A Phase 4, Multicenter, Open-Label, Infusion Duration Study To Assess Safety, Tolerability and Efficacy of Pegloticase Administered With a Shorter Infusion Duration in Subjects With Uncontrolled Gout Receiving Methotrexate
Phase: PHASE4
Conditions: Chronic Uncontrolled Gout, Gout, Uncontrolled Gout
Sponsor: Amgen

Horizon Therapeutics Ireland DAC
KRYSTEXXA IND: 010122
Date: 09NOV2022
Protocol: HZNP-KRY-403
Version 5.0, Amendment 4
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC
Page 1 of 104
CLINICAL STUDY PROTOCOL 
FOR PEGLOTICASE
IND: 010122
Protocol Number: HZNP-KRY-403
Version 5.0, Amendment 4
A Phase 4, Multicenter, Open-Label, Infusion Duration Study To Assess 
Safety, Tolerability and Efficacy of Pegloticase Administered With a Shorter 
Infusion Duration in Subjects with Uncontrolled Gout Receiving 
Methotrexate
Date: 09 NOV 2022
Sponsor:
Horizon Therapeutics Ireland DAC
70 St. Stephen’s Green
Dublin 2 Ireland D02 E2X4
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: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 2 of 104 
 
PROTOCOL 
1 
TITLE PAGE 
Study Title:  A Phase 4, Multicenter, Open-Label, Infusion Duration Study 
To Assess Safety, Tolerability and Efficacy of Pegloticase 
Administered With a Shorter Infusion Duration in Subjects with 
Uncontrolled Gout Receiving Methotrexate 
Protocol Number:  HZNP-KRY-403  
Version:  5.0, Amendment 4 
Investigational 
Products:  
Pegloticase (recombinant modified mammalian urate oxidase 
[uricase])  
Indication:  Chronic gout refractory to conventional therapy in 
adult patients  
Sponsor:  Horizon Therapeutics Ireland DAC 
70 St. Stephen’s Green 
Dublin 2 Ireland D02 E2X4 
Development Phase:  4  
Sponsor’s Responsible 
Medical Officer:  
M.D.  
Medical Director, Rare Disease  
Horizon Therapeutics U.S.A., Inc.   
Two Tower Place, 12th Floor 
South San Francisco, CA  94080 
Sponsor Signatory:  
M.D.  
Medical Director, Rare Disease   
Horizon Therapeutics U.S.A., Inc.   
Two Tower Place, 12th Floor 
South San Francisco, CA  94080 
Approval Date:  09NOV2022 
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: 800-860-7836 
Email: clinicalsafety@horizontherapeutics.com 

Horizon Therapeutics Ireland DAC
KRYSTEXXA IND: 010122
Date: 09NOV2022
Protocol: HZNP-KRY-403
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC
Page 3 of 104
SPONSOR SIGNATURE PAGE
Protocol Number: 
HZNP-KRY-403
Version:
5.0, Amendment 4
Protocol Title: 
A Phase 4, Multicenter, Open-Label, Infusion Duration Study To Assess 
Safety, Tolerability and Efficacy of Pegloticase Administered With a 
Shorter Infusion Duration in Subjects with Uncontrolled Gout Receiving 
Methotrexate
Version Date: 
09NOV2022
Approved by:
M.S.
Director, Biostatistics
Horizon Therapeutics U.S.A., Inc.  
Date
M.D.
Medical Director, Rare Disease  
Horizon Therapeutics U.S.A., Inc.
Date

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M.S.
Di
Di
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Di
Di
Di
Dirererer ctc or, Biostatistics

	
M.D.
Me
Me
Me
Me
Me
Me
Me
Medid cal Director, Rare Disease

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
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Page 4 of 104 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number:  
HZNP-KRY-403    
Version: 
5.0, Amendment 4 
Protocol Title:  
A Phase 4, Multicenter, Open-Label, Infusion Duration Study To Assess 
Safety, Tolerability and Efficacy of Pegloticase Administered With a 
Shorter Infusion Duration in Subjects with Uncontrolled Gout Receiving 
Methotrexate 
Version Date: 
09NOV2022 
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: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
Version 5.0, Amendment 4 
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Page 5 of 104 
 
 
SUMMARY TABLE OF CHANGES 
 
Protocol Version 1.0, Original (20 April 2020) to 
Protocol Version 2.0, Amendment 1 (14May2020) 
Protocol Version 3.0, Amendment 2 (07JUL2020) 
Protocol Version 4.0, Amendment 3 (14FEB2022) 
Protocol Version 5.0 Amendment 4 (09NOV2022) 
 
 
The table below highlights the primary changes to Version 5 of the Protocol. Administrative 
and typographical updates have also been made. Track changes version of the protocol can be 
provided on request. 
 
Text 
Version 4.0, Amendment 3 
14FEB2022 
Amended Text 
Version 5.0, Amendment 4 
09NOV2022 
Reason for Change 
Number and Country of Study Sites:  
Approximately 25 study centers in the United 
States. 
 
 
Number and Country of Study Sites:  
Approximately 40 study centers in the United 
States. 
 
Increased estimated 
number of sites to 
support enrollment of 
the increased sample 
size. 
Overall Study Objective (Synopsis and 
Section 9): 
The overall objective of this study is to assess 
the tolerability and efficacy of pegloticase 
administered with a shorter infusion duration in 
subjects with uncontrolled gout receiving 
methotrexate and select the shortest infusion 
duration able to be well tolerated. 
Overall Study Objective (Synopsis and Section 
9): 
The overall objective of this study is to assess the 
tolerability and efficacy of pegloticase 
administered with a shorter infusion duration in 
subjects with uncontrolled gout receiving 
methotrexate. 
Updated objective to 
simplify. 
Study Design (synopsis and Section 9.1): 
Approximately 80 subjects will be enrolled. 
Study Design (synopsis and Section 9.1): 
Approximately 10 subjects in each cohort are 
planned to be enrolled initially. If deemed safe, 
an additional 100 subjects to be enrolled in the 
selected cohort in order to have approximately 
110 subjects exposed. 
Updated to reflect 
targeted sample size. 
Study Design (synopsis and Section 9.1): 
Cohorts of approximately 10 subjects will be 
enrolled sequentially at progressively shorter 
infusion durations, beginning with the 60-
minute infusion duration, progressing down to 
the 45-minute infusion duration and then to the 
30-minute infusion duration. If deemed safe, 
enrollment will continue until approximately 60 
subjects are enrolled in the last infusion 
duration cohort (e.g. 60 subjects in the 30-
minute infusion cohort, unless 30-minute 
infusion was not tolerated and then 
approximately 60 subjects may be enrolled in 
the 45-minute infusion cohort).   
Study Design (synopsis and Section 9.1): 
Initially, cohorts of approximately 10 subjects 
will be enrolled sequentially at progressively 
shorter infusion durations, beginning with the 60-
minute infusion duration, progressing down to the 
45-minute infusion duration and then to the 30-
minute infusion duration. If deemed safe, 
enrollment will continue in the chosen infusion 
duration cohort until approximately 110 subjects 
are enrolled (e.g. targeted 110 subjects in the 30-
minute infusion cohort, unless 30-minute infusion 
is not tolerated, then approximately 110 subjects 
may be enrolled in the 45-minute or 60-minute 
infusion cohort).   
Updated targeted 
number of subjects 
enrolled. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
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Study Design (synopsis and Section 9.1): 
Enrollment will be paused after the 10th subject 
of each infusion duration cohort is enrolled 
until after the 4-week (3-infusion visits) safety 
assessment analysis results are known and 
reviewed by Safety Review Committee.   
Study Design (synopsis and Section 9.1): 
None. 
Removed – this didn’t 
apply to cohorts 
beyond initial cohort. 
Study Design (synopsis and Section 9.1): 
Further, if the Safety Review Committee 
confirms that the percentage of subjects 
meeting infusion speed-limiting criteria are less 
than the thresholds specified in Section 9.2 
after approximately 10 subjects receive 
infusions at the 30-minute infusion duration, 
then additional subjects will be enrolled. 
Study Design (synopsis and Section 9.1): 
Further, if the Safety Review Committee 
confirms that the percentage of subjects meeting 
infusion speed-limiting criteria are less than the 
thresholds specified in Section 9.2 then additional 
subjects will be enrolled (for a total of 
approximately 110 subjects in the given cohort). 
Updated targeted 
number of subjects 
enrolled. 
Study Design (synopsis and Section 9.1): 
The Safety Review Committee can increase the 
number of subjects at the chosen infusion 
duration level to up to approximately 80 
subjects, if they determine that more safety data 
is needed. 
Study Design (synopsis and Section 9.1): 
The Safety Review Committee can modify the 
number of subjects at the chosen infusion 
duration level, if they determine that more safety 
data is needed. 
Updated for 
clarification. 
Study Design (synopsis and Section 9.1): 
If any of the safety assessments indicate that a 
specific infusion duration is not tolerated based 
on pre-determined criteria, then the study will 
enroll additional subjects at the previous 
infusion duration (which is 15 minutes longer 
than the one at which infusion speed limiting 
criteria were met). In the event that the initial 
60-minute infusion duration is not tolerated 
based on pre-determined criteria, then the study 
is terminated. 
 
Study Design (synopsis and Section 9.1): 
If any of the safety assessments indicate that a 
specific infusion duration is not tolerated based 
on pre-determined criteria, then the study may 
enroll additional subjects at a previous infusion 
duration. In the event that the initial 60-minute 
infusion duration is not tolerated based on pre-
determined criteria, then the study may be revised 
or terminated (after internal review and 
assessment). 
Updated for 
clarification. 
Study Design (synopsis and Section 9.1): 
An External Adjudication Committee and 
internal Safety Review Committee (SRC) will 
be established for this study to adjudicate the 
AESIs and to review the aggregate safety data.  
Subject safety and tolerability of the 
pegloticase regimen will be discussed and the 
committee will make a recommendation to the 
Sponsor as whether to continue the current 
treatment regimen or to modify the assigned 
treatment regimen.   
AESIs defined in the protocol (See Section 
9.6.1.2.1.5) include IRs, anaphylaxis and 
cardiovascular events.  The AESI of gout flare 
will not be adjudicated. 
The Safety Review Committee will be 
comprised of members of the Horizon Clinical 
Development and Patient Safety and 
Pharmacovigilance Teams.  External 
Adjudication committee will be comprised of 
external experts with experience in 
immunology, allergic reactions, rheumatology 
Study Design (synopsis and Section 9.1): 
An External Adjudication Committee will be 
established for this study to adjudicate the AESIs.  
The External Adjudication Committee will be 
comprised of external experts with experience in 
immunology, allergic reactions, rheumatology 
and/or cardiovascular diseases. Details outlining 
the responsibilities of the Adjudication 
Committee will be included in the Adjudication 
Committee charter. AESIs defined in the protocol 
(See Section 9.6.1.2.1.5) include IRs, anaphylaxis 
and cardiovascular events.  The AESI of gout 
flare will not be adjudicated. 
Aggregate safety data will be reviewed by the 
internal Safety Review Team (SRT) and Safety 
Review Committee (SRC). Subject safety and 
tolerability of the pegloticase regimen will be 
discussed to establish a recommendation as to 
whether to continue the current treatment regimen 
or to modify the assigned treatment regimen.   
The SRC will be comprised of members of the 
Horizon Clinical Development and Patient Safety 
Clarified 
responsibilities and 
expectations of 
reviews/assessments 
for each of the 
committees involved. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
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and/or cardiovascular diseases.  Meetings will 
occur at pre-determined timepoints or ad-hoc 
dependent on any potential safety signals 
reported (e.g. anaphylaxis or any SAE related 
to pegloticase infusion).  Details outlining the 
responsibilities of the adjudication committee 
will be included in the adjudication committee 
charter. 
and Pharmacovigilance Teams.  Meetings will 
occur at pre-determined timepoints or ad-hoc 
dependent on any potential safety signals reported 
(e.g. anaphylaxis or any SAE related to 
pegloticase infusion). If any anaphylaxis event or 
SAE related to pegloticase infusion occurs with 
any subject, real-time with expedited review of 
patient profiles and/or relevant data available in 
the electronic data capture will occur. 
Study Design: (Schematic) 
 
Original Study Schematic Diagram 
 
Study Design: (Schematic) 
 
Amended Schematic added 
Updated schematic - 
administrative 
change (added Week 
10 to the list of 
infusions) 
Study Design (Schematic – Footnote 3): 
The determination on whether to enroll the next 
cohort of subjects to a lower infusion duration 
level will be based on whether the previous 
cohort meets the Infusion Speed-Limiting 
Criteria as well as the Safety Review 
Committee decision. Expansion Cohort may 
follow Cohort 2 or Cohort 3, depending on 
tolerability assessment decision. 
Study Design (Schematic – Footnote 3): 
The determination on whether to enroll the next 
cohort of subjects to a different infusion duration 
level will be based on whether the previous 
cohort meets the Infusion Speed-Limiting Criteria 
as well as the Safety Review Committee decision. 
Removed reference to 
expansion – it’s not 
applicable. 
Dosage Form and Strength Formulation 
(synopsis and Section 9.5.4): 
Pegloticase will be supplied as KRYSTEXXA 
which 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.   
Dosage Form and Strength Formulation 
(synopsis and Section 9.5.4): 
Pegloticase will be supplied as KRYSTEXXA 
which is commercially available in the United 
States and will be packaged in sterile, single-use 
2-mL glass vials with coated (latex-free) rubber 
injection stopper to deliver pegloticase as 8 mg of 
uricase protein in 1 mL volume.   
Removed based on 
the updated USPI. 
Infusion Speed-Limiting Criteria 
(throughout the protocol): 
If ≤ one-third of subjects meet infusion speed-
limiting criteria at the same infusion duration… 
Infusion Speed-Limiting Criteria (throughout 
the protocol): 
If ≤ one-eighth of subjects meet infusion speed-
limiting criteria at the same infusion duration… 
Updated threshold 
(<12.5%) based on 
the FDA feedback. 
Infusion Speed-Limiting Criteria (synopsis 
and Section 9.2): 
In the event that > one-third of subjects meet 
infusion-speed limiting criteria at the initial 60-
minute infusion duration, then the study is 
terminated. 
 
Infusion Speed-Limiting Criteria (synopsis 
and Section 9.2): 
In the event that > one-eighth of subjects meet 
infusion-speed limiting criteria at the initial 60-
minute infusion duration, then the study may be 
revised or terminated (after internal review and 
assessment). 
 
Updated to clarify 
that further 
reassessment/revision 
may be done before 
the study is 
terminated. 
Infusion Speed-Limiting Criteria (synopsis 
and Section 9.2): 
If any anaphylaxis event or SAE related to 
pegloticase infusion occurs with any subject, 
further enrollment and dosing with pegloticase 
will be suspended pending expedited review of 
all pertinent data by the Adjudication and 
Safety Review Committee.  An independent 
Infusion Speed-Limiting Criteria (synopsis 
and Section 9.2): 
If any anaphylaxis event or SAE related to 
pegloticase infusion occurs with any subject, all 
pertinent data will be provided for expedited 
review to the Adjudication Committee (for the 
purpose of adjudicating AESIs) and the 
SRT/SRC.  If any anaphylaxis event or SAE 
Updated to remove 
redundant 
information and to 
clarify the 
expectations for the 
review. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
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Adjudication Committee will meet on an ad 
hoc basis to review and assess the event and it 
will be the responsibility of the Adjudication 
Committee to make a recommendation to the 
Sponsor if they believe that enrollment and/or 
further dosing should be suspended for a 
specific infusion duration time.  Details 
outlining the responsibilities of the adjudication 
committee will be included in the adjudication 
committee charter. If any anaphylaxis event or 
SAE related to pegloticase infusion occurs with 
any subject and the Adjudication and Safety 
Review Committee recommends continuing at 
the same infusion duration, the next 3 subjects 
will be enrolled in a sequential manner.  Each 
of the next 3 subjects must complete 3 
infusions prior to enrollment of the next 
subject. 
related to pegloticase infusion occurs with any 
subject, real-time with expedited review of 
patient profiles and/or relevant data available in 
the electronic data capture will occur. 
Statistical Analysis on Primary and 
Secondary Endpoints (throughout the 
protocol): 
… one-sided 95% confidence interval… 
Statistical Analysis on Primary and Secondary 
Endpoints (throughout the protocol): 
… two-sided 95% confidence interval… 
Updated based on 
sample size 
justification  
Sample Size Estimate (synopsis and Section 
9.7.9): 
Cohorts of approximately 10 subjects will be 
enrolled sequentially at progressively shorter 
infusion durations, beginning with the 60-
minute infusion duration, progressing down to 
the 45-minute infusion duration and then to the 
30-minute infusion duration. Approximately 60 
subjects are planned to be enrolled into the 
shortest infusion cohort that does not meet the 
dose limiting criteria. Therefore, the total 
number of subjects enrolling across the 3 
different cohorts in the study is approximately 
80. The primary tolerability endpoint, the 
incidence of subjects experiencing IRs 
(including anaphylaxis) related to pegloticase 
from Day 1 to Week 24 Visit, will be 
demonstrated to be statistically less than 20% 
(clinically important threshold). If no more than 
6/60 (10%) of subjects at the chosen infusion 
duration are observed to have an IR during the 
course of the study treatment. In that case, the 
upper bound of a one-sided 95% confidence 
interval for the incidence of IRs is 18.8%. The 
Safety Review Committee may recommend 
increasing the sample size for the chosen 
infusion duration by up to 20 subjects, if they 
believe more safety data are needed. If 80 
subjects are enrolled at the chosen infusion 
duration and 9/80 (11.3%) subjects experience 
an IR, then the upper bound is 18.9%. 
Sample Size Estimate (synopsis and Section 
9.7.9): 
Initially, cohorts of approximately 10 subjects 
will be enrolled sequentially at progressively 
shorter infusion durations, beginning with the 60-
minute infusion duration, progressing down to the 
45-minute infusion duration and then to the 30-
minute infusion duration. Approximately 110 
subjects are planned to be enrolled into the 
selected cohort. Therefore, the minimum number 
of subjects enrolling across the 3 different cohorts 
in the study is approximately 130.  
Based on the MIRROR-RCT study, we expect 
approximately 5.0% of subjects to have an IR 
(including events of anaphylaxis) when taking 
pegloticase concurrently with MTX. The sample 
size of 110 for the selected cohort is chosen to 
ensure a high probability of ruling out an 
unacceptably high IR rate.  If the observed IR rate 
is 5%, there is a greater than 80% probability that 
the upper bound of the two-sided 95% exact 
confidence interval for the IR rate is less than 
13%. 
Updated description 
and justification for 
the sample size 
increase to 110 
subjects in the 
shortest infusion 
duration chosen. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
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2.1 Schedule of Assessments (Footnote 1): 
The Screening Visit can occur up to 35 days 
prior to Day 1 visit. 
2.1 Schedule of Assessments (Footnote 1): 
The Screening Visit can occur up to 35 days prior 
to Week -4 visit. HbA1c testing is required as 
part of the Hematology panel during Screening 
period (refer to Guidance on Blood Glucose 
Monitoring in Section 9.1). 
Administrative 
change.  
Updated to include 
requirement for the 
HbA1c to be 
collected during 
Screening. 
2.1 Schedule of Assessments (Footnote 6 and 
Section 9.5.9): 
Prior concomitant medications (not including 
gout medications) will be collected for 1 year 
prior to screening. 
 
