Average MTX or placebo dose (mg) (total dosage overall divided by number of 
doses taken overall) (summarized with descriptive statistics of mean, SD, median, 
minimum, and maximum) 
o Number of subjects with MTX dosage reductions (reduction in planned dose for 
reason of AE, abnormal labs, or titration down) from planned 15 mg/week. 
o Total MTX or placebo dosage (mg) per dose overall 
 
Treatment Compliance  
Other than the summarizations of Pegloticase infusions described in Section 11.1, the compliance 
with Pegloticase will not be summarized.  
Compliance with MTX or placebo 15 mg will be summarized based on drug accountability data 
for the Safety Population for the duration of the study after randomization.  Compliance will be 
calculated as 100 x (the number of capsules taken divided by the expected number of capsules).  
Subjects are expected to take 6 capsules (15 mg) each week. The number of capsules taken is 
defined as the number of capsules dispensed – number of capsules returned from the blinded 
bottles (i.e. excluding open label MTX given during MTX Tolerability Period).  If a bottle is not 
returned, it will be assumed that the subject took all pills in the bottle and the number of capsules 
returned is set to 0. The expected number of capsules is defined as: 
 
6 x [# of weeks between Week -4 visit date and the last infusion date] .  For subjects who 
complete pegloticase infusions through the end of the study, 6 will be added to the 
expected number of capsules (since subjects expected to take additional MTX/PBO dose 
after last infusion). 


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The # of weeks will be calculated as [(end date – start date + 7) / 7], dates for prescribed dose 
are based on the MTX/PBO diary data.    
Additionally, compliance with MTX or placebo during the Pegloticase + IMM period will be 
calculated from the MTX/PBO calendar log (a dosing dairy where subjects recorded date, time 
and # of capsules taken each week).  Compliance based on diary data is defined  as 100 x 
(number of MTX or placebo doses taken divided by the number of expected doses).  The number 
of MTX or placebo doses taken will be calculated by taking the number of MTX or placebo doses 
taken starting with the two most recent doses prior to the first pegloticase infusion up through the 
last pegloticase infusion. The expected number of doses is 2 times the number of pegloticase 
infusions received (as subjects should take 2 MTX or placebo doses in between each infusion). 
 
Adverse Events  
All adverse events will be coded using MedDRA version 23.1. AE monitoring will begin from the 
signature of the Informed Consent Form (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. 
Adverse events with an onset date strictly prior to the first MTX treatment in the MTX Tolerability 
Assessment Period will be called non-treatment-emergent events. 
Treatment-emergent AEs (TEAEs) for the MTX Tolerability Assessment Period are defined as 
events with an onset date on or after the first dose of MTX (but not on or after the first MTX or 
placebo date in subjects who entered  the  Run-in Period) through 30 days after the last dose of 
MTX for subjects who did not receive MTX or placebo in Run-in Period.  
Treatment-emergent AEs (TEAEs) for the Run-in period are defined as events with an onset date 
and time on or after the first dose of MTX or placebo in the Run-in Period (but not on or after the 
first infusion date of pegloticase in subjects who entered the Pegloticase + IMM Period) through 
30 days after the last dose of MTX or placebo for subjects who did not receive pegloticase. 
TEAEs for the Pegloticase + IMM Period are defined as events that occur on or after the start 
date and time of the first pegloticase infusion through 30 days after the last dose of pegloticase 
and/or MTX or placebo (whichever is later).  
Adverse events with an onset date more than 30 days after the last dose of pegloticase and/or 
MTX or placebo (whichever is later), will be adverse events in the follow-up period. 
All AEs, both serious and non-serious, will be assessed for severity using the Rheumatology 
Common Toxicity Criteria (CTC) v2.0. Missing data conventions for AEs are described in Section 
6.3.2. The imputed onset dates will be used to determine the period of onset. Summaries of 
TEAEs in the MTX Tolerability Assessment Period will be provided using the MTX Population. 
Summaries of TEAEs in the Run-in Period and in the Pegloticase + IMM Period will be provided 
for the safety population.  
An overall summary of TEAEs will be provided for the MTX Tolerability Assessment Period. 
TEAEs will be presented by treatment group for the Run-in Period and Pegloticase + IMM Period. 
Summaries will include the number and percentage of subjects with each AE type as well as the 
number of events for each of the following: 


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 
TEAEs 
 
Serious TEAEs 
 
TEAEs related to MTX or placebo 
 
TEAEs related to pegloticase (applicable to Pegloticase + IMM Period only) 
 
