Clinical trial NCT04772313
Conditions: Uncontrolled Gout
Keywords: Gout
Sponsor: Amgen
Start date: 2021-03-08; Completion date: 2023-04-24
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 4, multicenter, open-label trial of pegloticase with methotrexate (MTX) in adult participants with uncontrolled gout who were previously treated with pegloticase without a concomitant immunomodulator and stopped pegloticase due to failure to maintain serum uric acid (sUA) response and/or a clinically mild infusion reaction (IR). Approximately 30 participants will be enrolled. Pegloticase + MTX will be administered for approximately 24 weeks, with an optional extension up to 48 weeks.

The trial design will include 5 distinct components:

1. Screening Period, lasting up to 42 days;
2. 6-week MTX Tolerability Assessment Period (hereafter referred to as the MTX Run-in Period);
3. 24-week Pegloticase + MTX Treatment Period, which will include a Week 24/End of Trial/Early Termination Visit (subjects that end MTX and pegloticase treatment prior to the Week 24 will remain on trial for follow up until the Week 24 visit)
4. Optional Pegloticase + MTX Extension Period up to 24 weeks
5. 30-Day Post Treatment Follow -up

Detailed description:
All participants who meet eligibility criteria at Screening will begin once-weekly subcutaneous (SC) MTX Run-in period. Participants must be able to tolerate MTX at a minimum dose of 15 mg during the 6-week MTX Run-in Period to be eligible to participate in the Pegloticase + MTX Treatment Period.

All participants who meet the inclusion/exclusion criteria and complete the MTX Run-in Period will be considered enrolled participants. During the Pegloticase + MTX Treatment Period, pegloticase 8 mg will be administered IV every 2 weeks and MTX SC weekly.

Two sequential cohorts of participants will be enrolled in this trial. Cohort 1 is targeted to enroll 10 participants who previously failed to maintain sUA response with pegloticase monotherapy and stopped pegloticase treatment without a history of pegloticase-related infusion reaction.

If the safety assessment during Cohort 1 indicates that the pegloticase infusions are well tolerated, then the trial can begin enrolling Cohort 2 for 20 participants who failed to maintain sUA response with pegloticase monotherapy with or without a history of pegloticase-related clinically mild IRs.

Study acquired from Horizon in 2024.

Arms: arm 1: Pegloticase (8 mg) intravenous (IV) every two weeks. Methotrexate (15 or 25 mg weekly) SC.
Interventions: intervention 1: Pegloticase intervention 2: Methotrexate (MTX)
Intervention descriptions: intervention 1: Participants will receive pegloticase with MTX for up to 24 weeks during the treatment period. Participants may opt to receive pegloticase with MTX for an additional 24 weeks. intervention 2: Participants will receive MTX during the run-in period then pegloticase with MTX for up to 24 weeks during the treatment period. Participants may opt to receive pegloticase with MTX for an additional 24 weeks.

Protocol documents:
Prot_000.pdf: 
Horizon Therapeutics Ireland DAC
KRYSTEXXA® IND: 010122
Date: 02 May 2022
Protocol: HZNP-KRY-407
Version 2.0, amendment 1, admin change1
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC
Page 1 of 168
CLINICAL TRIAL PROTOCOL 
FOR PEGLOTICASE
IND: 010122
Protocol Number: HZNP-KRY-407
Version 2.0, Amendment 1.0, Administrative Change 1.0
A Phase 4, Multicenter, Open-label, Efficacy and Safety Trial of Pegloticase 
and Methotrexate Co-administered in Patients with Uncontrolled Gout who 
have Previously Received Pegloticase Monotherapy but did not Maintain a 
Serum Uric Acid Response (ADVANCE)
Date: 02 May 2022
Sponsor:
Horizon Therapeutics Ireland DAC
Dublin 2 Ireland D02 E2X4
This protocol is the confidential information of Horizon Therapeutics Ireland DACand 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: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 2 of 168 
 
PROTOCOL 
1 
TITLE PAGE 
Trial Title: A Phase 4, Multicenter, Open-label, Efficacy and Safety Trial of 
Pegloticase and Methotrexate Co-administered in Patients with 
Uncontrolled Gout who have Previously Received Pegloticase 
Monotherapy but did not Maintain a Serum Uric Acid Response  
(ADVANCE)  
Protocol Number: HZNP-KRY-407 
 
Version: 2.0, Amendment 1.0, Administrative Change 1.0  
Investigational Products: Pegloticase (recombinant modified mammalian urate oxidase 
[uricase]); methotrexate (MTX) 
Indication: Chronic gout in adult patients refractory to conventional therapy 
Sponsor: Horizon Therapeutics Ireland DAC 
 
Dublin 2 Ireland D02 E2X4 
Development Phase: 4 
 
Medical Officer: 
  
 
Horizon Therapeutics U.S.A., Inc. 
Two Tower Place, 12th Floor  
South San Francisco, CA 94080 
 