2.1 Schedule of Assessments (Footnote 6 and 
Section 9.5.9): 
Prior concomitant medications (not including 
gout medications) will be collected for 1 year 
prior to screening (as well as history of COVID-
19 vaccinations).   
Updated to include 
requirements for all 
historical COVID 
vaccinations to be 
captured under con 
meds. 
9.1 Overall Study Design and Plan 
None. 
9.1 Overall Study Design and Plan 
Guidance on Blood Glucose Monitoring: 
HbA1c testing must be performed at Screening 
for all subjects (locally or centrally): 
If HbA1c >6.5% and/or if subject has known 
diagnosis of diabetes mellitus, additional 
measures are recommended: 
• 
Investigator asked to closely monitor 
glucose levels and adjust any diabetic 
medications as necessary 
• 
Subject should consult their primary 
care physician and/or Endocrinologist managing 
their diabetes 
The pre-infusion IV steroid dose may be reduced 
(e.g., methylprednisolone 75 mg IV) after 
consulting with the Horizon Medical Monitor. 
Added guidance and 
instructions on blood 
glucose monitoring 
due to potential 
increased risk of 
steroid induced 
hyperglycemia. 
9.5.2.3 Infusion Reaction Prophylaxis 
None. 
9.5.2.3 Infusion Reaction Prophylaxis 
NOTE: If subject’s HbA1c is >6.5% at Screening 
and/or if subject has known diagnosis of diabetes 
mellitus, the pre-infusion IV steroid dose may be 
reduced (e.g., methylprednisolone 75 mg IV) 
after consulting with the Horizon Medical 
Monitor. 
Added guidance on 
blood glucose 
monitoring due to 
potential increased 
risk of steroid 
induced 
hyperglycemia. 
9.5.8 Method of Assigning Subjects to 
Treatment Groups 
Infusion duration assignment may be 
progressively shortened to 45 minute or 30-
minute infusion durations based on tolerability 
of previous subjects. 
 
After the investigator/study site identifies a 
potential patient, the investigator/study site 
should notify Sponsor of potential patient by 
sending a Screening Notification email to the 
Study Manager and Medical Monitor.  Formal 
screening procedures should not begin until a 
slot has been confirmed for the potential 
patient.  The sponsor will confirm by email that 
the patient is held a spot for potential treatment.   
 
9.5.8 Method of Assigning Subjects to 
Treatment Groups 
Infusion duration assignment may be 
progressively shortened to 45 minute or 30-
minute infusion durations based on tolerability of 
previous subjects and the infusion duration cohort 
may be modified based on the safety and 
tolerability assessments. 
 
 
Updated to clarify 
the expectations for 
screening and 
treatment 
assignment.   

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
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9.6.1.4 Medical/Surgical History 
None. 
9.4.1.4 Medical/Surgical History 
For subjects with reported allergic history (e.g., 
seasonal allergies, food allergies, allergies to 
medications) the Investigator/site should collect 
additional supplemental information (e.g., 
severity, current status etc.). In the event of 
multiple allergies and/or moderate to severe 
(Grade 2 or higher) allergic history the 
Investigator should consult with the Medical 
Monitor prior to enrolling the subject. 
Updated guidance to  
minimize the risk of 
potential IRs 
(patients with severe 
history of allergies 
may have a higher 
chance of 
IR/Anaphylaxis 
occurrence). 
9.7.2 Analysis Sets 
None. 
9.7.2 Analysis Sets 
x 
Safety set: all subjects who receive at least 1 
dose of pegloticase.     
Updated analysis set 
list.  
9.7.5 Endpoint Analysis 
All analyses will be performed using the mITT 
set.  Baseline characteristics and safety relating 
to only the MTX Run-in period will be 
summarized for the ITT set.  
 
9.7.5 Endpoint Analysis 
All efficacy analyses will be performed using the 
mITT set. Baseline characteristics and safety 
relating to only the MTX Run-in period will be 
summarized for the ITT set and/or mITT set.  All 
safety analyses relating to pegloticase + MTX 
period will be summarized using the safety set. 
Clarified analysis 
sets to be used for 
specific analyses. 
9.7.8 Interim Analysis 
• After 15 subjects complete at least 3 infusions 
at one assigned infusion duration level. 
• After 20 subjects complete at least 3 infusions 
at one assigned infusion duration level. 
• After all subjects complete at least 3 
infusions. 
• After all subjects complete at least 6 
infusions. 
9.7.8 Interim Analysis 
• After 15 subjects complete at least 3 infusions at 
one assigned infusion duration level if applicable. 
• After 20 subjects complete at least 3 infusions at 
one assigned infusion duration level if applicable. 
• After all subjects complete at least 3 infusions. 
 
Updated to clarify 
the safety data 
analysis expectations. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 09NOV2022 
 
Protocol: HZNP-KRY-403 
 
 
Version 5.0, Amendment 4 
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Page 11 of 104 
 
2 
SYNOPSIS 
Protocol Title: A Phase 4, Multicenter, Open-Label, Infusion Duration Study To Assess 
Safety, Tolerability and Efficacy of Pegloticase Administered With a Shorter Infusion 
Duration in Subjects with Uncontrolled Gout Receiving Methotrexate 
Protocol Number: HZNP-KRY-403 
Phase: 4 
Protocol Version: 5.0 
 
Test Drugs: KRYSTEXXA (pegloticase) 
Indication: Chronic gout refractory to 
conventional therapy in adult patients  
Number and Country of Study Sites: Approximately 40 study centers in the United States 
Objectives:  
The overall objective of this study is to assess the safety, tolerability and efficacy of 
pegloticase administered with a shorter infusion duration in subjects with uncontrolled gout 
receiving methotrexate. 
Primary Objective 
The primary objective is to assess the tolerability of pegloticase infusions administered with 
methotrexate (MTX) from Day 1 through Week 24 in the cohort chosen to be the most 
desirable duration for infusion, as measured by the incidence of infusion reactions (including 
anaphylaxis) related to pegloticase. 
Secondary Objectives 
The secondary objectives will be assessed for the cohort chosen to be the most desirable 
duration for infusion and include: 
x Estimate the response rate at Month 6 (Weeks 20, 22 and 24), as measured by the 
sustained normalization of sUA to <6 mg/dL for at least 80% of the time during 
Month 6.  
x Assess the proportion of subjects receiving pegloticase with MTX who experienced 
any of the following events: infusion reaction (IR) leading to discontinuation of 
treatment, anaphylaxis, or meeting Individual Subject sUA Discontinuation Criteria. 
x Assess the time to any of the following events: IR leading to discontinuation of 
treatment, anaphylaxis, or meeting Individual Subject sUA Discontinuation Criteria 
(two consecutive pre-infusion sUAs > 6 mg/dL). 
Exploratory Objectives 

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x Assess the pharmacokinetics of pegloticase. 
x Assess the profile of anti-uricase antibodies and anti-poly (ethylene glycol) 
antibodies. 
Safety Objectives 
x Assess the incidence of adverse events of special interest (AESI), including IRs, 
anaphylaxis, gout flares, cardiovascular events and the AE/SAE profile overall.  
x Assess the proportion of subjects who experienced IR leading to slowing down of the 
infusion rate or discontinuation of treatment. 
x Assess the time to first IR leading to slowing down of the infusion rate or 
discontinuation of treatment. 
x Assess the time to first IR. 
x Assess the proportion of subjects who were able to complete all infusions over the 
assigned treatment duration length or a lesser time, without clinically requiring an 
increased infusion time. 
x Assess the proportion of infusions completed over the assigned duration length or a 
lesser time, without clinically requiring an increased infusion time.  
x Laboratory tests and 12-lead electrocardiogram (ECG). 
x Vital signs and physical examinations. 
 
 
Study Design: 
This is a Phase 4, multicenter, open-label, infusion duration study of pegloticase administered 
over <120 minutes in combination with MTX to evaluate the safety, tolerability, and efficacy 
in treating adult subjects with uncontrolled gout.  Approximately 10 subjects in each cohort 
are planned to be enrolled initially. If deemed safe, an additional 100 subjects to be enrolled 
in the selected cohort in order to have approximately 110 subjects exposed.  Treatment 
duration with pegloticase will be approximately 24 weeks. 
The study design will include: 1) a Screening Period, lasting up to 35 days; 2) a 4-week MTX 
Run-in Period; 3) a 24-week Pegloticase + MTX Period which includes an End-of study 
Week 24/Early Termination Visit; 4) a safety Follow-up Phone/Email 30 days after the last 
pegloticase infusion and 5); a 3-month Post-Treatment Follow-up. 
All subjects who meet eligibility criteria at Screening will begin oral MTX at a dose of 15 mg 
weekly for 4 weeks prior to the first dose of pegloticase. 
Subjects will also take folic acid 1 mg orally every day beginning at Week -4 (the start of 
MTX) continuing until prior to the End of Pegloticase Infusion Visit (if applicable) or the 

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Week 24/End of Study/Early Termination Visit.  
Subjects must be able to tolerate MTX at a dose of 15 mg during the 4-week MTX Run-in 
Period (prior to Day 1) to be eligible to participate in the Pegloticase + MTX Period.  
Subjects who are unable to tolerate MTX at a dose of 15 mg during the MTX Run-in Period 
will be considered screen failures. 
Female subjects who take at least one dose of MTX 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 after the last dose of 
MTX.  If the subject has not ovulated, a urine pregnancy test will be performed.  For those 
subjects who take at least one dose of MTX and who are non-vasectomized males an inquiry 
will be conducted at the Post-Treatment 3-month Follow-up visit (or 3 months after the 
subject’s last dose of MTX) after MTX discontinuation regarding partner pregnancy. 
All subjects who complete the Run-In Period and meet the inclusion/exclusion criteria 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. 
Prior to the Treatment Period, subjects will begin taking at least one of the per protocol 
standard gout flare prophylaxis regimen (colchicine 0.6 mg/day and/or nonsteroidal anti-
inflammatory drug (NSAID) and/or low dose prednisone <10 mg/day) for ≥1 week before the 
first dose of pegloticase and continues flare prophylaxis throughout the pegloticase treatment 
period per American College of Rheumatology guidelines [Khanna D et al. 2012].   
For IR prophylaxis, fexofenadine (180 mg orally) will be taken the night 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) over an infusion duration 
between 10 and 30 minutes, will be administered immediately prior to each infusion.  
During the Pegloticase + MTX Period, all subjects will receive pegloticase 8 mg every 
2 weeks administered IV for a total of 12 infusions from Day 1 through Week 22, inclusive.  
Up to three pegloticase infusion durations will be assessed in the Pegloticase + MTX Period: 
60-minute infusion, 45-minute infusion and 30-minute infusion.  Initially, cohorts of 
approximately 10 subjects will be enrolled sequentially at progressively shorter infusion 
durations, beginning with the 60-minute infusion duration, progressing down to the 45-
minute infusion duration and then to the 30-minute infusion duration. If deemed safe, 
enrollment will continue in the chosen infusion duration cohort until approximately 110 
subjects are enrolled (e.g. targeted 110 subjects in the 30-minute infusion cohort, unless 30-
minute infusion is not tolerated, then approximately 110 subjects may be enrolled in the 45-
minute  or 60-minute infusion cohort).  The most desirable infusion duration is the shortest 
duration, which is shown to be safe and well tolerated.  
After the first 3 subjects at each infusion duration complete at least 4 weeks of the 
Pegloticase + MTX period (3 infusion visits), a holistic safety assessment will be performed 
by the internal Safety Review Committee on available subjects’ data.  Study enrollment will 
not be paused.  If a subject discontinues treatment or study prior to the third infusion visit, 
their available data is still included in the safety assessment.  If the safety assessment 

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indicates that the infusion duration is well tolerated (based on pre-determined infusion speed-
limiting criteria as described in Section 9.2), then additional safety assessments will continue 
to be performed based on available subjects’ data after 6 subjects and 10 subjects complete at 
least 4 weeks of the Pegloticase + MTX period (3 infusion visits).   
If the Safety Review Committee confirms that the percentage of subjects meeting infusion 
speed-limiting criteria are less than the thresholds specified in Section 9.2, then enrollment of 
subjects at the next progressively shorter infusion duration cohort (15 minutes shorter 
duration) will begin. Further, if the Safety Review Committee confirms that the percentage of 
subjects meeting infusion speed-limiting criteria are less than the thresholds specified in 
Section 9.2 then additional subjects will be enrolled (for a total of approximately 110 subjects 
in the given cohort). 
If any of the safety assessments indicate that a specific infusion duration is not tolerated 
based on pre-determined criteria, then the study may enroll additional subjects at a previous 
infusion duration. In the event that the initial 60-minute infusion duration is not tolerated 
based on pre-determined criteria, then the study may be revised or terminated (after internal 
review and assessments). 
If > 10 subjects are enrolled at any infusion duration, additional safety assessments will be 
performed when 15 subjects and 20 subjects complete at least 4 weeks of the Pegloticase + 
MTX period (3 infusion visits).  Once all subjects complete at least 4 weeks of the 
Pegloticase + MTX period (3 infusion visits), additional safety assessments will be done as 
needed (refer to the Safety Review Committee charter).  If a subject discontinues treatment or 
study prior to either of these time-points, their available data is still included in the safety 
assessment. 
The Safety Review Committee can modify the number of subjects at the chosen infusion 
duration, if they determine that more safety data is needed. 
Investigators will be permitted to adjust the duration of the infusion at a particular infusion 
visit regardless of initial treatment duration assignment, if needed.  The decision to modify 
the infusion duration at a visit will be allowed based on the investigator’s discretion.  
Subjects may return to the original infusion duration for subsequent infusions. 
Pegloticase will be administered after all pre-dose study visit assessments have been 
completed at each visit.  The date and time of infusion start and stop will be recorded.  
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.  
The total blood volume to be collected from each subject during this study is approximately 
450 mL. 

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An External Adjudication Committee will be established for this study to adjudicate the 
AESIs.  The External Adjudication Committee will be comprised of external experts with 
experience in immunology, allergic reactions, rheumatology and/or cardiovascular diseases. 
Details outlining the responsibilities of the Adjudication Committee will be included in the 
Adjudication Committee charter. AESIs defined in the protocol (See Section 9.6.1.2.1.5) 
include IRs, anaphylaxis and cardiovascular events.  The AESI of gout flare will not be 
adjudicated. 
Aggregate safety data will be reviewed by the internal Safety Review Team (SRT) and Safety 
Review Committee (SRC). Subject safety and tolerability of the pegloticase regimen will be 
discussed to establish a recommendation as to whether to continue the current treatment 
regimen or to modify the assigned treatment regimen.   
The SRC will be comprised of members of the Horizon Clinical Development and Patient 
Safety and Pharmacovigilance Teams.  Meetings will occur at pre-determined timepoints or 
ad-hoc dependent on any potential safety signals reported (e.g. anaphylaxis or any SAE 
related to pegloticase infusion). If any anaphylaxis event or SAE related to pegloticase 
infusion occurs with any subject, real-time with expedited review of patient profiles and/or 
relevant data available in the electronic data capture will occur.  

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Study Design (continued):   
 
 
IV = intravenous; MTX = methotrexate; PO = oral; Q2W = every 2 weeks; W = week 
Note: Study visits must be completed within ±3 days of the target visit date. 
1. 
Prior to the Treatment Period, subjects will begin taking at least one of the per protocol standard gout flare 
prophylaxis regimen (colchicine 0.6 mg/day and/or NSAID and/or low dose prednisone <10 mg/day) for ≥1 week 
before the first dose of pegloticase and continuing flare prophylaxis throughout the pegloticase treatment period per 
American College of Rheumatology guidelines. 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) over an infusion duration between 10 and 30 
minutes, will be administered immediately prior to each infusion. 
2. Stopping rules will be implemented: Subjects with 2 sUA levels > 6 mg/dL at 2 consecutive study visits beginning 
with the Week 2 Visit will discontinue from pegloticase therapy and complete the End of Pegloticase Infusions Visit 
and remain on study. 
3. The determination on whether to enroll the next cohort of subjects to a different infusion duration level will be based 
on whether the previous cohort meets the Infusion Speed-Limiting Criteria as well as the Safety Review Committee 
decision.  
4. 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 SAEs have occurred. If the subject discontinues treatment but continues in the study, then this follow-
up visit may be replaced by a scheduled study visit. 
 
Subject Population: 
Subjects diagnosed with gout eligible for this study will have sUA ≥6 mg/dL and inability to 
maintain sUA <6 mg/dL on other urate lowering therapy, or intolerable side effects 
associated with current urate-lowering therapy, or with a contraindication to xanthine oxidase 
inhibitor therapy. 

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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: 
x Hyperuricemia during the screening period defined as sUA ≥6 mg/dL and; 
x Failure to maintain normalization of sUA with xanthine oxidase inhibitors at 
the maximum medically appropriate dose, or with intolerable side effects or a 
contraindication to xanthine oxidase inhibitor therapy based on medical record 
review or subject interview and; 
x Symptoms of gout including at least 1 of the following: 
 Presence of at least one tophus 
 Recurrent flares defined as 2 or more flares in the past 12 months prior 
to screening 
 Presence of chronic gouty arthritis 
5. Willing to discontinue all oral urate-lowering therapy at least 7 days prior to MTX 
dosing at Week -4 and remain off of urate lowering therapy when receiving 
pegloticase infusions during the study.  
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;  
x 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 -4 (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 (whichever is the longest 
duration after the last does of pegloticase).  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 

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with the initiation of MTX at Week -4 and continuing through 3-Month Post-
Treatment Follow-up. 
8. Able to tolerate MTX 15 mg for 4 weeks during the MTX Run-in Period prior to the 
first dose of pegloticase. 
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 Week -4 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 (defined as 3 months or longer) would also 
meet exclusion criteria. 
5. Known history of any solid organ transplant surgery requiring maintenance 
Immunosuppressive therapy unless treated and no chronic or active infection 
confirmed by HBV serology. 
6. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA 
positivity, unless treated and viral load is negative and no chronic or active infection 
confirmed by HBV serology. 
7. Known history of hepatitis C virus RNA positivity unless treated and viral load is 
negative. 
8. Known history of Human Immunodeficiency Virus (HIV) positivity.  
9. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at Screening Visit).  
10. Severe chronic renal impairment (estimated glomerular filtration rate 
<40 mL/min/1.73 m2) at the Screening Visit based on 4 variable-Modification of Diet 
in Renal Disease [MDRD] formula or currently on dialysis. 
11. Non-compensated congestive heart failure or hospitalization for congestive heart 
failure or treatment for acute coronary syndrome (myocardial infarction or unstable 
angina) within 3 months of the Screening Visit, or current uncontrolled arrhythmia, or 
current uncontrolled blood pressure (BP) (>160/100 mmHg) prior to 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 (KRYSTEXXA), another recombinant uricase 
(rasburicase), or concomitant therapy with a polyethylene glycol-conjugated drug. 

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14. Known allergy to pegylated products or history of anaphylactic reaction to a 
recombinant protein or porcine product. 
15. Contraindication to methotrexate (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 -4, 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. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at Screening 
that is not subsequently controlled by the end of the Screening. 
24. Diagnosis of osteomyelitis. 
25. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such 
as Lesch-Nyhan and Kelley-Seegmiller syndrome. 
26. 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. 
27. Alcohol use in excess of 3 alcoholic beverages per week. 
28. A known intolerance to all protocol standard gout flare prophylaxis regimen (i.e. 
colchicine and/or non-steroidal anti‑inflammatory drugs and/or low‑dose prednisone 
≤10 mg/day).  
29. Currently receiving urate-lowering therapies and unable to discontinue treatment at 
least 7 days prior to MTX dosing at Week -4 and remain off of urate lowering therapy 
when receiving pegloticase infusions during the study. 
30. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis.  If deemed 
necessary by the Investigator, a chest X-ray may be performed during Screening. 