Serious TEAEs related to MTX or placebo 
 
Serious TEAEs related to pegloticase (applicable to Pegloticase + IMM Period only) 
 
TEAEs with an Rheumatology CTC Criteria of 3 or higher  
 
TEAEs leading to permanent withdrawal of MTX or placebo 
 
TEAEs leading to permanent withdrawal of pegloticase (applicable to Pegloticase + IMM 
Period only) 
 
TEAEs related to MTX or placebo leading to permanent withdrawal of MTX or placebo  
 
TEAEs related to pegloticase leading to permanent withdrawal of pegloticase (applicable 
to Pegloticase + IMM Period only) 
 
TEAEs leading to death 
For Pegloticase + IMM Period, the number and percentage of subjects as well as the number of 
events with any infusion reactions including/excluding anaphylaxis will be included in the 
summary. In addition, the overall summary of TEAEs during the Pegloticase + IMM Period based 
on subgroup will be provided. 
Using the safety population, an overall summary of AEs occurring during the follow-up period 
(with onset more than 30 days after the last dose of study medication), including the number and 
percentage of subjects with each AE type as well as the number of events for each of the 
following: 
 
AEs 
 
Serious AEs 
 
AEs with an Rheumatology CTC Criteria of 3 or higher  
 
AEs leading to death 
Percentages for the overall summary of AEs during follow-up will be based on the number of 
subjects who had follow-up more than 30 days after last dose of medication. 
Additional AE summaries will be provided by onset period, including the number, percentage of 
subjects, experiencing TEAEs for the following: 


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 
TEAEs overall and by SOC and PT for the: MTX Tolerability Assessment Period, Run-in 
Period, Pegloticase + IMM Period, and Follow-up Period  
 
TEAEs by maximum severity, overall and by SOC and PT for the MTX Tolerability 
Assessment Period, Run-in Period, and Pegloticase + IMM Period  
 
TEAEs related to MTX or placebo overall and by SOC and PT for the MTX Tolerability 
Assessment Period, Run-in Period, and Pegloticase + IMM Period 
 
TEAEs related to pegloticase overall and by SOC and PT for the Pegloticase + IMM 
Period only 
 
TEAEs Related to MTX or placebo by maximum severity, overall and by SOC and PT for 
the: MTX Tolerability Assessment Period, Run-in Period, and Pegloticase + IMM Period. 
 
TEAEs Related to Pegloticase by maximum severity, overall and by SOC and PT for the 
Pegloticase + IMM Period only 
 
Serious TEAEs, overall and by SOC and PT for the: MTX Tolerability Assessment Period, 
Run-in Period, Pegloticase + IMM Period, and Follow-up Period 
 
TEAEs leading to permanent withdrawal of MTX or placebo, overall and by SOC and PT 
for the: MTX Tolerability Assessment Period, Run-in Period, and Pegloticase + IMM 
Period) 
 
TEAEs leading to permanent withdrawal of pegloticase, overall and by SOC and PT for 
the Pegloticase + IMM Period only 
 
COVID-19 Infection TEAEs by maximum severity, overall and by SOC and PT for the: 
MTX Tolerability Assessment Period, Run-in Period, Pegloticase + IMM Period, and 
Follow-up Period 
In addition, the summary of TEAEs by SOC and PT during the Pegloticase + IMM Period based 
on subgroup will be provided.  Also, AEs that occur after the start of commercial pegloticase will 
be summarized by SOC and PT and relationship to commercial pegloticase for subjects who take 
commercial pegloticase after discontinuation of study pegloticase.  Similarly, AEs that occur after 
the start of commercial MTX will be summarized by SOC and PT and relationship to commercial 
MTX for subjects who take commercial pegloticase after discontinuation of study MTX. The tables 
summarizing commercial product use will only be created if at least 25 subjects take commercial 
product.   
The incidence per person years of exposure to MTX or placebo and incidence per person years 
of exposure to pegloticase will be provided on all tables except those summarizing events by 
maximum intensity, and those for the post-treatment follow-up period. The person years (PY) of 
exposure is defined as [(last treatment date in the period – first treatment date in the period + 
1)/365.25]. Total PY of exposure to pegloticase will be calculated separately for each treatment 
arm. 
For summaries by SOC, PT, and maximum severity, a subject will only be counted once for each 
SOC based on the maximum intensity level reported for that SOC and once for each unique PT 