 
Sponsor Signatory: 
 
Horizon Therapeutics U.S.A., Inc. 
Two Tower Place, 12th Floor  
South San Francisco, CA 94080 
 
Approval Date: 02 May 2022 
 
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 trial, 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 contacts provided below. 
Fax: 
 
Email: 
clinicalsafety@horizontherapeutics.com 
PPD
PPD
PPD




Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 4 of 168 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number:  
HZNP-KRY-407 
Version: 
2.0, Amendment 1.0, administrative change 1 
, Protocol Title:  
A Phase 4, Multicenter, Open-label, Efficacy and Safety Trial of 
Pegloticase and Methotrexate Co-administered in Patients with 
Uncontrolled Gout who have Previously Received Pegloticase 
Monotherapy but did not Maintain a Serum Uric Acid Response 
(ADVANCE)       
Version Date: 
 02 May 2022 
I agree to conduct the trial 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 trial drug supplied by the Sponsor will be used only as described in the protocol 
named above. 
Signature: 
 
 
 
 
 
 
 Name  
Trial Center 
Address 
City State Country 
 
 
 
 
Date 
 
 




Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 6 of 168 
 
All trial sites and subjects will be provided 
with FDA-approved handheld sUA devices to 
measure subject uric acid levels based on 
capillary samples. Results will be collected in 
the eCRF at non-infusion visits and pre- and 
post-infusion during pegloticase infusion visits. 
Subjects may also use the device to measure 
uric acid at home. Results will be collected for 
exploratory uses only. No in-trial treatment 
decisions will be made based upon the data 
generated with the handheld device. 
In addition, user experience by Investigators or 
patients will be assessed by a uric acid device 
questionnaire at the Week 6, Week 12 and 
Week 24/End of Trial/Early Termination 
Visits.  
 
Section 9.5 Trial Procedures Day 1 and all 
subsequent visits 
If handheld uric acid device is provided, 
measure blood uric acid level at the same time 
point as blood sample collection for central 
laboratory sUA analysis.  
 
Text removed 
Reason as above 
Section 9.5 Trial Procedures Day 1 , Week 4, 
6, 8, 12, 14, 32,34, 44, 46 
If handheld uric acid device is provided, 
measure blood uric acid level after the end of 
the pegloticase infusion (at least 1-hour post 
infusion) prior to discharge from the site.  
 
Text removed 
Reason as above 
Section 9.5 Trial Procedures.     Post infusion 
Day 1  Week 12 
If handheld uric acid device is provided, 
measure blood uric acid level at the same time 
point as blood sample collection for central 
laboratory sUA analysis.  
 