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Dose Regimen/Route of Administration: 
MTX: 
During the MTX Run-in Period, which begins 4 weeks prior to the first dose of pegloticase, 
subjects will take oral MTX at a dose of 15 mg weekly. 
Subjects will be instructed to take MTX weekly on the same day each week [(if dosing more 
frequently than once in a day (i.e. BID, TID)], the total weekly MTX dose should be taken 
within 24 hours, preferably the same calendar day) and record the date and time of each dose 
in the dosing calendar.  
During the MTX 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.  Investigators may choose to have subjects take the weekly dose divided over the day 
(i.e. BID, TID).  
During the Pegloticase + MTX Period, MTX should be taken 1 to 3 days prior to the 
pegloticase infusion and one additional weekly dose after the last infusion (at Week 22) for 
subjects who have not stopped pegloticase due to study sUA Discontinuation Criteria.  If a 
subject is not able to take the MTX 1 to 3 days prior to the pegloticase infusion, MTX must 
be taken ≥60 minutes prior to the pegloticase infusion. 
During the Pegloticase + MTX Period, if a subject becomes unable to tolerate the MTX the 
dosage may be decreased. 
Subjects will also take folic acid 1 mg orally every day beginning at Week -4 (the start of 
MTX) until prior to the Week 24 Visit.  
Pegloticase: 
All subjects who meet the inclusion/exclusion criteria and tolerate oral MTX 15 mg weekly 
during the MTX Run-in Period will receive pegloticase at a dose of 8 mg administered IV 
every 2 weeks for a total of 12 infusions from Day 1 through Week 22 inclusive (Pegloticase 
+ MTX 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 continuing throughout the 
pegloticase treatment per American College of Rheumatology guidelines [Khanna D et al. 
2012].   
Standardized IR prophylaxis consisting of pre-treatment with an antihistamine, 
acetaminophen and a corticosteroid will accompany each infusion.  
Dosage Form and Strength Formulation (Pegloticase and MTX): 
Pegloticase will be supplied as KRYSTEXXA which is commercially available in the United 
States and will be packaged in sterile, single-use 2-mL glass vials with  coated (latex-free) 

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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 50 mL of 0.45% or 0.9% Sodium 
Chloride Injection, United States Pharmacopeia (USP) for IV infusion by gravity feed or 
infusion pump.   
An alternative presentation of pegloticase is filled into sterile, single-use 50-mL glass vials 
with a Fluorotec-coated rubber injection stopper which delivers 8 mg uricase in a 50 mL 
ready-to-use solution.  
Pegloticase will not be administered as an IV push or bolus. 
MTX 2.5 mg tablets for oral administration will be provided to all subjects as a commercially 
available generic. 
Duration of Treatment and Follow-up: 
Screening: Up to 35 days prior to the Pegloticase + MTX Period. 
MTX Run-in Period (Week – 4 to Day 1):  4 weeks of MTX dosing prior to initial 
pegloticase dose.  
Pegloticase + MTX Period (Day 1 through Week 24): 24 weeks (infusion visits every 
2 weeks) plus the End-of study/Early Termination Visit (Week 24) 
Week 24/End-of-study/Early Termination Visit: Week 24 or earlier if the subject 
withdraws consent to participate in the study. 
End of Pegloticase Infusions Visit (if applicable): If the subject discontinues pegloticase 
treatment prior to infusion Week 22, such as due to the sUA Discontinuation Criteria, the 
subject will complete this visit within approximately 2 weeks of the last infusion.  Subjects 
will continue in study for Follow-Up visits, including the 30-day Follow-Up Email/Phone 
call, Week 24/End of Study/Early Termination and 3 Month Post-Treatment Follow-up 
Visits. 
Safety Follow-up Visit: All subjects will receive a safety Follow-up phone call/e-mail/visit 
approximately 30 days after the last dose of pegloticase to assess if any AE/SAE’s have 
occurred and to confirm if any previous AE/SAEs have resolved.  Subjects who receive at 
least one dose of 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 to verify at 
least one ovulatory cycle has occurred after the last dose of 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/site visit inquiry will be 
conducted 3 months after MTX discontinuation regarding partner pregnancy (inquiry can 
occur during the 3-month Post-Treatment Follow-up).  If the subject discontinues treatment 
but continues in the study, then this Follow-up visit may be replaced by a scheduled study 
visit. 
3-Month Post-Treatment Follow-up Visit:  All subjects will be followed for a minimum 
of 3 months following the last infusion, with follow-up after Week 24 as warranted.  
Restricted Medications 

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Subjects will be directed to discontinue current urate-lowering therapy prior to screening.  
Other medications used at the time of study initiation may be continued at the discretion of 
the Investigator.  
The following medications are prohibited during the study: 
x Concomitant therapy with allopurinol, febuxostat or other urate lowering medications 
or a polyethylene glycol-conjugated drug 
x Systemic or radiologic treatment for ongoing cancer, excluding non-melanoma skin 
cancer 
x Current or chronic treatment with systemic Immunosuppressive agents 
Removal of Subjects from Treatment or Assessment 
Every effort should be made to retain a subject in the study to monitor their safety.  However, 
subjects may withdraw consent or discontinue treatment or participation from the study at any 
time, without prejudice to further treatment.  In addition, the Investigator may terminate a 
subject’s treatment at any time.  The primary reason for discontinuation from the study and/or 
study drug should be recorded on the eCRF.  
Criteria for Evaluation: 
Safety and tolerability assessments will include monitoring and recording of all AEs, whether 
or not drug-related, measurement of vital signs, physical examinations, 12-lead ECG and 
monitoring of hematology and blood chemistry. 
Efficacy will be assessed by sUA levels. 
The incidence of anti-uricase and anti-polyethylene glycol antibodies will be assessed at 
specified time points. 
Infusion Speed-Limiting Criteria: 
Infusion speed-limiting criteria will be met if a subject experiences any severe (Grade ≥3) IRs 
or any other severe AEs within 24 hours of receiving pegloticase infusion and attributed to 
the infusion and not any other underlying disease process.  The signs and symptoms of the 
severe IRs are usually prolonged (e.g., not rapidly responsive to symptomatic medication 
and/or brief interruption of infusion) or recurrent following initial improvement.  Possible 
associated signs and symptoms of IRs may include but not limited to:  
x Respiratory: difficulty breathing with wheezing or stridor; upper airway 
swelling (lip, tongue, throat, uvula, or larynx); respiratory distress manifested 
as at least 2 or more of the following: tachypnoea, increased use of accessory 
respiratory muscles, cyanosis, recession, grunting  
x Cardiovascular: hypertension, tachycardia, measured hypotension, a decreased 
level of consciousness, loss of consciousness 
x Dermatological or mucosal: generalized urticaria (hives) or generalized 
erythema, angioedema, generalized pruritus with skin rash  
If ≤ one-eighth of subjects meet infusion speed-limiting criteria at the same infusion duration 
after 3 subjects and after 6 subjects, then enrollment may continue at the same infusion 

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duration.  If ≤ one-eighth of subjects meet infusion speed-limiting criteria at the same 
infusion duration after 10 subjects, then enrollment may continue at the next progressively 
shorter infusion duration.   
If > one-eighth of subjects meet infusion speed-limiting criteria, then enrollment at that 
infusion duration may be suspended.  The Safety Review Committee must confirm that 
infusion speed-limiting criteria were met, prior to additional patients being enrolled.. In the 
event that > one-eighth of subjects meet infusion-speed limiting criteria at the initial 60-
minute infusion duration, then the study may be revised or terminated (after internal review 
and assessment). 
 
If an anaphylaxis event occurs in any subject, further dosing with pegloticase for that subject 
will be terminated. 
If any anaphylaxis event or SAE related to pegloticase infusion occurs with any subject, all 
pertinent data will be provided for expedited review  to the Adjudication  Committee (for the 
purpose of adjudicating AESIs) and the SRT/SRC.  If any anaphylaxis event or SAE related 
to pegloticase infusion occurs with any subject, real-time with expedited review of patient 
profiles and/or relevant data available in the electronic data capture will occur.  
Individual Subject sUA Discontinuation Criteria: 
Subjects with a pre-infusion sUA level >6 mg/dL at 2 consecutive study visits beginning with 
the Week 2 Visit will discontinue treatment, but continue on study as described in Section 
9.4.3. 
Note:  The sUA Discontinuation Criteria only pertain to individual subjects and are not sUA 
Discontinuation Criteria for a group or specific infusion duration. 
Statistical Analyses: 
Primary Endpoint 
The primary endpoint is the incidence of subjects experiencing IRs (including anaphylaxis) 
related to pegloticase from Day 1 to Week 24 in the cohort chosen to be the most desirable 
duration for infusion. 
Secondary Endpoints 
The secondary endpoints will be assessed for the cohort chosen to be the most desirable 
duration for infusion and include: 
x The proportion of Month 6 (Weeks 20, 22 and 24) responders, defined as subjects 
achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 
6. 
x The proportion of subjects who experienced any of the following events: IR leading to 
discontinuation of treatment, anaphylaxis, or meeting Individual Subject sUA 
Discontinuation Criteria. 
x Time to any of the following events: IR leading to discontinuation of treatment, 
anaphylaxis, or meeting Individual Subject sUA Discontinuation Criteria (two 
consecutive pre-infusion sUAs > 6 mg/dL).   

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Exploratory Endpoints 
Pharmacokinetic and Anti-drug Antibody Endpoints 
x PK of pegloticase. 
x Incidence and titer of anti-PEG and anti-Uricase IgG antibodies. 
Safety Endpoints 
x Incidence of IRs, anaphylaxis, gout flares, cardiovascular events and the AE/SAE 
profile overall and potentially attributed to the combination of pegloticase and MTX. 
x The proportion of subjects who experienced IR leading to slowing down of the 
infusion rate or discontinuation of treatment. 
x The time to first IR leading to slowing down of the infusion rate or discontinuation of 
treatment. 
x Time to first IR. 
x The proportion of subjects who were able to complete all infusions over the assigned 
treatment duration length or a lesser time, without clinically requiring an increased 
infusion time 
x The proportion of infusions completed over the assigned duration length or a lesser 
time, without clinically requiring an increased infusion time.  
x Laboratory tests 
x Vital signs & physical examinations 

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Statistical Analysis on Primary and Secondary Endpoints 
The primary analysis will be performed using the modified intention-to-treat (mITT) 
population, defined as all enrolled subjects who received ≥1 dose of pegloticase. The primary 
endpoint is the incidence of subjects experiencing an IR (including anaphylaxis) related to 
pegloticase from Day 1 to Week 24 in the cohort chosen to be the most desirable duration for 
infusion (e.g. this may be the 30-minute infusion cohort if infusion-speed limiting criteria not 
met).  This endpoint will be analyzed with a summary of the incidence and the corresponding 
two-sided 95% confidence interval. Additionally, this endpoint will be analyzed for each of 
the other infusion duration cohorts. 
The proportion of responders during Month 6 will be summarized, along with a two-sided 
95% exact (Clopper-Pearson) confidence interval for the proportion. A responder is defined 
as a subject for whom the proportion of time that the sUA-time curve is <6 mg/dL during 
Month 6 (Weeks 20, 22 and 24) 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.  
The proportion of subjects experiencing any of the following events: IR leading to 
discontinuation of treatment, anaphylaxis, or meeting Individual Subject sUA 
Discontinuation Criteria will be presented.  This composite endpoint, each individual 
component of the composite and the proportion of subjects who experienced an IR leading to 
the slowing down of the infusion rate or discontinuation of treatment will be analyzed for 
each infusion duration regimen with a summary of the incidence and the corresponding two-
sided 95% confidence interval.  
Time to subjects meeting any of the composite endpoint criteria will be assessed by assigned 
treatment regimen.  Kaplan-Meier (KM) estimates of the time to event will be presented, 
along with the corresponding quartiles and two-sided 95% CI for the median time if there are 
sufficient number of events to perform the analysis.  The individual components of the 
composite endpoint, the time to first IR leading to slowing down of the infusion rate, time to 
first IR and time to first instance of IR leading to slowing down of the infusion rate or 
discontinuation of treatment will be summarized in the same way as the composite. 
 

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Sample Size Estimate: 
Initially, cohorts of approximately 10 subjects will be enrolled sequentially at progressively 
shorter infusion durations, beginning with the 60-minute infusion duration, progressing down 
to the 45-minute infusion duration and then to the 30-minute infusion duration. 
Approximately 110 subjects are planned to be enrolled into the selected cohort. Therefore, the 
minimum number of subjects enrolling across the 3 different cohorts in the study is 
approximately 130.  
Based on the MIRROR-RCT study (NCT03994731), approximately 5.0% of subjects are 
expected to have an IR (including events of anaphylaxis) when taking pegloticase 
concurrently with MTX. The sample size of 110 for the selected cohort is chosen to ensure a 
high probability of ruling out an unacceptably high IR rate.  If the observed IR rate is 5%, 
there is a greater than 80% probability that the upper bound of the two-sided 95% exact 
confidence interval for the IR rate is less than 13%. 
 

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2.1 
Schedule of Assessments  
Study Procedure/ 
Assessment 
Screening 
 
 
 
MTX 
Tolerability 
Assessment 
Period/  
Run-in Period2 
Pegloticase + MTX Period4 
Day 1 through Week 24 
End of-
Pegloticase-
Infusions 
Visit3  
(if 
applicable) 
End-of-
study/ 
Early 
Term. 
Safety 
Follow-up 
Phone/ 
Email 25 
Post 
Treatment 
Follow- 
Up23 
Screening 
Visit1  
(35 d) 
Week 
- 4  
 (±3 d)  
Week  
- 2 
(±3 d) 
Week (±3 d) 
Within 2 
weeks 
following 
final 
infusion if 
prior to Wk 
22 
Wk 24 
(±3 d) 
30 days 
after last 
pegloticase 
infusion 
(±3 d) 
3 Months 
 
Day 
1 
2 
 
4 
 
6 
 
8 
 
10 
 
12 
 
14 
 
16 
 
18 
 
20 
 
22 
 
 
Pegloticase 
infusion  
 
 
 
Inf 
1 
Inf 
2 
Inf 
3 
Inf 
4 
Inf 
5 
Inf 
6 
Inf 
7 
Inf 
8 
Inf 
9 
Inf 
10 
Inf 
11 
Inf 
12 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria  
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Procedure/ 
Assessment 
Screening 
 
 
 
MTX 
Tolerability 
Assessment 
Period/  
Run-in Period2 
Pegloticase + MTX Period4 
Day 1 through Week 24 
End of-
Pegloticase-
Infusions 
Visit3  
(if 
applicable) 
End-of-
study/ 
Early 
Term. 
Safety 
Follow-up 
Phone/ 
Email 25 
Post 
Treatment 
Follow- 
Up23 
Screening 
Visit1  
(35 d) 
Week 
- 4  
 (±3 d)  
Week  
- 2 
(±3 d) 
Week (±3 d) 
Within 2 
weeks 
following 
final 
infusion if 
prior to Wk 
22 
Wk 24 
(±3 d) 
30 days 
after last 
pegloticase 
infusion 
(±3 d) 
3 Months 
 
Day 
1 
2 
 
4 
 
6 
 
8 
 
10 
 
12 
 
14 
 
16 
 
18 
 
20 
 
22 
 
 
Medication/substance use 
history6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination7 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Vital signs, height and weight8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram9  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE Assessment10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications6  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Principle Investigator 
Assessment of gout  
flares and intensity  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 

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Study Procedure/ 
Assessment 
Screening 
 
 
 
MTX 
Tolerability 
Assessment 
Period/  
Run-in Period2 
Pegloticase + MTX Period4 
Day 1 through Week 24 
End of-
Pegloticase-
Infusions 
Visit3  
(if 
applicable) 
End-of-
study/ 
Early 
Term. 
Safety 
Follow-up 
Phone/ 
Email 25 
Post 
Treatment 
Follow- 
Up23 
Screening 
Visit1  
(35 d) 
Week 
- 4  
 (±3 d)  
Week  
- 2 
(±3 d) 
Week (±3 d) 
Within 2 
weeks 
following 
final 
infusion if 
prior to Wk 
22 
Wk 24 
(±3 d) 
30 days 
after last 
pegloticase 
infusion 
(±3 d) 
3 Months 
 
Day 
1 
2 
 
4 
 
6 
 
8 
 
10 
 
12 
 
14 
 
16 
 
18 
 
20 
 
22 
 
 
MTX dosing calendar 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
MTX dispensed11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
MTX dosing12 
 
Once weekly from Week -4 to Week 23, one week after the Week 22 Visit, inclusive 
 
 
 
 
Gout prophylaxis Rxs filled13 
 
 
Rxs filled as needed, start taking at least one protocol standard gout flare prophylaxis regimen 
≥1 week before first dose of pegloticase. 
 
 
 
 
Fexofenadine Rx filled14 
 
 
 
Rxs filled as needed, first dose of fexofenadine must be taken the day before D1; 
and in the morning or just prior to each infusion. 
 
 
 
 
Folic Acid Rx filled15 
 
Rxs filled as needed, 1 mg orally every day beginning at Week -4. 
 