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within that SOC level at the maximum intensity level reported for that PT. For summaries by SOC 
and PT only, a subject will be counted at most once at the SOC level and at most once at each 
unique PT within the SOC level. Summaries presenting the frequency of TEAEs by SOC and PT 
will be ordered alphabetically by SOC and then, within a SOC, alphabetically by PT.  
In addition to the listing of all AEs, separate listings will be provided for serious AEs, AEs leading 
to withdrawal of MTX or placebo, AEs leading to withdrawal of pegloticase, AEs leading to study 
discontinuation, AEs of special interest, COVID-19 AEs, AEs occurring while taking commercial 
pegloticase and/or MTX, adjudicated AEs, and AEs leading to death. TEAEs and the period of 
onset will be identified on each listing.  
 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) will include: IRs, anaphylaxis, gout flares, and 
cardiovascular events. All adverse events of special of interest will be summarized using MTX 
population for MTX Tolerability Period and Safety population for Run-in and Pegloticase + IMM 
Period, adjudicated as well as any identified by programming. IRs and anaphylaxis will be 
summarized in Pegloticase + IMM Period only. An independent external adjudication committee 
will review reported events of infusion reactions, cardiovascular events and anaphylaxis. The 
AESI of gout flare will not be adjudicated. 
When possible, a 12-lead ECG will be performed at the time the AESI of infusion reaction, 
anaphylaxis and cardiovascular event is suspected 
Infusion Reactions (IR) and Anaphylaxis 
An IR will be defined as any infusion-related AE or cluster of temporally-related AEs during the 
Pegloticase + IMM Period, 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 2 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. 
The signs and symptoms associated with each event are entered on the eCRF and will be coded 
with the MedDRA dictionary. 
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 
(NIAID/FAAN) 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: 


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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 millimeters mercury (mmHg) or >30% 
decrease from that subject’s baseline. 
Summaries of IRs and anaphylaxis will group events by 3 categories:   
 
anaphylaxis 
 
infusion reactions including anaphylaxis  
 
infusion reactions excluding anaphylaxis 
Both the investigator reported and adjudicated events and the associated signs and symptoms, 
will be summarized separately by SOC, PT, severity, and the time relative to the most recent 
pegloticase infusion for each category above. Time relative to the most recent pegloticase infusion 
will be categorized as: during infusion, ≤ 2 hours after infusion, > 2 hours to 24 hours after infusion, 
> 24 hours after infusion, and missing. Serious events and the associated symptoms will be 
summarized by SOC and PT. The number of events per subject, the number of events and serious 
events per infusion, and the number of subjects with the first event by infusion number will be 
summarized as well for each category. IRs (including anaphylaxis) that occur on the same date 
will be considered one event.   
In addition, the number and percentage of subjects with adjudicated infusion reactions including 
anaphylaxis will be summarized overall and by severity of event by the following categories for 
both anti-PEG and anti-uricase antibodies:    
 
ADA status at baseline (positive or negative) 
 
ADA status post-baseline (positive or negative): 
o ADA positive during treatment is defined as 
 
Negative at baseline and positive at any post-baseline timepoint, or 


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 
Positive at baseline and had an increase in titer  
o ADA negative post-baseline is defined as 
 
Negative at all time points 
 
Positive at baseline, but titer did not increase from baseline 
Time to first infusion reaction or anaphylaxis (Kaplan-Meier analysis) will be plotted. Time to first 
infusion reaction or anaphylaxis for subjects who experience infusion reaction or anaphylaxis 
(continuous variable descriptive stats) will be summarized. Subjects who do not experience an 
event will be censored at the date of their last pegloticase infusion. 
Cardiovascular Events  
Cardiovascular events will include Major Adverse Cardiovascular Events (MACE).  
Any MACE including Non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and 
congestive heart failure. Following search algorithm will be used to identify possible MACE: 
 
For cardiovascular death (for fatal cases only):  
o Standardized MedDRA Queries (SMQ): Myocardial infarction, Ischaemic 
Central Nervous System (CNS) Vascular conditions (narrow); Haemorrhagic 
central nervous system vascular conditions (narrow), Central nervous system 
vascular disorders, not specified as haemorrhagic or ischaemic (narrow),  
Embolic and thrombotic events (arterial, venous, vessel type unspecified and 
mixed arterial and venous) (narrow), Cardiac failure (broad), shock-associated 
conditions (narrow), Torsade de pointes/QT prolongation (narrow), Arrhythmia 
related investigations, signs and symptoms, Cardiomyopathy, Supraventricular 
tachyarrhythmias (narrow), Ventricular tachyarrhythmias (narrow), Conduction 
defects (narrow) 
o All PTs under SOC of Cardiac disorders 
o HLGT Aneurysm 
 