Text removed 
Reason as above 
Sponsor Contact for DECT imaging BioClinica 
 
Clario 
 
Vendor name change 










































Horizon Therapeutics Ireland DAC
KRYSTEXXA® IND: 010122
Date: 02 May 2022 
Protocol: HZNP-KRY-407 
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2. 
During the MTX Run-in Period, subjects with 
45 mL/min/1.73 m2 will inject SC MTX weekly at a starting dose of 15 mg at Weeks -6 and Week -5 increasing to 
25 mg at Week -4 and continuing 
45 mL/min/1.73 m2 will inject SC MTX at a starting dose of 10 mg at Week -6 
and Week -5 increasing to 15 mg at Week -4 and continuing weekly throughout the trial; subjects unable to tolerate the 15 mg dose of MTX will be considered MTX Run-in 
Screen Failures. If a subject becomes unable to tolerate MTX at 25 mg doses, the folic acid dose may be increased from 1 to 2 mg/day and/or the MTX dosage may be 
decreased to 20 or 15 mg, but to no less than 15 mg. Subjects who are unable to tolerate MTX at a minimum dose of 15 mg during the Run-in Period regardless eGFR will be 
considered MTX Run-in Screen Failures. 
3. 
Subjects will be enrolled at the Day 1 Visit to receive pegloticase 8 mg IV every 2 weeks from Day 1 through Week 22, inclusive. During this 24-week Pegloticase + MTX 
Treatment Period, subjects who meet the Individual Subject sUA Discontinuation Criteria or discontinue treatment for another reason will remain in the trial for biweekly 
visits, including the Week 24/End of Trial/ET and 30-Day Post-Treatment Follow-up Visits.  
4. 
Prior to Week 22, subjects who end treatment due to sUA level or other reasons should complete the End of Pegloticase Visit within 2 weeks of the last infusion and continue 
with trial procedures without infusion. Subjects will also complete all regularly scheduled Follow-up Visits, including the 30-Day Post-Treatment Follow-up email/phone call 
and Week 24/End of Trial/ET Visits. 
5. 
The Investigator or designee will collect a complete gout history, 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 screening visit, substance use history and all other 
medications up to the screening visit. Prior medications (not including gout medications and pegloticase) will be collected for 1 year prior to the screening visit. Detailed 
pegloticase use history, including reason for discontinuation and associated reactions, if any, will be collected.  
7. 
A complete physical examination, including assessment of head, eyes, ears, nose and throat; heart; lungs; abdomen; skin; extremities; neurological status and musculoskeletal 
system, including an assessment for the presence of 
 as well as gout history and symptom severity, will be performed at the Screening Visit. A targeted physical 
examination per Investigator judgement will be conducted at all other indicated time points. On days when pegloticase is administered, the examination is conducted prior to 
pegloticase administration. At a minimum, the targeted physical examination should include assessment of heart, lungs and abdomen. Clinically significant findings from the 
targeted physical examinations will be recorded as AEs.  
8. 
Routine vital signs, including blood pressure, respiratory rate, temperature and heart rate, will be measured. Heart rate and blood pressure measurements should be taken after 
the subject has been in a sitting position in a rested and calm state with proper positioning, including back support and feet flat on the floor, for at least 5 minutes. The 
subject s arm should be supported at heart level and the 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 trial visit. The Korotkoff phase V will be used to determine diastolic blood pressure. During the Pegloticase + MTX Treatment Period visits, vital signs should be 
om the site. Height will be collected at the Screening 
Visit only. 
9. 
Weight should be measured in kilograms or pounds when the subject is not wearing shoes. On days when pegloticase is administered, weight should be recorded prior to 
pegloticase administration.  
10. Electrocardiogram should be completed during Screening and will be read at the site. When possible, a 12-lead electrocardiogram will also be performed at the time when a 
select AE of special interest (IR, anaphylaxis and major adverse cardiovascular event, defined as non-fatal stroke, non-fatal myocardial infarction, cardiovascular death and 
congestive heart failure) is suspected. 
11. AEs/SAEs will be collected from the signing of the informed consent form until the 30-Day Post-Treatment Follow-up Visit. For each AE, the Investigator will be asked to 
record if the event was possibly an IR or anaphylaxis and if so, will be prompted to complete additional electronic case report forms. Females of childbearing potential will be 
asked to confirm if ovulation has occurred since the last dose of MTX. If the subject had not ovulated, a urine pregnancy test will be required.  
12. The initial DECT scan will be performed after the Screening Visit, during the MTX Run-in Period and prior to the Day 1 Visit. Subsequent DECT scans may be performed 
±10 days from the scheduled visit date. Subjects who end pegloticase infusions prior to Week 24 should follow the scheduled time points and have a DECT scan at the End of 
Pegloticase (if applicable) and Week 24/End of Trial/ET Visits (detailed guidance is provided within the Imaging Manual). DECT will be carried out for all subjects where 
the site has the capability to conduct the test. 
13. MTX will be dispensed and brought back to check compliance at each infusion visit. MTX should be injected 1 to 3 days prior to each pegloticase infusion; however, if a 
 
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Date: 02 May 2022 
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14. Subjects will take folic acid at a starting dose of 1 mg orally every day beginning Week -6 (preferably 2 days prior to the first dose of MTX) continuing until prior to the End 
of Pegloticase (if applicable) or until 1 week after the last pegloticase infusion for subjects who have not stopped pegloticase treatment. The folic acid dose can be increased 
or an alternative folate supplement can be used (see Section 9.4.6.3.2.2 for detailed instructions). 
15. Before a subject begins the Pegloticase + MTX Treatment Period, he or she must have been taking at least 1 standard gout flare prophylaxis regimen (i.e., colchicine and/or 
NSAIDs and/or low-dose prednisone 10 mg/day) per protocol for 
s per 
American College of Rheumatology guidelines (FitzGerald et al, 2020). Gout flare prophylaxis from Week 26 to the end of the trial will be administered, if needed, at the 
discretion of the Principal Investigator.  
16. IR prophylaxis includes fexofenadine (180 mg orally) and prednisone (50 mg orally) administered the night before each infusion; fexofenadine (180 mg orally), famotidine 
(20 mg orally), montelukast (10 mg orally) and acetaminophen (1000 mg orally) administered on the morning of each pegloticase infusion and methylprednisolone (125 mg 
IV) over an infusion duration between 10 and 30 minutes, prior to each pegloticase infusion.  
17. 
 
 
  