 
 
 

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Study Procedure/ 
Assessment 
Screening 
 
 
 
MTX 
Tolerability 
Assessment 
Period/  
Run-in Period2 
Pegloticase + MTX Period4 
Day 1 through Week 24 
End of-
Pegloticase-
Infusions 
Visit3  
(if 
applicable) 
End-of-
study/ 
Early 
Term. 
Safety 
Follow-up 
Phone/ 
Email 25 
Post 
Treatment 
Follow- 
Up23 
Screening 
Visit1  
(35 d) 
Week 
- 4  
 (±3 d)  
Week  
- 2 
(±3 d) 
Week (±3 d) 
Within 2 
weeks 
following 
final 
infusion if 
prior to Wk 
22 
Wk 24 
(±3 d) 
30 days 
after last 
pegloticase 
infusion 
(±3 d) 
3 Months 
 
Day 
1 
2 
 
4 
 
6 
 
8 
 
10 
 
12 
 
14 
 
16 
 
18 
 
20 
 
22 
 
 
IR prophylaxis16 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
IR Rx prophylaxis compliance 
check (Yes/No) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Gout flare prophylaxis 
compliance check (Yes/No) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pre-infusion 
MTX Polyglutamate sampling 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
Pegloticase PK  
sampling17 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
sUA18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology 1 
X1 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 

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Study Procedure/ 
Assessment 
Screening 
 
 
 
MTX 
Tolerability 
Assessment 
Period/  
Run-in Period2 
Pegloticase + MTX Period4 
Day 1 through Week 24 
End of-
Pegloticase-
Infusions 
Visit3  
(if 
applicable) 
End-of-
study/ 
Early 
Term. 
Safety 
Follow-up 
Phone/ 
Email 25 
Post 
Treatment 
Follow- 
Up23 
Screening 
Visit1  
(35 d) 
Week 
- 4  
 (±3 d)  
Week  
- 2 
(±3 d) 
Week (±3 d) 
Within 2 
weeks 
following 
final 
infusion if 
prior to Wk 
22 
Wk 24 
(±3 d) 
30 days 
after last 
pegloticase 
infusion 
(±3 d) 
3 Months 
 
Day 
1 
2 
 
4 
 
6 
 
8 
 
10 
 
12 
 
14 
 
16 
 
18 
 
20 
 
22 
 
 
Chemistry  
X 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 
Urine Albumin: Creatinine 
Ratio22 
X 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
Antibody testing19 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
C-Reactive Protein 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
G6PD  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy test21 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Partner pregnancy24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Abbreviations:  AE = adverse event; d = day(s); G6PD = glucose-6-phosphate dehydrogenase; IR = infusion reaction; PK = pharmacokinetic; Rx = prescription; SAE = serious 
adverse event; sUA = serum uric acid; UACR= Urinary Albumin Creatinine Ratio; V =  Visit; wk(s) = week(s) 
Footnotes:  
1. 
The Screening Visit can occur up to 35 days prior to Week -4 visit HbA1c testing is required as part of the Hematology panel during Screening period (refer to 
Guidance on Blood Glucose Monitoring in Section 9.1). 
2. 
During the MTX Tolerability Assessment Period (starting at Week -4 to Day 1), all subjects will take MTX 15 mg orally weekly.  The subject must tolerate MTX 
15 mg dose during MTX Run in Period to enroll into the Pegloticase + MTX Period.  If a subject does not tolerate the MTX 15 mg dose during the Pegloticase + 
MTX Period, MTX may be dose-reduced after discussion with the Sponsor medical monitor.  The subject should remain in the study.   
3. 
Subjects who end treatment due to the sUA Discontinuation Criteria or other reasons should complete the End of Pegloticase Infusions Visit within 2 weeks of the 
last infusion.  Subjects will also complete all regularly scheduled Follow-Up visits including the 30-day Follow-up email/phone call, Week 24/End of Study/Early 
Termination and 3 Month Post-Treatment Follow-up Visits. 
4. 
Subjects will be enrolled at the Day 1 Visit to receive pegloticase 8 mg administered IV every 2 weeks from Day 1 through Week 22, inclusive.  During this 24-
week treatment phase, subjects who meet the Individual Subject sUA Discontinuation Criteria or discontinue treatment for any other reason will enter the off-
treatment observation period.  During the off-treatment observation period, subjects will return for scheduled visits according to section 9.4.3.  
5. 
The Investigator or designee will collect a complete gout history and other relevant medical/surgical history.  
6. 
Medication history (i.e., prior medications) will include gout medications, starting at the time of diagnosis and up to (but not including) the Day 1 Visit; substance 
use history; and all other medications up to (but not including) the Day 1 Visit.  Prior concomitant medications (not including gout medications) will be collected 
for 1 year prior to screening (as well as history of COVID-19 vaccinations).   
7. 
A complete physical examination will be performed at the Screening Visit, including assessment of HEENT, heart, lungs, abdomen, skin, extremities and 
neurological status and musculoskeletal including an assessment for the presence of tophi, as well as gout history and symptom severity.  Physical examination 
findings at screening should be recorded on the medical and surgical history eCRF.  A targeted physical examination (for assessment of AEs) will be conducted 
based on potential risk for or occurrence of AEs at Week -4, Week -2, Day 1 and prior to administration of infusion at Weeks 4, 8, 12, 16, 20, End of Pegloticase 
Infusions Visit (if applicable), 24/End of Study/Early Termination Visits and 3-Month Follow-Up.  Clinically significant findings from the targeted physical 
examinations will be recorded as AEs.   
8. 
Routine vital signs, including BP, respiratory rate, temperature and heart rate will be measured at Screening, Week -4, Week -2 and at all infusion visits during the 
Pegloticase + MTX Period and the End of Pegloticase Infusions Visit (if applicable), Week 24/End of Study/Early Termination and 3-month Post-Treatment 
Follow-up Visit.  Heart rate and BP 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 

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diastolic BP.  During the Pegloticase + MTX 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.  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 -4 Visit; prior to pegloticase infusion on 
Day 1 and at the Weeks 8, 16 and at the non-infusion End of Pegloticase Infusions Visit (if applicable), Week 24/End of Study/Early Termination and Month 3 
Post-Treatment Follow-up Visits.  Height will be collected at the Screening Visit only. 
9. 
Electrocardiogram should be completed at Screening Visit, during the study per investigator discretion and during any potential or suspected IR. 
10. 
AEs/SAEs will be collected from the signature of the ICF through the 3-month Post-Treatment Follow-up visit.    
11. 
MTX tablets will be dispensed and brought back at each visit to check compliance.  MTX bottles are 36 count and bottles should be re-dispensed when 
appropriate.  New bottles should not be given at each visit.  If subjects require a MTX dose reduction, the Investigator will prescribe the subject the number of 
tablets to take weekly.  The updated number of tablets along with the date and time of each MTX dose should be recorded in the dosing calendar. 
12. 
15mg of MTX should be taken 1 to 3 days prior to pegloticase infusion; however, if a subject does not do so, MTX must be taken ≥60 minutes prior to pegloticase 
infusion. 
13. 
It is required that before a subject begins the pegloticase + MTX 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 
continuing throughout the pegloticase treatment period per American College of Rheumatology guidelines [Khanna D et al. 2012]. 
14. 
Fexofenadine (180 mg orally) will be taken the day before and the morning or just prior to each infusion.  Prescriptions are to be filled at a local pharmacy, as 
needed. 
15. 
Subjects will take folic acid 1 mg orally every day beginning at Week -4 (the start of MTX) until prior to the End of Pegloticase Infusions Visit (if applicable) or 
the Week 24/End of Study/Early Termination.  Prescriptions are to be filled at a local pharmacy, as needed. 
16. 
IR prophylaxis: 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) will be administered over an infusion duration between 10 – 30 minutes, 
immediately prior to each pegloticase infusion.   
17. 
For all subjects, serum samples for pegloticase PK analysis will be collected approximately 15 minutes to 2 hours after the end of infusion on Day 1; prior to 
infusion and approximately 15 minutes to 2 hours after the end of infusion at the Weeks 2, 6, 12, 20.  An additional PK sample will be collected at Week 24 End 
of Study/Early Termination Visits.   
18. 
Serum samples for measurement of sUA levels will be collected at the Screening Visit, the Week -4 Visit and the Week -2 Visit during the Run-in Period; within 
48 hours prior to each pegloticase infusion and after the end of each pegloticase infusion prior to discharge from the site during the Pegloticase + MTX Period on 
Day 1, at the Weeks 2, 6, 10, 12, 14, 20 and 22; within 48 hours prior to each pegloticase infusion at Weeks 4, 8, 16, 18.  Additional serum samples for sUA levels 
will be collected at non-infusion Visits at the End of Pegloticase Infusions Visit (if applicable) and the Week 24/End of study/Early Termination Visit and 3-

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month Follow-up Visit.  A subject with 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 and remain on study.If a subject’s previous visit pre-infusion sUA was <6 m/dL – sUA result is not required 
for the following infusion visit (local pre-infusion sUA may be drawn at the same time as central pre-infusion sample). If a subject’s previous visit pre-infusion 
sUA was >6 mg/dL – local sUA is required to be resulted (within 48 hours) to confirm stopping criteria was not met. See Section 9.6.2.1 and the Laboratory 
Manual for instructions for alternate scenarios.  In the event of an AE suspected to be an IR, a serum sample will be collected at that time or at the subsequent visit 
for evaluation of pegloticase antibodies.   
19. 
Serum samples for evaluation of anti-PEG antibodies and anti-uricase IgG antibodies will be collected prior to the infusion on Day 1 and at the Weeks 2, 6, 12, 20.  
An additional sample will be collected at each of the End of Study/Early Termination Visit and the 3-month Study Follow-up Visit.  In the event of an AE 
suspected to be an IR, a serum sample will be collected in a SST tube at that time or at the subsequent visit for evaluation of anti-drug antibodies.  
20. 
For women of childbearing potential, a serum pregnancy test will be performed at the Screening Visit; at the End-of-Study/Early Termination Visit.  
21. 
For women of childbearing potential, a urine pregnancy test will be performed at all indicated visits and results must be confirmed by site personnel prior to any 
infusion starting.  If the subject has not ovulated by the 30-day Follow-up email/phone call, the subject will be requested to return to the site for a urine pregnancy 
test. 
22. 
Urine Albumin: Creatinine Ratio is derived data by the lab using results from urine. 
23. 
The intent is to obtain at least 3 months of follow-up on each subject after cessation of pegloticase infusions.  If the subject ends treatment early but remains in the 
study and the 3-month Post-Treatment Follow-up Visit occurs prior to Week 24, the 3-month Post-Treatment Follow-up Visit will be adjusted accordingly based 
on the timing of the last treatment.  All subjects will be followed for a minimum of 3 months following Week 24/End-of-Study/Early Termination Visit. 
24. 
Subjects who are non-vasectomized males will be asked 3 months after MTX discontinuation regarding partner pregnancy.  This will occur at a regularly 
scheduled visit or by a separate phone/email visit.   
25. 
Thirty (30) days after the last MTX dose, subjects will be contacted by telephone or email to review AEs and 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. 

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3
TABLE OF CONTENTS
1
TITLE PAGE.......................................................................................................................... 2
2
SYNOPSIS............................................................................................................................ 11
2.1
Schedule of Assessments ............................................................................................... 27
3
TABLE OF CONTENTS...................................................................................................... 35
4
LIST OF ABBREVIATIONS............................................................................................... 41
5
ETHICS................................................................................................................................. 43
5.1
Institutional Review Board/Independent Ethics Committee.......................................... 43
5.2
Ethical Conduct of the Study ......................................................................................... 43
5.3
Subject Information and Consent................................................................................... 43
5.4
Compensation for Health Damage of Subjects/Insurance.............................................. 44
5.5
Confidentiality................................................................................................................ 44
6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................ 44
7
INTRODUCTION ................................................................................................................ 45
7.1
Background .................................................................................................................... 45
7.1.1
Gout......................................................................................................................... 45
7.1.2
Pegloticase .............................................................................................................. 45
Physiochemical Properties .................................................................................. 46
Nonclinical Pharmacology.................................................................................. 47
Non-clinical Pharmacokinetics ........................................................................... 47
Toxicology .......................................................................................................... 48
7.1.2.4.1
Clinical Pharmacokinetics............................................................................48
7.1.3
Risks of Pegloticase................................................................................................ 49
Safety................................................................................................................... 50
7.1.4
Risks of Methotrexate............................................................................................. 50
7.2
Rationale for this Study.................................................................................................. 51
7.3
Rationale for Dose Selection.......................................................................................... 52
8
STUDY OBJECTIVES......................................................................................................... 52
9
INVESTIGATIONAL PLAN............................................................................................... 53
9.1
Overall Study Design and Plan ...................................................................................... 53
9.2
Infusion Speed-Limiting Criteria ................................................................................... 58

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9.3
sUA Discontinuation Criteria......................................................................................... 59
9.4
Selection of Study Population........................................................................................ 60
9.4.1
Inclusion Criteria .................................................................................................... 60
9.4.2
Exclusion Criteria ................................................................................................... 61
9.4.3
Removal of Subjects from Therapy or Study ......................................................... 63
Removal of Subjects from Pegloticase Therapy ................................................. 63
9.4.3.1.1
Study considerations for subjects ending pegloticase infusions prior to 24 
weeks
......................................................................................................................63
Removal of Subjects From Study........................................................................ 64
9.4.4
Replacement Policy ................................................................................................ 64
Subjects ............................................................................................................... 64
Centers................................................................................................................. 65
Screen Failures .................................................................................................... 65
9.5
Treatments...................................................................................................................... 65
9.5.1
Treatment Assignment............................................................................................ 65
9.5.2
Treatments Administered........................................................................................ 65
Folic Acid............................................................................................................ 66
Gout Flare Prophylaxis........................................................................................ 67
Infusion Reaction Prophylaxis ............................................................................ 67
9.5.3
Identity of Investigational Products........................................................................ 67
Pegloticase........................................................................................................... 67
Methotrexate........................................................................................................ 68
9.5.4
Labeling .................................................................................................................. 68
9.5.5
Storage .................................................................................................................... 68
9.5.6
Drug Accountability................................................................................................ 69
9.5.7
Study Drug Administration and Timing of Dose for each Subject......................... 69
Description of Clinical Supplies ......................................................................... 69
Determination of Dose Volume .......................................................................... 69
Details Concerning Timing and Dose Administration........................................ 70
9.5.7.3.1
Preparation and Administration ...................................................................70
9.5.7.3.1.1
Preparation.........................................................................................................70
9.5.7.3.1.2
Dose and Administration ...................................................................................70

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9.5.7.3.2
Dose Modifications, Interruptions and Delays.............................................71
9.5.7.3.2.1
Pegloticase Modifications..................................................................................71
9.5.7.3.2.2
MTX Dose Algorithm and Intolerance Criteria.................................................71
9.5.7.3.2.3
Gout Flare Treatment.........................................................................................73
9.5.7.3.2.4
Infusion Reaction Treatment..............................................................................74
9.5.8
Method of Assigning Subjects to Treatment Groups.............................................. 74
9.5.9
Prior and Concomitant Therapy.............................................................................. 75
9.5.10
Restricted Medications............................................................................................ 75
9.5.11
Treatment Compliance............................................................................................ 76
9.5.12
Contraception Requirements................................................................................... 76
9.6
Safety/Tolerability, Efficacy and Pharmacokinetic Variables ....................................... 76
9.6.1
Safety/Tolerability Variables.................................................................................. 76
Adjudication and Safety Review Committee...................................................... 77
Adverse Events.................................................................................................... 77
9.6.1.2.1
Definitions....................................................................................................77
9.6.1.2.1.1
Adverse Event Definition ..................................................................................77
9.6.1.2.1.2
Serious Adverse Event Definition .....................................................................78
9.6.1.2.1.3
Non-Serious Adverse Event Definition .............................................................79
9.6.1.2.1.4
Unexpected Adverse Event Definition ..............................................................79
9.6.1.2.1.5
Adverse Events of Special Interest ....................................................................79
9.6.1.2.2
Documentation of Adverse Events...............................................................81
9.6.1.2.3
Intensity of Adverse Events .........................................................................81
9.6.1.2.4
Relationship to Study Drug..........................................................................82
9.6.1.2.5
Reporting and Documenting SAEs and Product Complaints ......................82
9.6.1.2.5.1
Serious Adverse Events .....................................................................................82
9.6.1.2.5.2
Product Complaints............................................................................................83
9.6.1.2.6
Follow-up of Adverse Events.......................................................................84
9.6.1.2.7
Medication Error and Overdose...................................................................84
9.6.1.2.8
Review of Adverse Events and Emerging New Safety Information............84
9.6.1.2.9
Reporting of IND Safety Reports.................................................................84
9.6.1.2.10 Development Safety Update Reports...........................................................84

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Pregnancy Reporting........................................................................................... 84
Medical/Surgical History .................................................................................... 85
Vital Signs, Height and Weight........................................................................... 86
Physical Examinations ........................................................................................ 86
Electrocardiogram ............................................................................................... 87
Clinical Laboratory Safety Tests......................................................................... 87
Blood Samples for Potential Analysis of Biomarkers......................................... 87
Assessment of Gout Flare ................................................................................... 88
9.6.2
Efficacy Variables................................................................................................... 88
Serum Uric Acid.................................................................................................. 88
9.6.3
Pharmacokinetic Measurements ............................................................................. 89
9.6.4
Anti-drug Antibody Measurements ........................................................................ 89
9.6.5
MTX Polyglutamate Measurements ....................................................................... 90
9.7
Statistical Methods and Determination of Sample Size................................................. 90
9.7.1
Endpoints ................................................................................................................ 90
Primary Endpoint ................................................................................................ 90
Secondary Endpoints........................................................................................... 90
Exploratory Endpoints......................................................................................... 90
Pharmacokinetic and Anti-drug Antibody Endpoints......................................... 91
Safety Endpoints ................................................................................................. 91
9.7.2
Analysis Sets........................................................................................................... 92
9.7.3
Demographics and Baseline Characteristics........................................................... 92
9.7.4
Subject Disposition................................................................................................. 92
9.7.5
Endpoint Analysis................................................................................................... 92
Primary and Secondary Endpoint Analysis......................................................... 92
Exploratory Endpoint Analysis........................................................................... 93
9.7.6
MTX Polyglutamate and Anti-drug Antibody Analysis......................................... 93
9.7.7
Safety Analysis ....................................................................................................... 94
9.7.8
Interim Analyses ..................................................................................................... 95

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9.7.9 
Sample Size and Power Considerations .................................................................. 95 
9.8 
Changes in the Conduct of the Study ............................................................................. 96 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES ....................................... 96 
11 CASE REPORT FORMS ..................................................................................................... 97 
12 STUDY MONITORING ...................................................................................................... 97 
13 DATA MANAGEMENT ...................................................................................................... 98 
14 RETENTION OF RECORDS ............................................................................................... 98 
15 PUBLICATION .................................................................................................................... 99 
16 REFERENCES ..................................................................................................................... 99 
17 APPENDICES .................................................................................................................... 102 
17.1 Administrative Appendix ............................................................................................. 102 
17.4 Polyethylene Glycol-Conjugated Drug List Appendix ................................................ 104 
 
 

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LIST OF TABLES 
No table of figures entries found. 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Study Design ........................................................................................ 58 
 
 

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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
BID 
Twice a day 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CRP 
C-Reactive Protein 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
HTI DAC 
Horizon Therapeutics Ireland DAC  
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
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) 
LLN 
Lower limit of normal 
MACE 
Major Adverse Cardiovascular Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease 
mITT 
modified intention-to-treat 
MRI 
Magnetic Resonance Imaging 
MTX 
methotrexate 
NSAID 
nonsteroidal anti-inflammatory drug 
PK 
pharmacokinetic(s) 
RNA 
ribonucleic acid 

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Abbreviation 
Definition 
SAE 
serious adverse event 
sUA 
serum uric acid 
TEAE 
Treatment-emergent adverse event 
TID 
Three times a day 
ULT 
urate lowering treatment 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopeia 
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 

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revised ICF.  Any revised written ICF and written information must receive the IRB`s 
approval/favorable opinion in advance of use. 
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 ICF 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, or designee will be responsible for timely 
reporting of serious adverse events (SAEs) to regulatory authorities, as required.  The Sponsor 

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will be responsible for timely reporting of SAEs and any other new pertinent safety information 
to all Investigators, as required. 
The study will be conducted at approximately 40 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. 
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].  Up to 400,000 persons (up to 5% 
of the estimated 8 million persons with gout) in the United States experience chronic symptoms 
of gout, despite trials of urate-lowering therapy.  Gout, which is sometimes referred to as chronic 
refractory gout, 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 
Pegloticase (KRYSTEXXA), a recombinant modified mammalian urate oxidase [uricase]), is 
indicated for treatment-failure gout to control hyperuricemia and to manage the signs and 
symptoms of gout.  Pegloticase was granted orphan designation by the FDA on 21 February 
2001 (ODA #00-1356) and pegloticase 8 mg every 2 weeks was approved by the FDA on 14 
September 2010 for the treatment of adult patients with chronic gout refractory to conventional 
therapy. 
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 sUA, reduction in gout flares and continued resolution of tophi, 

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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 IRs. 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, IRs were seen in 22/85 (26%) of subjects 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 IRs 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]. 
Physiochemical Properties
Pegloticase is a uric acid-specific enzyme that is a monomethoxy-poly (ethylene glycol) 
(PEG)ylated product consisting of recombinant modified mammalian urate oxidase (uricase) 
produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated 
to methoxy PEG (mPEG) (10 kDa molecular weight). The cDNA coding for uricase is based on 
mammalian sequences. Each uricase subunit has a molecular weight of approximately 34 kDa. 
The average molecular weight of pegloticase (tetrameric enzyme conjugated to mPEG) is 
approximately 545 kDa.