For non-fatal myocardial infarction: SMQ Myocardial infarction   
 
For non-fatal stroke: SMQ: Ischaemic Central Nervous System (CNS) Vascular 
conditions; Haemorrhagic central nervous system vascular conditions; Central nervous 
system vascular disorders, not specified as haemorrhagic or ischaemic  
 
Congestive heart failure: SMQ Cardiac failure 
Using the safety population, the cardiovascular events identified using the aforementioned criteria 
and the adjudicated cardiovascular events will be summarized by SOC and PT for the Run-in 
Period and Pegloticase + IMM Period.  
Gout Flares 
The number and percentage of subjects who experienced a gout flare (recorded in the AE eCRF), 
and number of gout flare per subject will be summarized for the MTX Tolerability Assessment 


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Period using the MTX population. The number and percentage of subjects who experienced a 
gout flare and number of gout flares per subject during the Run-in Period and pegloticase + IMM 
Period (recorded in the AE eCRF) will be provided for the safety population. These events will be 
further summarized by month of occurrence. For the full pegloticase + IMM period, percentages 
will be calculated using the number of subjects in the safety population. For month 1, percentages 
will be based on the number of subjects in the safety population. For the other months of the 
pegloticase + IMM period, percentages will be based on the number of subjects who had follow-up 
at least through the start point of the period-specific time period. The 30 days following the end of 
treatment are included in the follow-up time period. For example, to be included in the Month 2 
denominator, the subjects need to have received pegloticase, methotrexate, or placebo with the 
study day relative to the first pegloticase infusion  ≥ 31 days. One month is defined as 30 days. 
Incidence of gout flares by severity will be summarized overall and by month. These events will 
be further summarized as occurring from the period from Day 1 to Week 12, after Week 12 – 
Week 24, after Week 24 – Week 36, and after Week 36 – Week 52. Events are summarized for 
each period according to the onset date of the flare, and only summarized in the period of onset. 
 
 
Laboratory Evaluations 
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 
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 of study/Early Termination Visit. 
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) 
 
Chemistry: 
albumin, 
transaminases 
(aspartate 
aminotransferase, 
alanine 
aminotransferase), alkaline phosphatase, total bilirubin, creatinine (including calculation 
for Estimated Glomerular Filtration Rate (eGFR) calculated by the Modification of Diet in 
Renal Disease (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 


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(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. 
Laboratory results will be displayed using the conventional units for all summaries and listings. 
Clinical laboratory test results (hematology, chemistry, and urinalysis) and their changes from 
baseline will be summarized by pegloticase treatment status (On Treatment, Post-Treatment, and 
Overall, see Section 9.4), visit, and treatment group for the safety using descriptive statistics.  
If a continuous laboratory value is reported as either below or above the limits of quantification, 
the qualifiers will be dropped and the numeric value used in the analysis (e.g., “< 3” will be 
summarized as “3” and “> 200” will be summarized as “200”).  
For all laboratory tests, results will be categorized as low, normal, or high based on their normal 
ranges. Results out of range will be identified as such on subject listings.  
Using the safety population , shift tables using categories of low, normal, and high, comparing 
laboratory test results from baseline to each visit will be presented with percentages based on 
subjects with a non-missing value at baseline and post-baseline visit. A summary of elevated liver 
function test values as well as Hy’s law will be provided by visit and for any post-baseline visit: 
 
alanine aminotransferase > ULN, 2xULN, 3xULN, 5xULN, 10xULN, and 20xULN  
 
aspartate aminotransferase > ULN, 2xULN, 3xULN, 5xULN, 10xULN, and 20xULN  
 
alkaline phosphatase ≥ 1.5xULN, 2.5xULN, and 3xULN  
 
total bilirubin ≥ 1.5xULN, 2xULN, and 3xULN  
Hy’s law: 
 
(alanine aminotransferase or aspartate aminotransferase ≥ 3xULN) and total bilirubin ≥ 
2xULN  
 
(alanine aminotransferase or aspartate aminotransferase ≥ 3xULN) and total bilirubin ≥ 
2xULN and alkaline phosphatase < 2xULN 
For tests where the Common Terminology Criteria for Adverse Events (CTCAE) criteria is 
available, shift tables will be based on the CTCAE grade. The CTCAE version 4.03 will be used 
for these summaries.  Laboratory results as well as results out of normal range will be presented 
in listings. 