18. Serum samples for evaluation of 
 will be collected prior to the first dose of MTX at Week -6, prior to 
pegloticase infusion on Day 1 and at Weeks 2, 6, 14, 22 and 36; and at the non-infusion End of Pegloticase (if applicable) or the Week 24 or 48/End of Trial/ET Visit. 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 measurement of sUA levels will be collected at the Screening, Week -6 (prior to the first dose of MTX) and Week -2 Visits. On Day 1, a pre- and 
post-infusion sUA will be collected to be shipped to the central laboratory. For the remainder of trial visits beginning at Week 2 during the Pegloticase +MTX Treatment 
Period, 2 sUA samples will be collected within 48 hou
sample will be sent to the central laboratory (the central laboratory sample may be drawn separately from the local collection). Additional serum samples for sUA levels will 
be collected after the end of each pegloticase infusion prior to discharge at Weeks 10, 12, 14, 20, 22, 32, 34, 44 and 46. Single serum samples for measurement of sUA will 
also be collected at non-infusion visits at Weeks 21 and 23 and at the End of Pegloticase (if applicable) or the Week 24 or 48/End of Trial/ET Visit. Serum for sUA analysis 
will also be collected following the first 7 pegloticase infusions (Infusion 1, 2, 3, 4, 5, 6 and 7) at Day 1, Weeks 2, 4, 6, 8, 10 and 12, respectively. The sUA will be collected 
at the following non-infusion days:  1st (~24 hours), 4th (~96 hours), 7th (~168 hours) and 10th (~240 hours) day after each of the first 4 infusions, and 1st (~24 hours), and 7th 
(~168 hours) day after each infusion number 5, 6, 7.  If infusion intervals of less than 2 weeks should occur due to scheduling issues the 1st day (~24hours) samples must be 
obtained at a minimum and also the 7th day (~168 hours) if feasible. 
20.  
21. G6PD testing should be performed by the central laboratory; however, if performed by the local laboratory, normal ranges should be provided.  
22. Optional serum and urine samples will be collected from each consenting subject prior to the first dose of MTX at Week -6, prior to pegloticase infusion on Day 1 and at 
Weeks 14, 24, 36 and the End of Pegloticase (if applicable) and Week 24 or 48/End of Trial/ET Visits. 
23. For women of childbearing potential, a serum pregnancy test will be performed at the Screening Visit. A urine pregnancy test will be performed at the End of Pegloticase (if 
applicable), Week 24 or 48/End of Trial/ET and 30 days after the last MTX dose if it is determined that the subject has not ovulated; a urine pregnancy test will be performed 
prior to MTX dosing during the MTX Run-in Period and prior to each pegloticase infusion at all other indicated visits. 
24. 
 
 
25. Thirty (30) days after the last MTX dose or pegloticase infusion (whichever is later), subjects will be contacted by telephone or email to review AEs, SAEs and concomitant 
medications. 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. 
26. Male subjects who are non-vasectomized will be asked 3 months after MTX discontinuation regarding partner pregnancy.  
 
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KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 2 
2 
SYNOPSIS .............................................................................................................................. 7 
2.1 
Schedule of Assessments ............................................................................................... 19 
3 
TABLE OF CONTENTS ...................................................................................................... 29 
4 
LIST OF ABBREVIATIONS ............................................................................................... 36 
5 
ETHICS ................................................................................................................................. 38 
5.1 
Institutional Review Board/Independent Ethics Committee .......................................... 38 
5.2 
Ethical Conduct of the Trial ........................................................................................... 38 
5.3 
Subject Information and Consent ................................................................................... 38 
5.4 
Compensation for Health Damage of Subjects/Insurance .............................................. 39 
5.5 
Confidentiality ................................................................................................................ 39 
6 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ............................. 40 
7 
INTRODUCTION ................................................................................................................ 41 
7.1 
Background .................................................................................................................... 41 
7.1.1 
Gout......................................................................................................................... 41 
7.1.2 
Pegloticase .............................................................................................................. 41 
7.1.2.1 
 .................................................................................... 43 
7.1.2.2 Nonclinical Pharmacology .................................................................................... 44 
7.1.2.3 Nonclinical Pharmacokinetics .............................................................................. 44 
7.1.2.4 Toxicology ............................................................................................................ 44 
7.1.2.5 Clinical Pharmacokinetics .................................................................................... 45 
7.1.2.6 Risks of Pegloticase .............................................................................................. 45 
7.1.3 
Methotrexate Overview and Risks .......................................................................... 46 
7.2 
Rationale for This Trial .................................................................................................. 47 
7.3 
Rationale for Dose Selection .......................................................................................... 48 
7.3.1 
Pegloticase Dose Selection ..................................................................................... 48 
7.3.2 
Methotrexate Dose Selection .................................................................................. 48 
8 
TRIAL OBJECTIVES .......................................................................................................... 50 
9 
INVESTIGATIONAL PLAN ............................................................................................... 52 
9.1 
Overall Trial Design and Plan ........................................................................................ 52 
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9.2 
Discussion of Trial Design ............................................................................................. 56 
9.3 
Selection of Trial Population ......................................................................................... 56 
9.3.1 
Inclusion Criteria .................................................................................................... 56 
9.3.2 
Exclusion Criteria ................................................................................................... 57 
9.3.3 
Removal of Subjects From Therapy or Trial .......................................................... 59 
9.3.3.1 Removal of Subjects From Pegloticase Therapy .................................................. 59 
9.3.3.1.1 Trial Considerations for Subjects Ending Pegloticase Infusions Prior to 
Week 24 or Week 48 ................................................................................ 60 
9.3.3.2 Removal of Subjects From Trial ........................................................................... 60 
9.3.4 
Replacement Policy ................................................................................................ 61 
9.3.4.1 Subjects ................................................................................................................. 61 
9.3.4.2 Centers .................................................................................................................. 61 
9.3.4.3 Screen Failures ...................................................................................................... 61 
9.4 
Treatments ...................................................................................................................... 61 
9.4.1 
Treatments Administered ........................................................................................ 61 
9.4.1.1 Methotrexate ......................................................................................................... 61 
9.4.1.2 Pegloticase ............................................................................................................ 62 
9.4.1.3 Folic Acid.............................................................................................................. 63 
9.4.1.4 Gout Flare Prophylaxis ......................................................................................... 64 
9.4.1.5 Infusion Reaction Prophylaxis .............................................................................. 64 
9.4.2 
Identity of Investigational Products ........................................................................ 64 
9.4.2.1 Pegloticase ............................................................................................................ 64 
9.4.2.2 Methotrexate ......................................................................................................... 65 
9.4.3 
Labeling .................................................................................................................. 65 
9.4.4 
Storage .................................................................................................................... 65 
9.4.5 
Drug Accountability................................................................................................ 65 
9.4.6 
Trial Drug Administration and Timing of Dose for Each Subject .......................... 66 
9.4.6.1 Description of Clinical Supplies ........................................................................... 66 
9.4.6.2 Determination of Dose Volume ............................................................................ 66 
9.4.6.3 Details Concerning Timing and Dose Administration.......................................... 66 
9.4.6.3.1 Preparation ..................................................................................................... 66 
9.4.6.3.2 Dose Modifications, Interruptions and Delays .............................................. 67 