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INN:
Pegloticase
Chemical name (INN):
Oxidase, urate (synthetic Sus scrofa variant pigKS-ΔN subunit), 
homotetramer, amide with α-carboxy-ω-methoxypoly(oxy-1,2-
ethanediyl)
National drug code 
(NDC):
75987-080-10
CAS number
885051-90-1
Molecular formula:
CxHyN1632OzS32
Wherein, x = ~22,920, y = ~43,095, z = ~10,191
Molecular weight:
Monomer pegloticase approximately 545 kDa 
(based on the estimation of amino acid sequence of uricase and 
an average of 10.2 strands of approximately 10 kDa 
monomethoxypoly(ethylene glycol) (mPEG) per uricase 
monomeric subunit. The monomethoxypoly(ethylene glycol) 
strands attached to the uricase protein comprise approximately 
three-quarters of the molecular weight of pegloticase.)
Chemical Structural 
Formula:
{[H3C-O-(CH2CH2-O)m-CO-]n-NH-
[TYKKNDEVEFVRTGYGKDMI KVLHIQRDGK  YHSIKEVATT  
VQLTLSSKKD
YLHGDNSDVI PTDTIKNTVN VLAKFKGIKS IETFAVTICE HFLSSFKHVI 
RAQVYVEEVP WKRFEKNGVK HVHAFIYTPT GTHFCEVEQI
RNGPPVIHSG IKDLKVLKTT QSGFEGFIKD QFTTLPEVKD
RCFATQVYCK WRYHQGRDVD FEATWDTVRS IVLQKFAGPY
DKGEYSPSVQ KTLYDIQVLT LGQVPEIEDM EISLPNIHYL  
NIDMSKMGLI  NKEEVLLPLD NPYGKITGTV KRKLSSRL]}4
Wherein, m=~225, n=~10.2 and each uricase monomeric subunit 
having the amino acid sequence listed above.
Approximately 10.2 units of methoxypoly(ethylene glycol) are 
attached to Lysine(K) residues per uricase monomeric subunit.
Appearance:
Clear colorless solution, free of visible particles.
Nonclinical Pharmacology
Unlike most mammalian species, humans lack the urate oxidase enzymatic pathway for the 
oxidation and disposition of uric acid and are susceptible to the development of gout. To 
develop an animal model of hyperuricemia and gout for a therapeutic uricase proof-of-concept 
study, a mouse was genetically modified by knocking out its endogenous uricase gene (Uox). 
This genetic lesion results in a marked elevation of plasma uric acid levels, leading to deposition 
of urate in kidney tissue and causing a profound defect in renal concentrating ability and 
nephrogenic diabetes insipidus. The studies in the mouse Uox-/- system demonstrate the 
therapeutic potential of pegloticase administration for the treatment of hyperuricemia and 
provided a “proof of principle” for the clinical use of pegloticase.
Non-clinical Pharmacokinetics
A series of pharmacokinetic (PK) studies was conducted in rats, rabbits, dogs and pigs to 
determine the circulation half-life and bioavailability as a function of the route of pegloticase 
administration. Plasma pegloticase levels were determined by assaying uricase bioactivity in 

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plasma. As part of the PK studies, antibody levels in plasma were determined 2 weeks after the 
last injection in the rabbit, dog and rat. Collectively, the results of the PK studies in these 
animals lend support to the expectation of high bioavailability and prolonged retention of 
pegloticase after administration in humans.
Absorption, distribution, metabolism and excretion of pegloticase were examined in rat studies. 
Approximately 70% of the dose was excreted in the urine during the course of 7 days after 
injection. 
Refer to the current version of the pegloticase (KRYSTEXXA) Investigator’s Brochure for 
detailed information.
Toxicology
An observation in the chronic toxicology studies is the finding of a dose-dependent increase in 
vacuolated cells. There were no associated clinical manifestations in any animals in which 
vacuolated cells were present. Evidence of vacuolated cells, especially in the spleen, has been 
observed with pegloticase administration in all the chronic toxicity studies as well as the 
embryo/fetal development and absorption, distribution, metabolism and excretion studies in the 
rat. It is thought that vacuolation of spleen macrophages is a result of lysosomal overloading 
following phagocytosis of persistent circulating macromolecules of high molecular weight. In 
the 39-week, long-term toxicity studies in dogs, vacuolated cells were also present in the basal 
area of the lamina propria within the duodenum and jejunum, adrenal cortical cells, hepatic 
Kupffer cells and the intimal cells within the aortic outflow area of the heart. The vacuolated 
cells in the heart and adrenal gland did not stain as macrophages. In the aortic outflow tract of 
the heart, vacuoles were seen in the cytoplasm of endothelial cells in the intimal lining of the 
aorta. In the adrenal gland, vacuoles were located within cortical cells in the zona reticularis and 
zona fasciculata. The clinical significance of these findings and functional consequences are 
unknown.
Refer to the current version of the pegloticase (KRYSTEXXA) Investigator’s Brochure for 
detailed information.
7.1.2.4.1 Clinical Pharmacokinetics
Pegloticase levels were determined in serum based on measurements of uricase enzyme activity. 
Following single IV infusions of 0.5 mg to 12 mg pegloticase in 23 patients with symptomatic 
gout, maximum serum concentrations of pegloticase increased in proportion to the dose 
administered. 
The PK of pegloticase has not been studied in children and adolescents. 
In patients undergoing hemodialysis (Study M0403), pegloticase serum concentrations were not 
clinically meaningfully affected by 2 hemodialysis sessions. Pre- and post-dialyzer samples, as 

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well as samples taken during dialysis, demonstrated that study drug was not removed by the 
dialysis process. 
No formal studies have been conducted to examine the effects of hepatic impairment on 
pegloticase PK.   
7.1.3 Risks of Pegloticase 
Pegloticase is efficacious in reducing sUA levels and improving clinical signs and symptoms of 
gout.  The risks of pegloticase use are detailed in the full prescribing information and include: 
x IRs, including anaphylaxis 
x Hemolysis and methemoglobinemia in patients with glucose-6-phosphate dehydrogenase 
(G6PD) deficiency 
x Gout flares 
x Congestive heart failure exacerbation 
Subjects with diseases or conditions (e.g., non-compensated congestive heart failure) that could 
potentially place them at increased risk for these events will be excluded from the study. 
It is required that all subjects receive prophylactic treatment to reduce the risk of acute gout 
flares, unless medically contraindicated or not tolerated, as noted in the pegloticase prescribing 
information. Subjects should begin a regimen of colchicine (0.6 mg/day) and/or NSAID and/or 
low-dose prednisone (≤10 mg/day) prophylaxis ≥1 week before the first dose of pegloticase and 
continuing flare prophylaxis throughout the pegloticase treatment period per American College 
of Rheumatology guidelines [Khanna D et al. 2012].  All subjects who experience a gout flare 
during the study will be prescribed anti-inflammatory treatment (e.g., NSAIDs, colchicine), as 
deemed clinically indicated by the study physician. 
Since IRs can occur, all subjects will receive pre-treatment prophylaxis consisting of an 
antihistamine, acetaminophen and a corticosteroid prior to each infusion of pegloticase.  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 the infusion duration 10-30 minutes 
(recommended) will be administered immediately prior to each infusion.  
The risk of anaphylaxis and IRs is higher in patients whose sUA level increases to >6 mg/dL.  
Therefore, beginning with Week 2, 2 pre-dose blood samples (within 48 hours prior to dosing 
pegloticase) will be obtained to verify the sUA level is ≤6 mg/dL prior to infusion of pegloticase 
(see Section 9.6.2.1).  A subject with sUA level >6 mg/dL at 2 consecutive study visits, 
beginning with the Week 2 Visit, will be classified as a non-responder and will be discontinued 
from pegloticase treatment, but continue on study as described in Section 9.4.3. 

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Refer to the current version of the FDA-approved KRYSTEXXA Full Prescribing Information
and pegloticase (KRYSTEXXA) Investigator’s Brochure for detailed information concerning the 
safety profile of pegloticase.
Safety
The principal safety risks associated with pegloticase include anaphylaxis, IRs and gout flares. 
Pegloticase has not been formally studied in patients with congestive heart failure, but some 
subjects in the clinical trials experienced exacerbation. Exercise caution when using pegloticase 
in patients who have congestive heart failure and monitor patients closely following infusion. 
The data support that monitoring of sUA and discontinuation of pegloticase therapy in patients 
who lose the ability to maintain uric acid <6 mg/dL can lead to the avoidance of the majority of 
IRs and unnecessary exposure to drug. The longer-term exposure evidenced by the open-label 
extension study supports the benefit-to-risk assessment of 8 mg of pegloticase IV every 2 weeks 
as an effective therapy in chronic gout patients, particularly those with tophi who are 
unresponsive to other therapies.
7.1.4
Risks of Methotrexate 
MTX is a folic acid reductase inhibitor used as a disease-modifying, anti-rheumatic drug for the 
treatment of autoimmune diseases. Methotrexate is a drug well-known to rheumatologists, has a 
well-established and understood safety profile and is known to prevent the formation of antidrug 
antibodies (Strand et al., 2017).
Adverse events (AEs) that may be experienced by subjects treated with MTX include:
x
Gastrointestinal: nausea, vomiting, diarrhea, stomatitis
x
Hematologic and oncologic: leukopenia, thrombocytopenia
x
Hepatic: hepatotoxicity, increased serum alkaline phosphatase, increased serum bilirubin, 
increased serum transaminases
x
Infection: increased susceptibility to infection
x
General: malaise, fatigue, dizziness, alopecia, photosensitivity
Additionally, MTX can cause fetal death or teratogenic effects.  Pregnancy should be avoided if 
either partner is receiving MTX, during and for a minimum of three months after MTX therapy 
for the non-vasectomized male.  For females of child bearing potential, pregnancy should be 
avoided for at least one ovulatory cycle after MTX therapy.  Refer to the current version of the 
FDA-approved MTX Full Prescribing Information for detailed information concerning the safety 
profile of MTX.
Baseline assessments should include a complete blood count with differential and platelet counts, 
hepatic enzymes, renal function tests and chest X-ray.

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7.2 
Rationale for this Study 
Pegloticase (KRYSTEXXA, a recombinant modified mammalian urate oxidase [uricase]), is 
approved by the United States FDA and the European Commission for use in patients with gout, 
at a dose of 8mg IV every two weeks.  Pegloticase is efficacious in reducing sUA levels and 
improving clinical signs and symptoms of gout.  Pegloticase provides medical benefits by 
lowering sUA and eliminating tophi in patients who currently have no therapeutic options.  The 
pooled response rate for pegloticase 8 mg at 6 months is 42%, based on at least 80% of the sUA 
values being less than 6 mg/dL at both the 3 month and 6 month time points, with placebo 
response rates of 0%, a difference that was clinically important and statically significant.     
Currently, pegloticase is FDA approved for intravenous administration over no less than 
120 minutes [KRYSTEXXA Full Prescribing Information].  Pegloticase needs to be re-
administered every two weeks to achieve optimal therapeutic outcomes and prevent elevations in 
sUA levels and reduce tophus burden [Baraf  2013].  Compliance with such a regimen can be 
burdensome and pose a barrier to treatment for some patients who may otherwise benefit from 
the infusion.  Therefore, there is an unmet need for patients with uncontrolled gout to have 
access to a therapy that is effective with limited AEs, amenable to high patient compliance over 
several months.  Administering pegloticase over a shorter duration time may address this unmet 
need. 
One concern, however, is that a shorter infusion duration may lead to increased AEs.  Pegloticase 
has been associated with IRs, including anaphylaxis.  In a Phase 2 study in which pegloticase 
was administered at 30 minutes in the majority of subjects, 44% of subjects experienced an IR 
(no subjects experienced anaphylaxis).  It is important to note that there was no methotrexate as 
part of the protocol and the majority of subjects did not receive any IR prophylaxis.  In Phase 3 
studies (which included IR prophylaxis for all subjects), with pegloticase administered over 120 
minutes, IRs occurred in 26% of subjects receiving pegloticase compared to 5% of subjects 
receiving placebo and anaphylaxis was reported in 5% of subjects receiving pegloticase and 0% 
of subjects receiving placebo (pegloticase (KRYSTEXXA) Investigator’s Brochure).  The nature 
and the severity of the IRs in the Phase 2 and Phase 3 studies were relatively similar.  These AEs 
are thought to be related to the development of anti-drug antibodies and can be reduced by 
avoiding infusions in patients who initially respond and then have a rebound of their serum uric 
acid above 6 mg/mL.  These anti-drug antibodies are also associated with loss of efficacy as 
reflected in this increase in sUA levels [Schellekens 2005; Sundy et al, 2011]. 
Reducing anti-drug antibodies via pre-treatment with and concomitant administration of an 
immune-modifying drug, methotrexate (MTX), has been shown to be useful in other infused 
products, such as infliximab, in the setting of rheumatoid arthritis treatment.  Based on results 
from MIRROR RCT (NCT03994731), pretreatment and coadministration of pegloticase with 
methotrexate 15 mg orally once weekly was shown to significantly reduce failure rates and the 
incidence of infusion reactions in patients with chronic gout as compared to pegloticase alone 
[Botson et al, 2022]. 

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To address the possibility of increased AEs with a shorter infusion duration, this study will 
incorporate an IR prophylaxis regimen as well as pre-treatment and concomitant use of MTX 
with pegloticase [Hershfield et al, 2014].   
Individual subject sUA Discontinuation Criteria will also be in place to minimize the potential 
for AEs in subjects who are non-responders to treatment.  Since the risk of anaphylaxis and IRs 
is higher in patients who have lost therapeutic response, this study will also discontinue 
treatment if sUA levels increase to above 6 mg/dL at 2 consecutive study visits to minimize the 
potential for such AEs. 
7.3 
Rationale for Dose Selection 
The current approved dose of pegloticase for intravenous infusions, 8 mg every 2 weeks, will be 
tested in this study.  Refer to the current version of the FDA-approved KRYSTEXXA Full 
Prescribing Information.  
The study will be initiated enrolling subjects assigned to 60-minute infusion durations.  Based on 
tolerability, this infusion duration may be progressively shortened to 45-minute and 30-minute 
infusions.  A previous trial (n=41) was conducted using 30 minute and 60 minute infusions.  The 
adverse event profile was similar in nature and severity to that which is seen with the FDA-
approved 120 minute infusions [Sundy et al, 2008].  The consistent adverse event profile 
supports initiating this trial with subjects receiving infusions at 60 minute durations and 
progressively moving to shorter durations of 45 minutes and 30 minutes.   
8 
STUDY OBJECTIVES 
The overall objective of this study is to assess the tolerability and efficacy of pegloticase 
administered with a shorter infusion duration in subjects with uncontrolled gout receiving 
methotrexate. 
Primary Objective 
The primary objective is to assess the tolerability of pegloticase infusions administered with 
methotrexate (MTX) from Day 1 through Week 24 in the cohort chosen to be most desirable 
duration for infusion, as measured by the incidence of IRs (including anaphylaxis) related to 
pegloticase. 
Secondary Objectives 
The secondary objectives will be assessed for the cohort chosen to be the most desirable duration 
for infusion and include: 
x Estimate the response rate at Month 6 (Weeks 20, 22 and 24), as measured by the 
sustained normalization of sUA to <6 mg/dL for at least 80% of the time during Month 6. 
x Assess the proportion of subjects receiving pegloticase with MTX who experienced any 
of the following events: Infusion Reaction (IR) leading to discontinuation of treatment, 
anaphylaxis, or meeting Individual Subject sUA Discontinuation Criteria. 

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x Assess the time to any of the following events: IR leading to discontinuation of treatment, 
anaphylaxis, or meeting Individual Subject sUA Discontinuation Criteria (two 
consecutive pre-infusion sUAs >6 mg/dL).  
Exploratory Objectives 
x Assess the pharmacokinetics of pegloticase. 
x Assess the profile of anti-uricase antibodies and anti-poly (ethylene glycol) antibodies. 
Safety Objectives 
x Assess the incidence of adverse events of special interest (AESI), including IRs, 
anaphylaxis, gout flares, cardiovascular events and the AE/SAE profile overall.  
x Assess the proportion of subjects who experienced IR leading to slowing down of the 
infusion rate or discontinuation of treatment. 
x Assess the time to first IR leading to slowing down of the infusion rate or discontinuation 
of treatment. 
x Assess the time to first IR. 
x Assess the proportion of subjects who were able to complete all infusions over the 
assigned treatment duration length or a lesser time, without clinically requiring an 
increased infusion time. 
x 
Assess the proportion of infusions completed over the assigned duration length or a lesser 
time, without clinically requiring an increased infusion time. 
x Laboratory tests and 12-lead electrocardiogram (ECG). 
x Vital signs and physical examinations. 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study is a Phase 4, multicenter, open-label, infusion duration, study of pegloticase 
administered over < 120 minutes in combination with MTX to evaluate the safety, tolerability 
and efficacy in treating adult subjects with uncontrolled gout.  

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Approximately 10 subjects in each cohort are planned to be enrolled initially. If deemed safe, an 
additional 100 subjects to be enrolled in the selected cohort in order to have approximately 110 
subjects exposed.  Treatment duration with pegloticase will be approximately 24 weeks. 
 
The study design will include: 1) a Screening Period, lasting up to 35 days; 2) a 4-week MTX 
Run-in Period; 3) a 24-week Pegloticase + MTX Period which includes an End-of study 
Week 24/Early Termination Visit; 4) a safety Follow-up Phone/Email 30 days after the last 
pegloticase infusion and 5); a 3-month Post-Treatment Follow-up. 
Guidance on Blood Glucose Monitoring: 
HbA1c testing must be performed at Screening for all subjects (locally or centrally): 
If HbA1c >6.5% and/or if subject has known diagnosis of diabetes mellitus, additional measures 
are recommended: 
• 
Investigator asked to closely monitor glucose levels and adjust any diabetic medications 
as necessary 
• 
Subject should consult their primary care physician and/or Endocrinologist managing 
their diabetes 
The pre-infusion IV steroid dose may be reduced (e.g., methylprednisolone 75 mg IV) after 
consulting with the Horizon Medical Monitor. 
 