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Pregnancy Tests 
Pregnancy test results will be provided in a listing. 
 
Vital Signs  
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. 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 blood pressure readings 
measured to the nearest mmHg prior to pegloticase infusion.  If any of the 3 systolic blood 
pressure measurements differ by more than 8 mmHg or if diastolic measurements differ by more 
than 5 mmHg, a repeat sets of 3 sitting blood pressure measurements will be obtained until the 
difference is less than 8 mmHg for systolic and less than 5 mmHg for diastolic. All values will be 
recorded in the eCRF. Additional sets of 3 measurement may be taken until none of the 3 systolic 
measurements differ by 8 mmHg and none of the 3 diastolic measurements differ by more than 5 
mmHg. The average of the 3 values will be used in the summary. If more than 1 set of 
measurements is taken, the set of measurements performed last will be used for the pre-infusion 
timepoint at a visit. 
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. BMI will be determined using the weight 
recorded in kg and the height measured at screening. 
Descriptive summaries of observed and change from baseline values will be presented for each 
vital sign parameter by pegloticase treatment status (On Treatment, Post-Treatment, and Overall, 
see Section 9.4), and visit, using the safety population. Vital sign measurements that are 
monitored as a result of an infusion-associated event will not be included in the descriptive 
summaries but will be presented in subject listings. 
The following conversion factor will be used to convert any temperatures reported in degrees 
Fahrenheit to Celsius: 
Temperature (in °C) = 5/9 (Temperature [in °F]-32). 
The following conversion factor will be used to convert any weights reported in pounds to 
kilograms: 


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Weight [kg] = Weight [in lbs] * 0.4536. 
The following formula will be used to determine the BMI (in kg/m2) using weight [in kg] and height 
[in cm]:  
BMI = Weight / (Height/100)2; 
 
Electrocardiograms 
A 12-lead ECG will be performed at Screening and at the discretion of the Investigator thereafter. 
The results will be recorded as normal or abnormal on the eCRF and all abnormal results will be 
evaluated as clinically significant (CS) or not clinically significant (NCS) by the investigator. 
Using the safety population, a summary will be provided of subjects at Screening (using the count 
and percentage of subjects) with:  
 
Normal 
 
Abnormal NCS 
 
Abnormal CS 
Percentages will be based on the number of subjects with an assessment completed. 
Because the post-Screening ECGs are done at the discretion of the investigators, or in the event 
of an infusion reaction, only the following summaries will be provided using the safety population:  
 
Incidence of post-Screening Abnormal ECGs (includes NCS and CS) findings 
 
Incidence of post-Screening Abnormal, Clinically Significant ECGs 
For the post-Screening ECG summary, percentages will be calculated using the number of 
subjects who have a post-Screening assessment. 
 
Physical Examination 
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. 
Physical examination data will be listed. No summarizations of the physical examination data will 
be presented. 


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Changes from Analysis Planned in Protocol 
In those cases in which this SAP details changes from the analyses specified by the protocol, the 
analyses specified in this SAP will supersede those in the protocol. There are no changes from 
Amendment 3 of the protocol but details and clarifications are described in this SAP. 
 


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Programming Considerations 
 
General Considerations 
 
All TLFs will be produced in landscape format. 
 
All TLFs will be produced using the Courier New font, size 8  
 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 
TLFs will be in black and white (no color) 
 
Specialized text styles, such as bolding, italics, borders, and shading will not be used in the 
TLFs, unless otherwise specified. On some occasions, superscripts 1, 2, or 3 may be used. 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., m2, Ctrough) will be 
employed on a case-by-case basis. 
 
Title case or mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 
 
 
 
Table, Listing, and Figure Format 
 
General 
 Headers and footers for figures will be in Courier New font, size 8 which is the smallest 
acceptable point size for the Regulatory Authorities. 
 Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 Tables, Figures and Listings (TLFs) will be in black and white (no color), unless 
otherwise specified 
 Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TLFs, unless otherwise specified. On some 
occasions, superscripts 1, 2, or 3 may be used (see below). 
 Only standard keyboard characters will be used in the TLFs. Special characters, such as 
non-printable control characters, printer-specific, or font-specific characters, will not be 
used. Hexadecimal-derived characters will be used, where possible, if they are 
appropriate to help display math symbols (e.g., μ). Certain subscripts and superscripts 
(e.g., cm2, Cmax) will be employed on a case-by-case basis. 
 Title case of mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 


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Headers 
 All output should have the following header at the top left of each page: 
Horizon Therapeutics Ireland DAC  
Protocol HZNP-KRY-202 
 All output should have Page n of N at the top or bottom right corner of each page. TLFs 
are internally paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table). 
 The date output was generated should appear along with the program name as a footer 
on each page. 
 