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KRYSTEXXA® IND: 010122 
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9.4.7 
Method of Assigning Subjects to Treatment Groups .............................................. 70 
9.4.8 
Blinding................................................................................................................... 70 
9.4.9 
Prior and Concomitant Therapy .............................................................................. 70 
9.4.9.1 Gout Flare Treatment ............................................................................................ 71 
9.4.9.2 Infusion Reaction Treatment................................................................................. 71 
9.4.10 
Restricted Medications............................................................................................ 72 
9.4.11 
Treatment Compliance ............................................................................................ 73 
9.4.12 
Contraception Requirements ................................................................................... 73 
9.5 
Efficacy, Quality-of-Life, 
 and Safety Variables ................................ 74 
9.5.1 
Efficacy Variables ................................................................................................... 74 
9.5.1.1 Serum Uric Acid ................................................................................................... 74 
9.5.1.2 Dual-energy Computed Tomography ................................................................... 75 
9.5.1.3 
 .......................................................................................................... 75 
9.5.1.4 
 ............................................................................... 75 
9.5.1.5 
 .................................................................................... 76 
9.5.1.6 Health Assessment Questionnaire......................................................................... 76 
9.5.1.7 
 ........................................................... 76 
9.5.2 
 ................................................................................... 77 
9.5.2.1 
 ...................................... 77 
9.5.2.2 
 ....................................................................................................... 77 
9.5.2.3 
 ........................... 78 
9.5.3 
 ...................................... 78 
9.5.3.1 Additional Sample Collection for Future Use ...................................................... 78 
9.5.4 
Safety Variables ...................................................................................................... 79 
9.5.4.1 Adverse Events ..................................................................................................... 79 
9.5.4.1.1 Definitions ..................................................................................................... 79 
9.5.4.1.2 Documentation of Adverse Events ................................................................ 84 
9.5.4.1.3 Intensity of Adverse Events ........................................................................... 84 
9.5.4.1.4 Relationship to Trial Drug ............................................................................. 84 
9.5.4.1.5 Reporting and Documenting SAEs and Product Complaints ........................ 85 
9.5.4.1.6 Follow-up of Adverse Events ........................................................................ 86 
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KRYSTEXXA® IND: 010122 
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9.5.4.1.7 Medication Error and Overdose .................................................................... 86 
9.5.4.1.8 Review of Adverse Events and Emerging New Safety Information ............. 86 
9.5.4.1.9 Reporting of Investigational New Drug Safety Reports ................................ 86 
9.5.4.1.10 Development Safety Update Reports ........................................................ 86 
9.5.4.2 Pregnancy Reporting ............................................................................................. 86 
9.5.4.3 Medical History .................................................................................................... 87 
9.5.4.4 Vital Signs, Height and Weight ............................................................................ 87 
9.5.4.5 Physical Examinations .......................................................................................... 88 
9.5.4.6 Electrocardiogram ................................................................................................. 88 
9.5.4.7 Clinical Laboratory Safety Tests .......................................................................... 89 
9.5.4.8 Assessment of Gout Flare ..................................................................................... 90 
9.5.5 
Safety Review Team ............................................................................................... 90 
9.5.6 
Adjudication Committee ......................................................................................... 90 
9.5.7 
Appropriateness of Measurements .......................................................................... 90 
9.5.8 
Trial Procedures ...................................................................................................... 90 
9.5.8.1 Screening Visit (Within 42 Days Prior to the First Dose of MTX at Week -6) ... 90 
9.5.8.2 MTX Run-in Period .............................................................................................. 92 
9.5.8.2.1 Week -6 .......................................................................................................... 92 
9.5.8.2.2 Week -4 .......................................................................................................... 93 
9.5.8.2.3 Week -2 .......................................................................................................... 93 
9.5.8.3 Pegloticase + MTX Treatment Period .................................................................. 94 
9.5.8.3.1 Day 1.............................................................................................................. 94 
9.5.8.3.2 Week 2 ........................................................................................................... 96 
9.5.8.3.3 Week 4 ........................................................................................................... 98 
9.5.8.3.4 Week 6 ......................................................................................................... 100 
9.5.8.3.5 Week 8 ......................................................................................................... 102 
9.5.8.3.6 Week 10 ....................................................................................................... 104 
9.5.8.3.7 Week 12 ....................................................................................................... 105 
9.5.8.3.8 Week 14 ....................................................................................................... 107 
9.5.8.3.9 Week 16 ....................................................................................................... 109 
9.5.8.3.10 Week 18 .................................................................................................. 110 