All subjects who meet eligibility criteria at Screening will begin oral MTX at a dose of 15 mg 
weekly for 4 weeks prior to the first dose of pegloticase.  
Subjects will also take folic acid 1 mg orally every day beginning at Week -4 (the start of MTX) 
continuing until prior to the End of Pegloticase Infusion Visit (if applicable) or the Week 24/End 
of Study/Early Termination Visit.  Subjects must be able to tolerate MTX at a dose of 15 mg 
during the 4-week MTX Run-in Period (prior to Day 1) to be eligible to participate in the 
Pegloticase + MTX Period.  Subjects who are unable to tolerate MTX at a dose of 15 mg during 
the MTX Run-in Period will be considered screen failures and not proceed to pegloticase dosing. 
Female subjects who take at least one dose of MTX and who are 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 after the last dose of MTX.  If the subject has 
not ovulated, a urine pregnancy test will be performed.  For male subjects who take at least one 
dose of MTX and who are non-vasectomized an inquiry will be conducted at the Post-Treatment 
3-month Follow-up visit (or 3 months after the subject’s last dose of MTX) after MTX 
discontinuation regarding partner pregnancy. 
All subjects who complete the Run-In Period and meet the inclusion/exclusion criteria 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 + MTX Period, he or she has been 
taking at least one protocol standard gout flare prophylaxis regimen (i.e.  colchicine and/or 

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NSAIDs and/or low-dose prednisone ≤10 mg/day) for ≥1 week before the first dose of 
pegloticase and continuing flare prophylaxis per American College of Rheumatology guidelines 
[Khanna D et al. 2012].  
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 + MTX Period, all subjects will receive pegloticase 8 mg every 2 weeks 
administered IV for a total of 12 infusions from Day 1 through Week 22, inclusive for a total of 
12 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.  sUA 
Discontinuation Criteria will be applied: subjects with sUA level >6 mg/dL at 2 consecutive 
study visits beginning with the Week 2 Visit will discontinue treatment but continue on study as 
described in Section 9.4.3. 
Up to three pegloticase infusion durations may be assessed for the Pegloticase + MTX Period:  
x 60-minute infusion 
x 45-minute infusion 
x 30-minute infusion 
Initially, cohorts of approximately 10 subjects will be enrolled sequentially at progressively 
shorter infusion durations initially, beginning with the 60-minute infusion duration, progressing 
down to the 45-minute infusion duration and then to the 30-minute infusion duration. If deemed 
safe, enrollment will continue in the chosen infusion duration cohort until approximately 110 
subjects are enrolled (e.g. targeted 110 subjects in the 30-minute infusion cohort, unless 30-
minute infusion is not tolerated, then approximately 110 subjects may be enrolled in the 45-
minute or 60-minute infusion cohort). The most desirable infusion duration is the shortest 
duration which is shown to be safe and well tolerated.  
After the first 3 subjects at each infusion duration complete at least 4 weeks of Pegloticase + 
MTX period (3 infusion visits), a holistic safety assessment will be performed by the internal 
Safety Review Committee on available subjects’ data.  Study enrollment will not be paused.  If a 
subject discontinues treatment or study prior to the third infusion visit, their available data is still 
included in the safety assessment.  If the safety assessment indicates that the infusion duration is 
well tolerated (based on pre-determined criteria, see Section 9.2), then additional safety 
assessments will continue to be performed based on available subjects’ data after 6 subjects and 
10 subjects complete at least 4 weeks of the Pegloticase + MTX period (3 infusion visits).   
If the Safety Review Committee confirms that the percentage of subjects meeting infusion speed-
limiting criteria is less than the threshold specified in Section 9.2, then enrollment of subjects at 
the next progressively shorter infusion duration cohort (15 minutes shorter duration) will begin. 
Further, if the Safety Review Committee confirms that the percentage of subjects meeting 
infusion speed-limiting criteria are less than the thresholds specified in Section 9.2,then 

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additional subjects will be enrolled (for a total of approximately 110 subjects in the given 
cohort). 
If any of the safety assessments indicate that a specific infusion duration is not tolerated based on 
pre-determined criteria, then the study may enroll additional subjects at any infusion durations. 
In the event that the initial 60-minute infusion duration is not tolerated based on pre-determined 
criteria, then the study may be revised or terminated (after internal review and assessment). 
If >10 subjects are enrolled at any infusion duration, additional safety assessments will be 
performed when 15 subjects and 20 subjects complete at least 4 weeks of the Pegloticase + MTX 
period (3 infusion visits).  
Once all subjects have at least 4 weeks of Pegloticase + MTX period (3 infusion visits), 
additional safety assessments will be done as needed (refer to the Safety Review Committee 
charter).  If a subject discontinues treatment or study prior to either of these time-points, their 
available data is still included in the safety assessment.   
The Safety Review Committee can  modify the number of subjects at the chosen infusion 
duration, if they determine that more safety data is needed. 
Investigators will be permitted to adjust the duration of the infusion at a particular infusion visit 
regardless of initial treatment duration assignment, if needed.  The decision to modify the 
infusion duration at a visit, will be allowed based on the investigator’s discretion, after a 
discussion with the Medical Monitor.  
Subjects may return to the original infusion duration for subsequent infusions at investigator’s 
discretion. 
Pegloticase will be administered after all pre-dose study visit assessments have been completed 
at each visit.  The date and time of infusion start and stop will be recorded.  
During the Pegloticase + MTX Period, subjects will be instructed to take 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 
Discontinuation Criteria; however, if a subject does not do so, MTX must be taken ≥60 minutes 
prior to each pegloticase infusion. 
After Day 1, if a subject becomes unable to tolerate 15 mg of MTX, the MTX dose may be 
reduced and/or discontinued and the subject may remain in the study (see Section 9.5.7.3.2.2).  
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. 

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The total blood volume to be collected from each subject during this study is approximately 
450 mL.  
An External Adjudication Committee will be established for this study to adjudicate the AESIs. 
The External Adjudication Committee will be comprised of external experts with experience in 
immunology, allergic reactions, rheumatology and/or cardiovascular diseases. Details outlining 
the responsibilities of the Adjudication Committee will be included in the Adjudication 
Committee charter. AESIs defined in the protocol (See Section 9.6.1.2.1.5) include IRs, 
anaphylaxis and cardiovascular events.  The AESI of gout flare will not be adjudicated. 
Aggregate safety data will be reviewed by the internal Safety Review Team (SRT) and Safety 
Review Committee (SRC). Subject safety and tolerability of the pegloticase regimen will be 
discussed to establish a recommendation as whether to continue the current treatment regimen or 
to modify the assigned treatment regimen.   
The SRC will be comprised of members of the Horizon Clinical Development and Patient Safety 
and Pharmacovigilance Teams. Meetings will occur at pre-determined timepoints or ad-hoc 
dependent on any potential safety signals reported (e.g. anaphylaxis or any SAE related to 
pegloticase infusion).  If any anaphylaxis event or SAE related to pegloticase infusion occurs 
with any subject, real-time with expedited review of patient profiles and/or relevant data 
available in the electronic data capture will occur.  Changes may include, but are not limited to, 
increasing the pegloticase infusion duration or modifying the methotrexate dosage.  An overview 
of the study design is presented in the schematic below and details of study activities are 
provided in Section 9.1.  

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Figure 9.1 
Schematic of Study Design 
 
  
IV = intravenous; MTX = methotrexate; PO = oral; Q2W = every 2 weeks; W = week 
Note: Study visits must be completed within ±3 days of the target visit date. 
1. 
Prior to the Treatment Period, subjects will begin taking at least one of the per protocol standard gout flare prophylaxis 
regimen (colchicine 0.6 mg/day and/or NSAID and/or low dose prednisone <10 mg/day) for ≥1 week before the first 
dose of pegloticase and continuing flare prophylaxis throughout the pegloticase treatment period per American College 
of Rheumatology guidelines. 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) over an infusion duration between 10 and 30 minutes, will be 
administered immediately prior to each infusion. 
2. 
Stopping rules will be implemented: Subjects with 2 sUA levels > 6 mg/dL at 2 consecutive study visits beginning with 
the Week 2 Visit will discontinue from pegloticase therapy and complete the End of Pegloticase Infusions Visit and 
remain on study. 
3. 
The determination on whether to enroll the next cohort of subjects to a different infusion duration level will be based on 
whether the previous cohort meets the Infusion Speed-Limiting Criteria as well as the Safety Review Committee 
decision. 
4. 
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 SAEs have occurred. If the subject discontinues treatment but continues in the study, then this follow-up 
visit may be replaced by a scheduled study visit. 
9.2 
Infusion Speed-Limiting Criteria 
Infusion speed-limiting criteria will be met if a subject experiences any severe (Grade ≥3) IRs or 
any other severe AEs within 24 hours of receiving pegloticase infusion and attributed to the 
infusion and not any other underlying disease process.  The signs and symptoms of the severe 
IRs are usually prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief 

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interruption of infusion) or recurrent following initial improvement.  Possible associated signs 
and symptoms of IRs may include but not limited to:  
x Respiratory: difficulty breathing with wheezing or stridor; upper airway swelling 
(lip, tongue, throat, uvula, or larynx); respiratory distress manifested as at least 2 
or more of the following: tachypnoea, increased use of accessory respiratory 
muscles, cyanosis, recession, grunting  
x Cardiovascular: hypertension, tachycardia, measured hypotension, a decreased 
level of consciousness, loss of consciousness 
x Dermatological or mucosal: generalized urticaria (hives) or generalized erythema, 
angioedema, generalized pruritus with skin rash 
  
If ≤ one-eighth of subjects meet infusion speed-limiting criteria at the same infusion duration 
after 3 subjects and after 6 subjects, then enrollment may continue at the same infusion duration.  
If ≤ one-third of subjects meet infusion speed-limiting criteria at the same infusion duration after 
10 subjects, then enrollment may continue at the next progressively shorter infusion duration. 
If > one-eighth of subjects meet infusion speed-limiting criteria, then enrollment at that infusion 
duration may be suspended.   
Safety Review Committee must confirm that infusion speed-limiting criteria were met, prior to 
additional patients being enrolled at the previous infusion duration.  In the event that > one-
eighth of subjects meet infusion-speed limiting criteria at the initial 60-minute infusion duration, 
then the study may be revised or terminated (after internal review and assessment). 
If an anaphylaxis event occurs in any subject, further dosing with pegloticase for that subject will 
be terminated. 
If any anaphylaxis event or SAE related to pegloticase infusion occurs with any subject, all 
pertinent data will be provided for expedited review to the Adjudication Committee (for the 
purpose of adjudicating AESIs) and the SRT/SRC.   
If any anaphylaxis event or SAE related to pegloticase infusion occurs with any subject, real-
time with expedited review of patient profiles and/or relevant data available in the electronic data 
capture will occur.  
9.3 
sUA Discontinuation Criteria 
Individual Subject sUA Discontinuation Criteria: Subjects with a pre-infusion sUA level >6 
mg/dL at 2 consecutive study visits beginning with the Week 2 Visit will discontinue treatment 
and remain in the study for Follow-Up visits only, including the 30-day Follow-up Email/Phone 
call, Week 24/End of Study/Early Termination and 3 Month Post-Treatment Follow-up Visits.  
Note:  The sUA Discontinuation Criteria only pertain to individual subjects and are not sUA 
Discontinuation Criteria for a group or specific infusion duration. 

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9.4 
Selection of Study Population 
Subjects diagnosed with gout eligible for this study will have sUA ≥6 mg/dL and inability to 
maintain sUA <6 mg/dL on other urate-lowering therapy or intolerable side effects associated 
with current urate-lowering therapy, or with a contraindication to xanthine oxidase inhibitor 
therapy. 
9.4.1 Inclusion Criteria 
Eligible subjects must meet 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: 
x Hyperuricemia during the screening period defined as sUA ≥6 mg/dL and; 
x Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the 
maximum medically appropriate dose, or with intolerable side effects or a 
contraindication to xanthine oxidase inhibitor therapy based on medical record 
review or subject interview and; 
x Symptoms of gout including at least 1 of the following: 
 Presence of at least one tophus 
 Recurrent flares defined as 2 or more flares in the past 12 months prior to 
screening 
 Presence of chronic gouty arthritis 
5. Willing to discontinue all oral urate-lowering therapy at least 7 days prior to MTX dosing 
at Week -4 and remain off of urate lowering therapy when receiving pegloticase infusions 
during the study.  
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;  
x 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 -4 (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 (whichever is the longest duration after 
the last does of pegloticase).  Highly effective contraceptive methods (with a 
failure rate <1% per year), when used consistently and correctly, include implants, 

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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 -4  and continuing through 3-Month Post-Treatment 
Follow-up. 
8. Able to tolerate MTX 15 mg for 4 weeks during the MTX Run-in Period prior to the first 
dose of pegloticase. 
9.4.2 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 Week -4 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 (defined as 3 months or longer) would also meet 
exclusion criteria. 
5. Known history of any solid organ transplant surgery requiring maintenance 
Immunosuppressive therapy unless treated and no chronic or active infection confirmed 
by HBV serology.   
6. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA 
positivity, unless treated and viral load is negative and no chronic or active infection 
confirmed by HBV serology. 
7. Known history of hepatitis C virus RNA positivity unless treated and viral load is 
negative. 
8. Known history of Human Immunodeficiency Virus (HIV) positivity  
9. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at Screening Visit). 
10. Severe chronic renal impairment (estimated glomerular filtration rate 
<40 mL/min/1.73 m2) at the Screening Visit based on the 4 variable-Modification of Diet 
in Renal Disease [MDRD] formula or currently on dialysis. 
11. Non-compensated congestive heart failure or hospitalization for congestive heart failure 
or treatment for acute coronary syndrome (myocardial infarction or unstable angina) 
within 3 months of the Screening Visit, or current uncontrolled arrhythmia, or current 
uncontrolled BP (>160/100 mmHg) prior to 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. 

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13. Prior treatment with pegloticase (KRYSTEXXA), 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 methotrexate (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 - 4, 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. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at Screening that 
is not subsequently controlled by the end of the Screening. 
24. Diagnosis of osteomyelitis. 
25. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as 
Lesch-Nyhan and Kelley-Seegmiller syndrome. 
26. 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. 
27. Alcohol use in excess of 3 alcoholic beverages per week. 
28. A known intolerance to all protocol standard gout flare prophylaxis regimen (i.e. 
colchicine and/or non-steroidal anti‑inflammatory drugs and/or low‑dose prednisone ≤10 
mg/day).  
29. Currently receiving urate-lowering therapies and unable to discontinue treatment at least 
7 days prior to MTX dosing at Week -4 and remain off of urate lowering therapy when 
receiving pegloticase infusions during the study. 
30. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis.  If deemed 
necessary by the Investigator, a chest X-ray may be performed during Screening 

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9.4.3
Removal of Subjects from Therapy or Study
Every effort should be made to retain a subject in the study to monitor their safety for at least 3-
months of follow-up. Subjects who are removed from pegloticase therapy should remain on 
study for Follow-Up visits only, including the 30-day Follow-up Email/Phone call, Week 24/End 
of Study/Early Termination and 3 Month Post-Treatment Follow-up Visits barring withdrawal of 
consent for study participation.  However, subjects may withdraw consent or discontinue 
participation from the study at any time, without prejudice to further treatment. In addition, the 
Investigator may discontinue a subject from treatment at any time. The primary reason for 
discontinuation from the study and/or study drug should be recorded on the eCRF.
Removal of Subjects from Pegloticase Therapy
For subjects who do not complete therapy through Week 24, the reason for discontinuation from 
the therapy should be recorded on the eCRF using 1 of the following categories:
x
Lack of Efficacy.  (i.e., sUA level >6 mg/dL at 2 consecutive study visits beginning with 
the Week 2 Visit).
x
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 treatment due to an AE should be 
followed until resolution or stabilization of the AE, or an adequate explanation for the 
event is obtained.
x
Physician Decision. The Investigator has determined that pegloticase administration 
poses an unacceptable risk to the subject (specify reason). 
x
Withdrawal of Consent.   Subject refusal of additional therapy (specify reason).
x
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.
x
Study Terminated by Sponsor. The Sponsor, IRB, or regulatory agency terminates the 
study.
x
Pregnancy
x
Death
9.4.3.1.1 Study considerations for subjects ending pegloticase infusions prior to 24 weeks
x
Methotrexate, along with folic acid, will be discontinued at the time of cessation of 
pegloticase infusions prior to Week 24. 
x
All subjects will complete the End of Pegloticase Infusions Visit and should be 
encouraged to remain on study and attend all Follow-Up visits, including the 30-day 
Follow-up Email/Phone call, Week 24/End of Study/Early Termination and 3 Month 
Post-Treatment Follow-up Visits barring withdrawal of consent from study participation.    
x
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 compliance/reconciliation

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o
IR 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  
Post-Treatment Follow-up:
The intent is to obtain at least 3 months of follow up on each subject after cessation of 
pegloticase infusions.  If the subject ends treatment early but remains in the study and the 3-
month Post-Treatment Follow-up Visit occurs prior to Week 24, the 3-month Post-Treatment
Follow-up Visit will be adjusted accordingly based on the timing of the last treatment.
Removal of Subjects From Study
In addition to completion of therapy, the Follow-Up visits, the Week 24 visit and the reason for 
discontinuation from the study should be recorded on the eCRF using one of the following 
categories:
x
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.
x
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.
x
Study Terminated by Sponsor. The Sponsor, IRB, or regulatory agency terminates the 
study. 
x
Death.
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject. At least two phone calls and a registered letter should be 
documented before considering subject lost to follow-up. When a subject withdraws before 
completing the study, attempts of follow-up information should be documented in the source 
documents to include reasons of withdrawal.
9.4.4
Replacement Policy
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 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.

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Centers
A center may be closed and/or replaced for several reasons.  Prior to a site being recommended 
for closure, the site PI, Medical Monitor, Study Manager and possibly the Site Monitor will 
discuss the decision for closure.
Screen Failures
Subjects who do not meet all of the inclusion criteria or meet any of the exclusion criteria will be 
considered screen failures. In addition, subjects who are unable to tolerate MTX at an oral dose 
of 15 mg weekly during the MTX Run-in Period will be considered screen failures. Screen 
failure subjects who are females of childbearing potential who took at least one dose of MTX, 
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 after the last dose of MTX.  If the subject has not 
ovulated, a urine pregnancy test will be performed at the study site. Screen failure subjects who 
receive at least 1 dose of MTX and are non-vasectomized males will receive a Phone/E-mail/Site 
Visit 3 months after MTX discontinuation regarding partner pregnancy.
Screen failure subjects may be allowed to rescreen for the study if both the Investigator and 
Sponsor are in agreement regarding rescreening and if the Investigator determines that the 
subject can satisfy all of the eligibility criteria.
9.5
Treatments
9.5.1
Treatment Assignment
This is an open-label, non-randomized study therefore the study site personnel, sponsor and 
patient will all know the treatment.
The treatment assignment is coordinated centrally by the Sponsor.  
After the investigator/study site identifies a potential patient, the investigator/study site should 
notify sponsor of potential patient by sending a Screening Notification email to the Study 
Manager and Medical Monitor.  Formal screening procedures should not begin until a slot has 
been confirmed for any potential patient.  The Sponsor will confirm that the patient is held a spot 
for potential treatment.  
At any time, the study can end prior to the potential patient getting dosed. 
9.5.2
Treatments Administered
Methotrexate
During the MTX Run-in Period, which begins 4 weeks prior to the first dose of pegloticase, 
subjects will take oral MTX at a dose of 15 mg weekly. 
Subjects will be instructed to take MTX weekly on the same day each week (if dosing more 
frequently than once in a day (i.e. BID, TID), the total weekly MTX dose should be taken within 

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24 hours, preferably the same calendar day) and record the date and time of each dose in the 
dosing calendar. 
During the MTX 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. 
Investigators may choose to have subjects take the weekly dose divided over the day (i.e. BID, 
TID). 
During the Pegloticase + MTX Period, MTX should be taken 1 to 3 days prior to the pegloticase 
infusion and one additional weekly dose after the last infusion (at Week 22) for subjects who 
have not stopped pegloticase due to study sUA Discontinuation Criteria.  If a subject is not able 
to take the MTX 1 to 3 days prior to the pegloticase infusion, MTX must be taken ≥60 minutes 
prior to the pegloticase infusion.
During the Pegloticase + MTX Period, if a subject becomes unable to tolerate the MTX the 
dosage may be decreased.
Subjects will also take folic acid 1 mg orally every day beginning at Week -4 (the start of MTX) 
until prior to the Week 24 Visit.
Pegloticase
All subjects who meet the inclusion/exclusion criteria and tolerate oral MTX 15 mg weekly 
during the MTX Run-in Period will receive pegloticase at a dose of 8 mg administered IV every 
2 weeks for a total of 12 infusions from Day 1 through Week 22 inclusive (Pegloticase + MTX 
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 continuing flare prophylaxis 
throughout the pegloticase treatment period per American College of Rheumatology guidelines 
[Khanna D et al. 2012].
Standardized IR prophylaxis consisting of pre-treatment with an antihistamine, acetaminophen 
and a corticosteroid will accompany each infusion.
Folic Acid
Subjects will take folic acid 1 mg orally every day beginning at Week -4 (the start of MTX) until 
prior to the Week 24/End of Study/Early Termination Visit. 
If the subject discontinues pegloticase due to the sUA Discontinuation Criteria or other reason, 
MTX and folic acid should also be discontinued.  
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.