Display Titles 
 Each Table, Figure, and Listing is identified by the designation and a numeral. (i.e., Table 
14.1.1). ICH E3 numbering is strongly recommended, but sponsor preferences are 
obtained before final determination. A decimal system (x.y and x.y.z) will be used to 
identify TLFs with related contents. The title is centered. The analysis set are identified on 
the line immediately following the title. The title and table designation are single spaced. A 
solid line spanning the margins will separate the display titles from the column headers. 
There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Population) 
 
 
Column Headers 
 Column headings are displayed immediately below the solid line described above in initial 
upper-case characters.  
 In the case of efficacy tables, the variable (or characteristic) column will be on the far left 
followed by the population columns. Within-treatment comparisons may have p-values 
presented in a row beneath the summary statistics for that treatment. 
 For numeric variables, include “unit” in column or row heading when appropriate. 
 Analysis set sizes will be presented for each treatment group in the column heading as 
(N=xx) (or in the row headings, if applicable). This is distinct from the ‘n’ used for the 
descriptive statistics representing the number of subjects in the analysis set. 


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Body of the Data Display 
13.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
 Alphanumeric values are left-justified; 
 Whole numbers (e.g., counts) are right-justified; and 
 Numbers containing fractional portions are decimal aligned. 
13.2.5.2. 
Table Conventions 
 Units will be included where available 
 If the categories of a parameter are ordered, then all categories between the maximum 
and minimum category are presented in the table, even if n=0 for all treatment groups in a 
given category that is between the minimum and maximum level for that parameter. For 
example, the frequency distribution for symptom severity will appear as: 
Severity 
Rating 
N 
Severe 
0 
moderate 
8 
Mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and 
so counts of 0 will be presented as 0 and not as 0 (0%). 
 If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from 
the Study, etc.), then only those categories for which there is at least 1 subject 
represented in 1 or more groups are included. 
 An Unknown or Missing category are added to each parameter for which information is 
not available for 1 or more subjects.  
 Unless otherwise specified, the estimated mean and median for a set of values are printed 
out to 1 more significant digit than the original values, and standard deviations are printed 
out to 2 more significant digits than the original values. The minimum and maximum 
should report the same significant digits as the original values. For example, for systolic 
blood pressure: 
N 
  XX 
Mean 
XXX.X 
SD 
     X.XX 
Median 
XXX.X 




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missing months (e.g. UNJUL2000, UNUNK2000). Dates that are missing because they are 
not applicable for the subject are output as “NA”, unless otherwise specified. 
 All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS 
format (e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of 
the study. 
 Units will be included where available 
13.2.5.4. 
Figure Conventions 
 Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and 
endpoint (e.g., treatment mean change from Baseline) values will be displayed on the Y-
axis. 
 
Footnotes 
 A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
 Subject specific footnotes are avoided, where possible. 
 Footnotes will be used sparingly and add value to the table, figure, or listing. If more than 
six lines of footnotes are planned, then a cover page is strongly recommended to be used 
to display footnotes, and only those essential to comprehension of the data will be 
repeated on each page.  
 The last line of the footnote section will be a standard source line that indicates the name 
of the program used to produce the data display, date the program was run, and the listing 
source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in 
Syneos Health Standard Operating Procedure (SOP) Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of 
Biostatistical Deliverables (3908) describes the quality control procedures that are performed for 
all SAS programs and output. Quality control is defined here as the operational techniques and 
activities undertaken to verify that the SAS programs produce the output by checking for their 
logic, efficiency and commenting and by review of the produced output. 


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Index of Tables 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
   
  
 
 
 
  
  


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References 
Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: dimensions and practical 
applications. Health Qual Life Outcomes. 2003;1:20. 
Johnson J. Richard, Choi K. Hyon, Yeo E. Anthony, Lipsky E. Peter. Pegloticase treatment 
significantly decreases blood pressure in patients with chronic gout; Hypertension. 2019; 74:95-
101. 
Khanna D et al. 2012 ACR guidelines for management of gout; part 2. ACR Vol 64, No 10, Oct 
2012, p1447-1461. 
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.