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9.5.8.3.11 Week 20 .................................................................................................. 111 
9.5.8.3.12 Week 21 .................................................................................................. 112 
9.5.8.3.13 Week 22 .................................................................................................. 113 
9.5.8.3.14 Week 23 .................................................................................................. 114 
9.5.8.3.15 Week 24/1st Infusion of Optional Pegloticase + MTX Extension 
Period ...................................................................................................... 115 
9.5.8.4 End of Pegloticase Visit ...................................................................................... 117 
9.5.8.5 Optional Pegloticase + MTX Extension Period Visits After Week 24 - Subjects 
Who May Gain Further Benefit Beyond 12 Infusions ........................................ 118 
9.5.8.5.1 Week 26 ....................................................................................................... 118 
9.5.8.5.2 Week 28 ....................................................................................................... 120 
9.5.8.5.3 Week 30 ....................................................................................................... 121 
9.5.8.5.4 Week 32 ....................................................................................................... 123 
9.5.8.5.5 Week 34 ....................................................................................................... 124 
9.5.8.5.6 Week 36 ....................................................................................................... 126 
9.5.8.5.7 Week 38 ....................................................................................................... 128 
9.5.8.5.8 Week 40 ....................................................................................................... 129 
9.5.8.5.9 Week 42 ....................................................................................................... 130 
9.5.8.5.10 Week 44 .................................................................................................. 132 
9.5.8.5.11 Week 46 .................................................................................................. 133 
9.5.8.6 Week 24 or 48/End of Trial/Early Termination Visit ......................................... 134 
9.5.8.7 30-Day Post-Treatment Follow-up Phone/Email Visit ....................................... 136 
9.5.8.8 MTX Partner Pregnancy Follow-up.................................................................... 136 
9.6 
Statistical Methods and Determination of Sample Size ............................................... 136 
9.6.1 
Endpoints .............................................................................................................. 136 
9.6.1.1 Primary Endpoint ................................................................................................ 136 
9.6.1.2 Secondary Endpoints .......................................................................................... 136 
9.6.1.3 Exploratory Endpoints ........................................................................................ 137 
9.6.1.4 
 Endpoints ......................................... 137 
9.6.1.5 Safety and Tolerability Endpoints ...................................................................... 137 
9.6.2 
Analysis Sets ......................................................................................................... 138 
9.6.3 
Demographic Variables ........................................................................................ 138 
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9.6.4 
Subject Disposition ............................................................................................... 138 
9.6.5 
Efficacy Analysis .................................................................................................. 138 
9.6.5.1 Primary and Secondary Endpoint Analysis ........................................................ 138 
9.6.5.2 Exploratory Endpoint Analysis ........................................................................... 139 
9.6.6 
 ............................................. 139 
9.6.7 
Safety Analysis ..................................................................................................... 140 
9.6.8 
Interim Analyses ................................................................................................... 140 
9.6.9 
Sample Size and Power Considerations ................................................................ 141 
9.7 
Changes in the Conduct of the Trial............................................................................. 141 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES ..................................... 142 
11 CASE REPORT FORMS ................................................................................................... 143 
12 TRIAL MONITORING ...................................................................................................... 144 
13 DATA MANAGEMENT .................................................................................................... 145 
14 RETENTION OF RECORDS ............................................................................................. 146 
15 PUBLICATION .................................................................................................................. 147 
16 REFERENCES ................................................................................................................... 148 
17 APPENDICES .................................................................................................................... 152 
17.1 Administrative Appendix ............................................................................................. 152 
17.2 Health Assessment Questionnaire (Disability Index, Pain and Health Scales) ............ 153 
17.3 
 ........................................................................................... 157 
17.4 
....................................................................................... 158 
17.5 
 ............................................................ 159 
17.6 
 .............................................................................................................. 161 
17.7 
 .................................. 162 
17.8 
 .................................................................. 165 
17.9 Infusion Reaction and Anaphylaxis Assessment Guidance ......................................... 166 
17.10 Polyethylene Glycol-Conjugated Drug List ................................................................. 168 
 