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Gout Flare Prophylaxis 
It is required that before a subject begins the Pegloticase + MTX Period, he or she has been 
taking at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or 
NSAIDs and/or lowdose prednisone ≤10 mg/day) for ≥1 week before the first dose of pegloticase 
and continuing flare prophylaxis throughout the pegloticase treatment period per American 
College of Rheumatology guidelines [Khanna D et al. 2012]. 
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.
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 Solumedrol 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.  
NOTE: If subject’s HbA1c is >6.5% at Screening and/or if subject has known diagnosis of 
diabetes mellitus, the pre-infusion IV steroid dose may be reduced (e.g., methylprednisolone 75 
mg IV) after consulting with the Horizon Medical Monitor.
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.
9.5.3
Identity of Investigational Products
Pegloticase
8 mg/mL Uricase:
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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0.16 mg/ml Uricase:
Pegloticase is a clear, colorless, sterile solution in phosphate-buffered saline provided for ready-
to-use for IV infusion. 50 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.
Methotrexate
MTX 2.5 mg tablets for oral administration will be provided to subjects as a commercially 
available generic (MTX Full Prescribing Information).
A dosing calendar will be provided to subjects at the Week -4 Visit to record each dose of MTX 
and the date and time of each dose on each calendar day of MTX administration.  Additional 
calendar pages may be provided on future visits as needed.  
9.5.4
Labeling
Pegloticase (KRYSTEXXA) is commercially available as 8 mg/mL uricase in the United States 
and will be supplied by PCI Pharma Services packaged in sterile, single-use 2-mL glass vials 
with 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.
The alternative ready-to-use presentation of pegloticase (0.16 mg/ml uricase) will be supplied by 
PCI Pharma Services packaged sterile, single-use 50-mL glass vials with a Fluorotec-coated 
rubber injection stopper which delivers 8 mg uricase in a 50 mL solution. 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 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 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 inclusion/exclusion 
criteria are confirmed.
9.5.5
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. 

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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).
MTX will be stored between 20°C to 25°C (68°F to 77°F) [See USP Controlled Room 
Temperature] and protected from light.
9.5.6
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 subject drug 
logs/electronic logs to account for MTX dispensed and subject compliance will be monitored by 
the site at each visit (see Section 9.5.11).
Subjects will bring the MTX dosing calendar to each study visit for assessment of compliance. 
Subjects will bring the MTX bottle to each visit for a compliance check by the site. The site will 
manually count the pills 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 and 
pegloticase packaging, labeling, storage and destruction.
9.5.7
Study Drug Administration and Timing of Dose for each Subject
Description of Clinical Supplies
PCI Pharma Services will supply study drugs (pegloticase and MTX) to clinical sites. Ancillary 
supplies for dosing will be provided by the study site (i.e., infusion bags containing normal 
saline, syringes, needles, alcohol swabs, gauze pads, bandages and biohazard containers for safe 
storage of used needles and syringes).
Determination of Dose Volume 
Pegloticase will be administered as an admixture of 8 mg in 50 mL of 0.45% or 0.9% Sodium 
Chloride Injection, United States Pharmacopeia (USP) for IV infusion. Alternatively, pegloticase 
is administered as a ready-to-use solution with 8 mg uricase formulated in 50 mL phosphate-
buffered saline that is suitable 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. Modifications to the infusions at subsequent visits following an 
IR can be discussed with Medical Monitor. 

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Details Concerning Timing and Dose Administration
9.5.7.3.1 Preparation and Administration
9.5.7.3.1.1 Preparation
8 mg/mL Uricase:
Vials of pegloticase will be visually inspected for particulate matter and discoloration before 
administration, whenever solution and container permit. Vials should 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 50 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.
0.16 mg/ml Uricase:
Vials of pegloticase of the alternative ready-to-use presentation (50 mL) will be visually 
inspected for particulate matter and discoloration before administration, whenever solution and 
container permit. Vials should not be used if either is present. 
Before administration, allow the solution of pegloticase to reach room temperature. Pegloticase 
must never be subjected to artificial heating.
9.5.7.3.1.2 Dose and Administration
Methotrexate
All subjects will take oral MTX at a dose of 15 mg weekly.
Folic Acid
All subjects will take folic acid 1 mg orally daily.  Folic acid will be supplied by a local 
pharmacy.
Pegloticase
All subjects will receive pegloticase at a dose of 8 mg administered IV every 2 weeks for a total 
of 12 infusions from Day 1 through Week 24, inclusive (Pegloticase + MTX Period). Subjects 
will not be fasting on the day of infusion and will be encouraged to have a snack or normal meal 

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before or after the infusion.  Pre-infusion sUA results must be reported by the local or central 
laboratory prior to pegloticase infusion (see Section 9.6.2.1). 
Standardized IR prophylaxis consisting of pre-treatment with antihistamines, acetaminophen and 
corticosteroids will accompany each infusion (see Section 9.5.2.3).  
Pegloticase will be administered either as a ready-to-use 0.16 mg/mL IV solution (50 mL) or an 
admixture of 8 mg in 50 mL of 0.45% or 0.9% Sodium Chloride Injection, USP for IV infusion 
by gravity feed or infusion pump. After approximately 30 subjects in 30 min cohort receive 
admixture of 8 mg in 50 mL of 0.45% or 0.9% Sodium Chloride Injection, USP for IV infusion, 
newly enrolled subjects will be assigned to ready-to-use 0.16mg/mL IV solution (50 mL). 
Pegloticase will not be administered as an IV push or bolus. 
In a patient with IV site, using tubing with no in-line filter, the pegloticase preparation will be 
infused over approximately 30 to 60 ±5 minutes, depending on cohort assignment, 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.   
9.5.7.3.2 Dose Modifications, Interruptions and Delays 
9.5.7.3.2.1 Pegloticase Modifications 
Administration 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. 
9.5.7.3.2.2 MTX Dose Algorithm and Intolerance Criteria 
During the MTX Run-in a subject 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  

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b. Albumin < lower limit (LLN) 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 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 mg in the morning and evening on the day of dosing); if symptoms 
improve, subject will not be considered a screen failure on the basis of that symptom. 
During the Run-In and Pegloticase + MTX Period, MTX dose guidance based on new laboratory 
findings or new symptoms is as follows: 
Lab Parameters 
Value 
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 

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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 
(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: 
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 back towards 15 mg after dose reduction, based on improvement 
or resolution of abnormal liver enzymes (>2 × ULN): 
1. When liver enzymes return to values ≤1.5 × ULN, increase MTX or dose by 2.5 mg and 
reassess in 2 weeks. 
2. If liver enzymes remain ≤1.5 × ULN, increase MTX or dose by 2.5 mg and reassess in 2 
weeks. 
Improvement of other laboratory abnormalities potentially attributed to MTX or may also 
warrant titration back up to 15 mg weekly, based on Investigator judgement and in discussion 
with the Sponsor medical monitor. 
9.5.7.3.2.3 Gout Flare Treatment 
An increase in gout flares is frequently observed upon initiation of urate lowering treatment 
(ULT), 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 9.6.1.10.  All subjects who experience a gout flare during the study will be 
prescribed anti-inflammatory treatment (e.g., corticosteroids, colchicine and intra-articular 
steroid injections), as is clinically indicated or deemed necessary on an individual basis at the 
discretion of the investigator (Becker, 2019).  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 can be prescribed.  The precise dose and regimen of colchicine should be 
individualized for each subject based on renal function and gastrointestinal intolerance by the 
Investigator and documented on the concomitant medication eCRF. 

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9.5.7.3.2.4 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:  
x 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. 
x Vital signs (sitting or supine BP, heart rate, respiratory rate and body temperature) will be 
captured at least every 30 minutes until the resolution or stabilization of the AE. 
x A 12-lead ECG will be performed. 
x 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. 
If, in the Investigator’s opinion, the subject is experiencing an anaphylactic reaction (see 
Section 9.6.1.2.1.5), 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 9.6.1.2.1.5) 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 prednisone 
(e.g. 20 mg) 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. 
9.5.8 Method of Assigning Subjects to Treatment Groups 
This study is an open-label, single-arm design in which all subjects will receive the same study 
drugs (i.e., MTX and pegloticase).  Study will be initiated enrolling patients assigned to 60 
minute infusion durations.  Infusion duration assignment may be progressively shortened to 45 
minute or 30 minute infusion durations based on tolerability of previous subjects and the infusion 
duration cohort may be modified based on the safety and tolerability assessments.  

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This is an open-label, non-randomized study therefore the study site personnel, sponsor and 
patient will all know the treatment. 
The treatment assignment is coordinated centrally by the Sponsor.   
At any time, the study can end prior to the potential patient getting dosed. 
9.5.9 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 
and up to the Screening Visit (as well as history of COVID-19 vaccinations). 
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, 
COVID-19 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. 
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.  
9.5.10 Restricted Medications 
Subjects should not receive the following medications from the time of Screening through the 
end of pegloticase and MTX treatment:  
x Oral urate-lowering therapies including allopurinol, febuxostat, probenecid, lesinurad, or 
other ULT for gout; re-introduction of oral ULTs should not start until after the End of 
Pegloticase Visit (or End of Study) laboratory tests are collected. 
x Any PEG-conjugated drug 
x Any other investigational agent 
x Methotrexate (other than study 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 
x If a subject is treated with antibiotics, refer to Section 9.5.7.3.2.2. 
x  Systemic immunosuppressive agents 

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9.5.11 Treatment Compliance 
A dosing calendar will be provided to subjects at the Week -4 Visit for recording each dose of 
MTX on each calendar day of MTX administration (Additional calendar pages may be provided 
at future visits as required).  The dosing calendar and bottle of MTX should be brought to each 
study visit for assessment of compliance with MTX.  Adherence to the MTX regimen will also 
be recorded by the study coordinator at study visits in the eCRF by recording the date of each 
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 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. 
9.5.12 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 
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 -4 (start of MTX dosing) 
and continue for 30 days after the last dose of pegloticase or at least one ovulatory cycle after the 
last dose of MTX (whichever is the longest duration after the last dose of pegloticase or 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 a female partner of reproductive potential during the study and for at least 3 months 
after the last dose of MTX.  Contraception methods include condom use and abstinence. 
9.6 
Safety/Tolerability, Efficacy and Pharmacokinetic Variables 
The Schedule of Assessments is provided in Section 2.1. 
9.6.1 Safety/Tolerability Variables 
Safety will be assessed via AE and concomitant medication use monitoring, physical 
examinations, vital signs, clinical safety laboratory evaluations (hematology, chemistry, urine 
albumin: creatinine ratio), pregnancy testing (if applicable), ECGs and AEs of special interest 
(i.e., IRs, anaphylaxis, gout flares and cardiovascular events).  

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Adjudication and Safety Review Committee
An external Adjudication Committee will be established for this study to adjudicate the AESIs. 
An internal Safety Review Committee (SRC) will be established to review the aggregate safety 
data.  Subject safety and tolerability of the pegloticase regimen will be discussed and the 
committee will make a decision as to continue the current treatment regimen or to modify the 
assigned treatment regimen.  
AESIs defined in the protocol (See Section 9.6.1.2.1.5 ) include IRs, anaphylaxis and
cardiovascular events.  The AESI of gout flare will not be adjudicated.
The internal Safety Review committee will be comprised of members of the Horizon Clinical
Development and Patient Safety and Pharmacovigilance Teams at pre-determined timepoints or 
ad-hoc dependent on any potential safety signals reported (e.g. anaphylaxis or any SAE related to 
pegloticase infusion).  An independent external Adjudication committee will be established for 
this study to adjudicate the adverse events of special interest (AESIs) defined in the protocol 
(See 9.6.1.2.1.5). It will be comprised ofl external experts with experience in immunology, 
allergic reactions, rheumatology and/or cardiovascular diseases. Details outlining the 
responsibilities of the adjudication committee will be included in the adjudication committee 
charter. 
Decisions of the committee will be documented and the IRB will be notified if changes to the 
pegloticase regimen are made.  Changes may include, but are not limited to, increasing the 
pegloticase infusion duration or modifying the methotrexate dosage.
Adverse Events
9.6.1.2.1 Definitions
9.6.1.2.1.1 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: 
x
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
x
Conditions known to have been present prior to the start of the study that worsen after the 
signing of the ICF
x
Signs, symptoms, or the clinical sequelae of a suspected drug interaction

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x 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:  
x Conditions present at the start of the study should be recorded as medical history 
x 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) 
x Situations where an untoward medical occurrence did not occur (e.g., social, diagnostic, 
elective, or convenience admission to a hospital) 
x 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 
x 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. 
9.6.1.2.1.2 Serious Adverse Event Definition 
Based on ICH guidelines, an SAE is any untoward medical occurrence that at any dose: 
a. Results in death 
b. 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. 
c. 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. 

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d. 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. 
e. Is a congenital anomaly/birth defect 
f. Is a suspected transmission of any infectious agent via a medicinal product 
g. 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 or not an event qualifies as an 
‘important medical event,’ consult the Sponsor’s Medical Monitor. 
9.6.1.2.1.3 Non-Serious Adverse Event Definition 
AEs that do not result in any of the outcomes listed in Section 9.6.1.2.1.2 are considered 
non-serious. 
9.6.1.2.1.4 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 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. 
9.6.1.2.1.5 Adverse Events of Special Interest 
AEs of special interest include IRs, anaphylaxis, gout flares and cardiovascular events.  AEs of 
special interest will be collected on a separate eCRF that captures data related to each AE of 
special interest. 
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 2 hours post 
infusion.  Other AEs that occur outside of the 2 hour window following the infusion may also be 

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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.  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. 
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]:  
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 BP 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 BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d. 
Persistent gastrointestinal symptoms (e.g., crampy, abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that subject (minutes to several hours): 
systolic BP <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 9.6.1.10.  
Cardiovascular Events 
x The following cardiovascular events will be collected.  Major Adverse Cardiovascular 
Events (MACE) defined as: 

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o  Non-Fatal Myocardial Infarction: The presence of at least 2 of the 3 following 
criteria: 1) chest pain consistent with angina, 2) abnormal values of cardiac 
enzymes (> ULN of the MB fraction of creatinine phosphokinase and/or 
troponin that follows a pattern of myocardial injury), 3) myocardial injury 
current (ST segment elevation) or the development of new Q waves in 2 
contiguous leads of the electrocardiogram. 
o  Non-Fatal Stroke: ischemic or hemorrhagic stroke defined as an acute, focal 
neurologic event that persisted for > 24 hours.  If neurologic symptoms last 
for < 24 hours but magnetic resonance imaging (MRI) confirms an infarct, it 
will be considered as a stroke.  Confirmation by imaging studies (magnetic 
resonance imaging or computerized tomography of the brain) will be sought 
in all cases, but will not be an absolute requirement for consideration of the 
event. 
o Cardiovascular deaths: including any death from a cardiovascular cause 
including: myocardial infarction, stroke, heart failure, arrhythmic death, aortic 
dissection or rupture, any fatal thromboembolic event, sudden cardiac death, 
any death of unknown cause and unwitnessed death. 
x 
Congestive heart failure defined as: hospitalization or prolonged (> 12 hours) 
emergency department visit due to dyspnea, shortness of breath, with progressive 
edema accompanied by clinical findings of pulmonary vascular congestion.  
Radiographic and/or echocardiographic documentation is desirable but not required.  
Treatment by intravenous (Parenteral) diuretics or inotropes is required to confirm 
this diagnosis versus ultrafiltration, hemodialysis or left ventricular assist devices. 
9.6.1.2.2 Documentation of Adverse Events 
AE and SAE monitoring will begin from the signature of the ICF until the 3-month Post-
Treatment Follow-up Visit. 
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. 
AEs recorded before the first dose of MTX in the Run-In Period will be recorded as medical 
history. 
9.6.1.2.3 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.  

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x Grade 1 (mild) – asymptomatic or transient, short duration (<1 week), no change in 
lifestyle, no medication or over-the-counter 
x Grade 2 (moderate) – symptomatic, duration 1 to 2 weeks, alter lifestyle occasionally, 
medications give relief (may be prescription) 
x Grade 3 (severe) – prolonged symptoms, reversible, major functional impairment, 
prescription medications/partial relief, hospitalized <24 hours, temporary or permanent 
study drug discontinuation 
x Grade 4 (includes life-threatening) – at risk of death, substantial disability, especially if 
permanent, hospitalized >24 hours, permanent study drug discontinuation 
9.6.1.2.4 Relationship to Study Drug 
The relationship of each AE to MTX and/or pegloticase will be determined by the Investigator 
and the Sponsor based on the following definitions: 
1. Not related: There is no plausible temporal relationship or there is another explanation 
that unequivocally provides a more plausible explanation for the event. 
2. 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. 
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. 
9.6.1.2.5 Reporting and Documenting SAEs and Product Complaints 
9.6.1.2.5.1 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 

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reported by submitting the completed SAE form via email or fax to the contact numbers 
provided below.   
Fax (800) 860-7836 
E-mail clinicalsafety@horizontherapeutics.com 
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 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 
clinicalsafety@horizontherapeutics.com 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 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. 
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). 
9.6.1.2.5.2 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. 

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9.6.1.2.6 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 end of the study 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 subject exits the study. 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
9.6.1.2.7 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 9.6.1.2.7.
In the event of drug overdose, the subject is to be treated as appropriate.
9.6.1.2.8 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.
9.6.1.2.9 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.
9.6.1.2.10 Development Safety Update Reports
The Sponsor will prepare and submit annual safety reports to competent authorities.
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 and the End of Study/Early Termination Visit.  Urine pregnancy tests will also 
be performed at all other time points, as indicated in the schedule of assessments (Section 2.1)

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and results must be confirmed by site personnel prior to any infusion starting. 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. 
Male subjects who are not vasectomized must not impregnate their female partner during the 
study until at least 3 months after the last dose of MTX.
Information must be obtained and reported if a female subject suspects that she has become 
pregnant during the study (including the MTX Run-in Period) up to 30 days after the last dose of 
study treatment (either pegloticase or MTX), or if a female partner of male subject suspects that 
she has become pregnant during the study (including the MTX Run-in Period) up to 3 months 
(approximately 90 days) after their male subject partner discontinues 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 withdrawn from the study. 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.
Subjects who are non-vasectomized males will be asked 3 months after MTX for MTX 
discontinuation regarding partner pregnancy. This will occur at a scheduled visit or by 
phone/email.
Medical/Surgical History
Medical history, including surgical history, 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. 
For subjects with reported allergic history (e.g., seasonal allergies, food allergies, allergies to 
medications) the Investigator/site should collect additional supplemental information (e.g., 
severity, current status etc.). In the event of multiple allergies and/or moderate to severe (Grade 2 
or higher) allergic history the Investigator should consult with the Medical Monitor prior to 
enrolling the subject.

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Vital Signs, Height and Weight
Routine vital signs, including BP, respiratory rate, temperature and heart rate will be measured at 
Screening, Week -2, Week -4 and at all infusion visits during the Pegloticase + MTX Period and 
the End of Pegloticase Infusions Visit (if applicable), Week 24/End of Study/Early Termination 
and 3-month Post-Treatment Follow-up Visit. Heart rate and BP 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 BP.  
During the Pegloticase + MTX 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.  
Every effort should be made to standardize the conditions of clinic BP measurements at each 
visit whenever possible. The same arm and same cuff size should be used. 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 -4 Visit; prior to pegloticase infusion on Day 1 and at the 
Weeks 8, 16 and at the End of Pegloticase Infusions Visit (if applicable), Week 24/End of 
Study/Early Termination and Month 3 Post-Treatment Follow-up Visits. Height will be 
collected at the Screening Visit only.
Vital sign monitoring during IR is described in Section 9.5.7.3.2.4.
Physical Examinations
A complete physical examination will be performed at the Screening Visit, including assessment 
of HEENT, heart, lungs, abdomen, skin, extremities and neurological status and musculoskeletal 
including an assessment for the presence of tophi.
A targeted physical examination per the investigator judgement but at a minimum should include 
heart, lungs and abdominal exam and include a joint and skin evaluation and assessment of AEs 
at Week -4, Week -2, Day 1 and prior to administration of pegloticase at Weeks 4, 8, 12, 16, 20 
and the End of Pegloticase Infusions Visit (if applicable), Week 24/End of Study/Early 
Termination and 3-month Post-Treatment Follow-up Visit.
Physical examination findings at screening should be recorded on the medical and surgical 
history eCRF. 
Clinically significant findings from the targeted physical examinations will be recorded as AEs. 