LIST OF TABLES 
Table 6.1 
Table of Non-Sponsor Trial Responsibilities ............................................................ 40 
Table 9.1 
Sample Pegloticase Infusion Rate Modification Following an Infusion Reaction .... 67 
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Table 9.2 
Methotrexate Dose Guidance Based on New Laboratory Findings or New 
Symptoms .................................................................................................................. 69 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Trial Design ......................................................................................... 55 






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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 trial documentation to be used in this trial 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, applicable trial 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 
trial. A copy of the approved ICF will also be forwarded to the Sponsor or its designee. 
Appropriate reports on the progress of the trial 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 Trial 
The Investigators will ensure that this trial 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 subject. The trial 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, 
,
,
.  
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 trial 
after adequate explanation of the aims, methods, anticipated benefits and potential hazards of the 
trial. 
The Investigator or designee must also explain that the subjects are completely free to refuse to 
enter the trial 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 
there is an amendment to the protocol that necessitates a change to the content of the subject 
information and/or the 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 trial by signing the revised 
ICF. Any revised ICF and written information must receive the IRB`s approval/favorable 
opinion before use. 


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All signed ICFs are to remain in the Investigator  site file or, if locally required, in the subject  
notes/files of the medical institution. 
The electronic case report forms (eCRFs) for this trial 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 sign the revised ICF.  
5.4 
Compensation for Health Damage of Subjects/Insurance 
The Sponsor maintains clinical trial insurance coverage for this trial in accordance with the laws 
and regulations of the country in which the trial 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. Trial findings stored in a computer will be 
stored in accordance with local data protection laws. As part of the informed consent process, the 
subjects will be informed in writing that representatives of the Sponsor, IRB or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
If the results of the trial 
emain 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 trial complies with the federal and/or regional legislation related to the privacy 
and protection of personal information (Health Insurance Portability and Accountability Act).  


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6 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
The Sponsor of this trial is Horizon Therapeutics Ireland DAC (Horizon). Horizon personnel will 
serve as the Medical Monitor 
 Appendix 17.1 for 
details). 
serious adverse events (SAEs) to regulatory authorities, as required. The Sponsor will be 
responsible for timely reporting of SAEs and any other new pertinent safety information to all 
Investigators, as required. 
The trial will be conducted at approximately 10 to 15 trial sites in the United States. Prior to 
initiation of the trial, 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 trial and the 
1-year period following its completion. 
Table 6.1 lists organizations that are critical to the conduct of the trial, with a brief description of 
their roles: 
Table 6.1 
Table of Non-Sponsor Trial Responsibilities 
Trial Responsibility 
Organization 
Clinical drug supply and distribution 
PCI Pharma Services 
Central safety laboratory 
LabCorp Central Laboratory Services 
Clinical Research Organization 
LabCorp Drug Development Inc. 
External Adjudication Committee  
WIRB-Copernicus Group Inc. 
Central imaging vendor 
BioClinica, Inc. 
 


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7 
INTRODUCTION 
7.1 
Background 
7.1.1 Gout 
Gout affects approximately 4% of the United States population, is the most common form of 
inflammatory arthritis in men and is associated with decreased quality of life (Saag and Choi, 
2006; Singh and Strand, 2008; Zhu et al, 2011; Sattui et al, 2014). The frequency of gout is 
increasing worldwide, with prevalence rates estimated to be as high as 7% in older men 
(Mikuls et al, 2005; Saag and Choi, 2006; Roddy and Doherty, 2010). While the exact 
prevalence is unknown, as many as 200,000 persons in the United States experience chronic 
symptoms of gout, despite trials of oral urate-lowering therapy. Uncontrolled 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) (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 
(Orphan Drug Act [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 trials for pegloticase were undertaken to establish the efficacy and 
safety of the product. The primary endpoint was defined as plasma uric acid (highly correlated to 
sUA) reduction to <6 mg/dL for 80% of the time in Months 3 and 6 combined. The pooled 
response rate for pegloticase 8 mg every 2 weeks was 42%, versus a placebo response rate of 0% 
(Sundy et al, 2011). There was also a greater reduction in 
us in the 
every 2 weeks treatment group, and favorable effect of pegloticase treatment in the reduction of 
the number of tender and swollen joints. In subsequent open-label extension trials, pegloticase 
led to continued control of plasma uric acid, reduction in gout flares and continued resolution of 
tophi, suggesting continuing benefit with extended pegloticase treatment beyond the initial 
6 months of therapy, particularly in subjects who met responder criteria in the placebo-controlled 
trials. 
In the Phase 3 pivotal trials, deaths, SAEs, other adverse events (AEs), as well as the laboratory 
abnormalities were generally equally distributed across placebo and pegloticase treatment 
groups, with the clear exception of gout flares and infusion reactions (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 compared with 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 