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Electrocardiogram
A 12-lead ECG will be performed at Screening for all subjects and at the discretion of the 
Investigator thereafter. When a subject experiences an AE suspected to be an IR, a 12-lead ECG 
will also be performed.
Clinical Laboratory Safety Tests
Blood (for hematology and clinical chemistry) will be collected at Screening, Week -2, prior to 
the pegloticase infusion on Day 1 and at the Week 2, 6, 14 and 22 Visits, the 
End -of -Pegloticase -Infusions Visit (if applicable), the Week 24/End -of -Study/Early 
Termination Visit and 3 -month Post -Treatment Follow -up Visit. 
Urine (for albumin: creatinine ratio) samples will be collected at Screening, prior to the 
pegloticase infusion on Day 1 and at the Week 2, Week 6, 14 and 22 Visits, the 
End -of -Pegloticase -Infusions Visit (if applicable) and Week 24/End -of -Study/Early 
Termination Visit.
Safety laboratory assessments will include: 
3. Hematology: complete blood count with differential (hemoglobin concentration, 
hematocrit, erythrocyte count, platelet count, leukocyte count and differential leukocyte 
count);
4. Chemistry: albumin, transaminases (aspartate aminotransferase, alanine 
aminotransferase), alkaline phosphatase, total bilirubin, creatinine (including calculation 
for 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 (1.212 if African 
American), glucose, sodium, potassium, calcium, chloride, total protein, blood urea 
nitrogen and human chorionic gonadotropin (at the Screening Visit and the Week 24/End
of Study/Early Termination Visit for all female subjects of childbearing potential); and
5. 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.
Blood Samples for Potential Analysis of Biomarkers
Exploratory inflammatory biomarkers including C-reactive protein levels, in response to 
pegloticase or other potential treatment for gout may be analyzed. Blood samples for this 
collection will occur on Day 1, Week 14 and Week 24.
Detailed instructions regarding blood sample timing and handling are provided in the Laboratory 
Manual.

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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 questioning 
and/or direct observation. All gout flares will be recorded as adverse events with the required 
AE reporting information. 
9.6.2
Efficacy Variables
Efficacy will be assessed based on measurement of sUA from blood samples. 
Serum Uric Acid
Serum samples for measurement of sUA levels will be collected at the Screening Visit, Week -4
and Week -2 Visits during the MTX Run-in Period; within 48 hours prior to each pegloticase 
infusion (except on Day 1 when only 1 pre-infusion sample is required) and after the end of each 
pegloticase infusion prior to discharge, from the Pegloticase + MTX Period through Week 22;  
and at the at the End of Pegloticase Infusion Visit (if applicable);  at the Week 24/End of
study/Early Termination Visit and Month 3 Visits. 
Two separate samples/tubes of blood will be collected within 48 hours prior to the pegloticase 
infusion for assessment of sUA (except on Day 1 when only 1 pre-infusion sample is required for 
the central laboratory). One sample/tube will be assessed by the site’s local laboratory to be used 
for on-study subject management; pre-infusion sUA results must be reported by the local or 
central laboratory prior to each pegloticase infusion. If a local laboratory sample is drawn 
(within 48 hours prior to the pegloticase infusion), a sample for the central laboratory will be 
drawn prior to the pegloticase infusion on the day of the visit. The second sample/tube will be 
sent to the central laboratory for analysis and recording in the database. Each sample/tube will 
be labelled with the date and time of the sample collection. The date and time of blood sample 
collection will be recorded. See the Laboratory Manual for instructions for alternate scenarios.
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 day of infusion (and not 
within 48 prior to infusion) – at the 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 tested 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. A 
subject with sUA level >6 mg/dL (based on the local or central laboratory) at 2 consecutive study 
visits, beginning with the Week 2 Visit (not including post-infusion samples), will be 
discontinued from pegloticase treatment and remain on study.
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 discontinue.

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9.6.3
Pharmacokinetic Measurements
For all subjects, serum samples for pegloticase PK analysis will be collected approximately 15 
minutes to 2 hours after the end of infusion on Day 1; prior to infusion and approximately 15 
minutes to 2 hours after the end of the infusion at Weeks 2, 6, 12 and 20. An additional PK 
sample will be collected at the End-of-Study (Week 24)/Early Termination Visit. 
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.
9.6.4
Anti-drug Antibody Measurements
Immunogenicity of pegloticase will be assessed via serum samples for evaluation of anti-PEG 
and anti-uricase IgG antibodies. Samples will be collected prior to the pegloticase infusion on 
Day 1 and at the Weeks 2, 6, 12, 20 and the End of study (Week 24)/Early Termination Visit and 
3-month Post-Treatment Follow-up Visits.  In the event of an AE suspected to be an IR, a serum 
sample will be collected at that time or at the subsequent visit for evaluation of pegloticase 
antibodies. 
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.

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9.6.5
MTX Polyglutamate Measurements
Blood samples will be collected prior to pegloticase infusion on Day 1, Weeks 14, 22, End of 
Pegloticase Infusions Visit (if applicable) and 24 Visits during the Pegloticase + MTX Period.
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. 
9.7
Statistical Methods and Determination of Sample Size 
9.7.1
Endpoints
Primary Endpoint
The primary endpoint is the incidence of subjects experiencing IRs (including anaphylaxis) 
related to pegloticase from Day 1 to Week 24 in the cohort chosen to be the most desirable 
duration for infusion.
Secondary Endpoints
The secondary endpoints will be assessed for the cohort chosen to be the most desirable duration 
for infusion and include: 
x
The proportion of Month 6 (Weeks 20, 22 and 24) responders, defined as subjects 
achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 6.
x
The proportion of subjects who experienced any of the following events: IR leading to 
discontinuation of treatment, anaphylaxis, or meeting Individual Subject sUA 
Discontinuation Criteria.
x
Time to any of the following events: IR leading to discontinuation of treatment, 
anaphylaxis, or meeting Individual Subject sUA Discontinuation Criteria (two 
consecutive pre-infusion sUAs > 6 mg/dL.
Exploratory Endpoints

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Pharmacokinetic and Anti-drug Antibody Endpoints
The PK and anti-drug antibody endpoints are: 
x
PK of pegloticase.
x
Incidence and titer of anti-PEG and anti-Uricase IgG antibodies.
Safety Endpoints
Safety endpoints are:
x
Incidence of IRs, anaphylaxis, gout flares, cardiovascular events and the AE/SAE profile 
overall and potentially attributed to the combination of pegloticase and MTX.
x
The proportion of subjects who experienced IR leading to slowing down of the infusion 
rate or discontinuation of treatment.
x
The time to first IR leading to slowing down of the infusion rate or discontinuation of 
treatment.
x
Time to first IR.
x
The proportion of subjects who were able to complete all infusions over the assigned 
treatment duration length or a lesser time, without clinically requiring an increased 
infusion time.
x
The proportion of infusions completed over the assigned duration length or a lesser time, 
without clinically requiring an increased infusion time.
x
Laboratory tests.
x
Vital signs and physical examinations.

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9.7.2
Analysis Sets
The following analysis populations will be defined for this study: 
x
Intent-to-treat (ITT) set: all subjects who take at least one dose of MTX
x
Modified intention-to-treat (mITT) set: all subjects who receive at least 1 dose of 
pegloticase
x
Safety set: all subjects who receive at least 1 dose of pegloticase.   
x
Pharmacokinetic (PK) set: all subjects who receive at least 1 dose of pegloticase and have 
a post-pegloticase sample evaluable for PK analysis
9.7.3
Demographics and Baseline Characteristics 
Demographic data, including age, race and sex, medical history and other disease characteristics, 
will be summarized using descriptive statistics. Summaries of demographic variables will be 
provided for the ITT and mITT populations. Listings will include all screened subjects.
9.7.4
Subject Disposition
The number and percentage of subjects who completed the study and who discontinued the study 
prematurely along with the reasons for discontinuation will be summarized for each analysis set.
In addition, the number and percentage of subjects who completed the pegloticase treatment and 
who discontinued pegloticase treatment prematurely along with the reasons for discontinuation 
will be summarized for each analysis set.
9.7.5
Endpoint Analysis
All efficacy analyses will be performed using the mITT set. Baseline characteristics and safety 
relating to only the MTX Run-in period will be summarized for the ITT set and/or mITT set. All 
safety analyses relating to pegloticase + MTX period will be summarized using the safety set.
Data will be summarized descriptively by assigned infusion duration regimen, unless otherwise 
specified. There will be no statistical testing. 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.
Primary and Secondary Endpoint Analysis
The primary analysis will be performed using the modified intention-to-treat (mITT) population, 
defined as all enrolled subjects who received ≥1 dose of pegloticase. The primary endpoint is 
the incidence of subjects experiencing IRs (including anaphylaxis) related to pegloticase from 
Day 1 to Week 24 in the cohort chosen to be the most desirable duration for infusion (e.g. this 
may be the 30-minute infusion cohort if infusion-speed limiting criteria not met). The proportion 
of subjects with an IR (including anaphylaxis) related to pegloticase will be summarized, along 

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with a 95% exact two-sided (Clopper-Pearson) confidence interval for the proportion. 
Additionally, this endpoint will be analyzed for each of the other infusion duration cohorts.
The proportion of responders during Month 6 will be summarized, along with a two-sided 95% 
exact (Clopper-Pearson) confidence interval for the proportion. A responder is defined as a 
subject for whom the proportion of time that the sUA-time curve is <6 mg/dL during Month 6 
(Weeks 20, 22 and 24) 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 sUA level > 6 mg/dL at 
2 consecutive study visits beginning with the Week 2 Visit.  In addition, a subject who 
withdraws from the study for any reason (other than meeting Individual Subject sUA 
Discontinuation Criteria) after the first dose of pegloticase in the pegloticase + MTX Period and 
prior to or during Month 6 will be considered a non-responder if sUA values are not collected at 
planned timepoints. 
The proportion of subjects experiencing any of the following events: IR leading to 
discontinuation of treatment, anaphylaxis, or meeting Individual Subject sUA Discontinuation 
Criteria (composite endpoint and for each individual component) will be summarized 
descriptively along with a two-sided 95% exact (Clopper-Pearson) confidence interval.
The time to subjects experiencing any of: IR leading to discontinuation of treatment, anaphylaxis 
or meeting Individual Subject sUA Discontinuation Criteria will be analyzed both as a composite 
endpoint and for each individual event. Kaplan Meier (KM) estimates of the time to event will 
be reported along with the corresponding quartiles and two-sided 95% CI for the median time if 
there are sufficient number of events to perform the analysis.
Exploratory Endpoint Analysis
9.7.6
MTX Polyglutamate and Anti-drug Antibody Analysis
Concentrations of pegloticase and MTX polyglutamate will be summarized by time point using 
descriptive statistics for the PK and mITT populations, respectively. 

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Incidence of anti-drug antibodies and titer levels will be summarized. 
9.7.7 Safety Analysis 
Treatment-emergent AEs (TEAEs) during the 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 + 
MTX 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 (whichever is later).  
TEAEs during the MTX Run-in Period will be summarized with the ITT population and TEAEs 
during the Pegloticase + MTX Period will be summarized with both the ITT and mITT 
populations.  TEAEs during any period (MTX Run-in Period or Pegloticase + MTX Period) will 
be summarized for the mITT population.  AEs that occur more than 30 days after the last dose of 
pegloticase and/or MTX through the 3-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 pegloticase 
will also be provided.  SAEs and AEs leading to discontinuation of MTX and pegloticase will be 
presented by system organ class and preferred term. 
Incidence of IRs, gout flares and other AEs of special interest will be summarized.  
The following safety endpoints will be summarized descriptively along with a two-sided 95% 
exact (Clopper-Pearson) confidence interval: 
x The proportion of subjects who experienced IR leading to slowing down of the infusion 
rate or discontinuation of treatment. 
x The proportion of subjects who were able to complete all infusions over the assigned 
treatment duration length or a lesser time, without clinically requiring an increased 
infusion time.  
x 
The proportion of infusions completed over the assigned duration length or a lesser time, 
without clinically requiring an increased infusion time.  
 
The time to subjects experiencing first IR leading to slowing down of the infusion rate or 
discontinuation of treatment, and time to subjects first IR will both be analyzed using Kaplan 
Meier (KM) estimates of the time to event will be reported along with the corresponding 
quartiles and a 95% CI for the median time if there are sufficient number of events to perform 
the analysis. 
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). 

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Vital signs, including BP, 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 Run-in Period and Pegloticase + MTX Period will be summarized separately, 
where applicable. 
9.7.8 Interim Analyses 
Safety data will be summarized at the following milestones for safety and tolerability 
monitoring: 
x After 3 subjects complete at least 3 infusions at one assigned infusion duration level. 
x After 6 subjects complete at least 3 infusions at one assigned infusion duration level. 
x After 10 subjects complete at least 3 infusions at one assigned infusion duration level.  
Enrollment will be paused from the time the 10th subject is enrolled until after the 
analysis results are known. 
x After 15 subjects complete at least 3 infusions at one assigned infusion duration level if 
applicable. 
x After 20 subjects complete at least 3 infusions at one assigned infusion duration level if 
applicable. 
x After all subjects complete at least 3 infusions. 
x Additional safety assessments will be done as needed, for additional subjects enrolled. 
The results of these analyses will determine if enrollment will continue at the present infusion 
duration, or if the assigned duration level should be modified for subsequent subjects.  
Final analysis of all data will occur when all subjects have completed the study (including 
Follow-up visits).   
9.7.9 Sample Size and Power Considerations 
Initially, cohorts of approximately 10 subjects are planned to be enrolled sequentially at 
progressively shorter infusion durations beginning with 60-minute infusion duration, progressing 
down to the 45-minute duration and then to the 30-minute infusion duration. Approximately 110 
subjects are planned to be enrolled into the selected infusion cohort. Therefore, the minimum  
number of subjects enrolling across the 3 different cohorts in the study is approximately 130. 
Based on the MIRROR-RCT study, we expect approximately 5.0% of subjects to have an IR 
(including events of anaphylaxis) when taking pegloticase concurrently with MTX. The sample 
size of 110 for the selected cohort is chosen to ensure a high probability of ruling out an 
unacceptably high IR rate.  If the observed IR rate is 5%, there is a greater than 80% probability 
that the upper bound of the two-sided 95% exact confidence interval for the IR rate is less than 
13%. 

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9.8 
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. 
The Sponsor’s Medical Monitor will consider any requests for exceptions to protocol entry 
criteria on a case-by-case basis.  The Investigator or other health professional in attendance must 
contact the Sponsor as soon as possible.  All protocol deviations and the reasons for such 
deviations must be documented in the eCRF.  In the event of a major protocol deviation, the 
Investigator and Sponsor’s Medical Monitor will determine whether the subject should continue 
to participate in the study. 
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 
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: 
x Medical history/physical condition and diagnosis of the subject before involvement in the 
study sufficient to verify that the subject meets protocol entry criteria.  
x Study number, assigned subject number and verification that written informed consent 
was obtained (each recorded in dated and signed progress notes). 
x Progress notes for each subject visit (each dated and signed). 
x Records of each study visit including each study assessment and the identity of the staff 
member performing the assessment. 
x Study drug dispensing and return. 

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x Review by the Investigator or qualified personnel on the 1572 of laboratory test results. 
x AEs (start and stop date, description, action taken and resolution). 
x Investigator or sub-investigator’s signed assessment of AEs. 
x Concomitant medications (start and stop dates, reason for use). 
x 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, 
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. 

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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 
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 

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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 
Baraf HS, Becker MA, Gutierrez-Urena SR, Treadwell EL, Vazquez-Mellado J, Rehrig CD, 
Ottery FD, Sundy JS, Yood RA.  Arthritis Res Ther. 2013 Sep 26;15(5):R137. doi: 
10.1186/ar4318. PMID: 24286509 
Botson K, Peterson J. Pretreatment and co-administration with methotrexate improved durability 
of pegloticase response: a prospective observational, proof-of-concept, case series.  Poster 
Presentation at American College of Rheumatology Meeting 2018.  Abstract #1286.  
Botson, J.K., et al. (2022), A Randomized Placebo-Controlled Study of Methotrexate to Increase 
Response Rates in Patients with Uncontrolled GOut Receiving Pegloticase (MIRROR RCT): 
Primary Efficacy and Safety Findings. Arthritis Rheumatol. 
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. 
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.  
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]. 
 
Hershfield MS, Ganson NJ, Kelly SJ, Scarlett EL, Jaggers DA, Sundy JS. Induced and 
pre-existing anti‐polyethylene glycol antibody in a trial of every 3 week dosing of pegloticase for 
refractory gout, including in organ transplant recipients. Arthritis Res Ther. 2014;16(2):R63. 

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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):3440. 
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. 
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. 
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, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment 
with multiple doses of pegloticase (polyethylene glycol–conjugated uricase) in patients with 
treatment-failure gout: results of a phase II randomized study. Arthritis Rheum. 2008 
Sep;58(9):2882-91.   
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. 
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. 

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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 
M.D. 
 
Horizon Therapeutics U.S.A., Inc. 
 
Two Tower Place, 12th Floor 
 
South San Francisco, CA  94080 
 
Mobile telephone number
 
 
 
Office number:
 
Email:
 
Sponsor 
 
Representative 
Sr. Study Manager, Clinical Operations 
 
Horizon Therapeutics USA, Inc. 
 
1 Horizon Way 
 
Deerfield, IL 60015 
 
Mobile telephone number:
 
Fax number:
 
Email
 
Sponsor Contact for 
Clinical Safety 
Serious Adverse Event Reporting 
Fax number:  800-860-7836 
 
Email: clinicalsafety@horizontherapeutics.com  
 
 
24-hour Phone Contact for 
Med Communications 
Safety Coverage 
Phone number:   855-479-6742 
 
 
 
 
 
 
 
 
 
 
 
 

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17.4 Polyethylene Glycol-Conjugated Drug List Appendix  
Please refer to this list but understand there may be more Polyethylene Glycol-Conjugated drugs not on 
this list. 
Brand name 
Generic name or Parent protein 
ADAGEN® 
Pegademase bovine 
ONCASPAR® 
Asparaginase 
DOXIL® 
Doxorubicin 
PEGASYS® 
PegInterferon alfa-2a 
PEGINTRON® 
PegInterferon alfa-2b 
SYLATRON® 
PegInterferon alfa-2b 
PLEGRIDY® 
PegInterferon beta-1a 
NEULASTA® 
Pegfilgrastim 
MACUGEN® 
Pegaptanib  
MIRCERA® 
Epoietin beta 
OMONTYS® 
Peginesatide 
SOMAVERT® 
Pegvisomant 
CIMZIA® 
Certolizumab pegol 
KRYSTEXXA® 
Pegloticase 
MOVANTIK® 
Naloxegol 
ADYNOVATE® 
Factor VIII 
JIVI® 
Factor VIII 
REBINYN® 
Coagulation Factor IX 
PALYNZIQ® 
Pegvaliase-pqpz 
ONIVYDE® 
Irinotecan liposome