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22/85 (26%) of subjects receiving the 8 mg every 2 weeks regimen. There was no specified 
definition of anaphylaxis in the Phase 3 protocols and no investigator-reported events of 
anaphylaxis in the Phase 3 trials with pegloticase. However, in a post hoc review applying the 
National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis 
Network 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 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 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 >6 mg/dL. Retrospective analyses showed that the loss of urate-lowering efficacy, as 
reflected by sUA of >6 mg/dL, preceded a subject
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 et al, 2015).  
Because of the limited treatment options for patients with uncontrolled gout, immunomodulators 
have been co-administered with pegloticase in an effort to prevent anti-drug antibody formation 
and increase the length of effective pegloticase therapy, similar to what is done in other 
rheumatic diseases treated with biologics (Krieckaert et al, 2012; Lie et al, 2015). The successful 
use of immunomodulators (MTX, azathioprine, leflunomide and cyclosporine) with pegloticase 
in patients who receive pegloticase treatment for the first time is supported by case reports that 
examined different immunomodulatory agents with varying doses, schedules and routes given 
prior to the start of pegloticase (Hershfield et al, 2014; Berhanu et al, 2017; Freyne 2018; 
Albert et al, 2019; Botson and Peterson, 2019; Bessen et al, 2019a; Bessen et al, 2019b; 
Rainey et al, 2020; Masri et al, 2020). In case reports of MTX with pegloticase, the proportion of 
responders (based on each case
 patients) (Botson and Peterson, 
2019), 100% (7/7 patients) (Bessen et al, 2019a; Bessen et al, 2019b) and 80% (8/10 patients) 
(Albert et al, 2019); these responder rates are higher than the 42% rate observed in early Phase 3 
clinical trials of pegloticase alone (Sundy et al, 2011). Similar to results of case studies, a recent 
prospective open-label clinical trial reported that a high proportion of subjects treated 
concomitantly with MTX (oral 15 mg/week started 4 weeks prior to the first pegloticase dose 
and throughout the pegloticase treatment period) maintained therapeutic response to pegloticase 
at 6 months (79% [11/14]) (Botson et al, 2020).  




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7.1.2.2 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 
 
In addition, in nonclinical toxicity studies in which uric acid levels were measured, a decline in 
uric acid levels following administration of pegloticase (all pegloticase doses associated with 
these studies) was observed. 
7.1.2.3 Nonclinical Pharmacokinetics 
A series of pharmacokinetic (PK) trials was conducted in rats, rabbits, dogs and pigs to 
determine the circulation half-life and bioavailability of pegloticase administration as a function 
of the route of administration. Plasma pegloticase levels were determined by assaying uricase 
bioactivity in plasma. As part of the PK trials, antibody levels in plasma were determined 
2 weeks after the last injection in the rabbit, dog and rat. Collectively, the results of the PK trials 
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.  
7.1.2.4 Toxicology 
The results from acute and chronic toxicity studies did not indicate any toxic or adverse effect of 
pegloticase administered with a human exposure 645 times higher than that in the Phase 3 
clinical trials (8 mg every 2 weeks) based on the area under the curve values from the 39-week, 
repeat-dose, dog study (high-dose).  
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 


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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 KRYSTEXXA® 
information. 
7.1.2.5 Clinical Pharmacokinetics 
Pegloticase levels were determined in serum based on measurements of uricase enzyme activity.  
Following single intravenous (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 (Trial M0403), pegloticase serum concentrations were not 
affected in a clinically meaningfully manner by 2 hemodialysis sessions. Pre- and post-dialyzer 
samples, as well as samples taken during dialysis, demonstrated that trial drug was not removed 
by the dialysis process. 
No formal trials have been conducted to examine the effects of hepatic impairment on 
. 
7.1.2.6 Risks of Pegloticase 
The risks of pegloticase use are detailed in the full prescribing information and include: 
 IRs, including anaphylaxis 
 Hemolysis and methemoglobinemia in patients with glucose-6-phosphate dehydrogenase 
(G6PD) deficiency 
 Gout flares 
 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 trial. 
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 will begin at least 1 protocol-specified standard gout flare prophylaxis 
regimen (i.e., colchicine and/or nonsteroidal anti-inflammatory drugs [NSAIDs] and/or low-dose 
prednisone 10 mg
f pegloticase and should continue 
flare prophylaxis for at least 6 months per American College of Rheumatology guidelines 
(FitzGerald et al, 2020). 
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Since IRs can occur, all subjects will receive pre-treatment prophylaxis consisting of 
antihistamine, acetaminophen, a leukotriene inhibitor and corticosteroids prior to each 
pegloticase infusion of pegloticase. To standardize this regimen, subjects will receive, at a 
minimum, fexofenadine (180 mg orally) and prednisone (50 mg orally) the night before each 
infusion, fexofenadine (180 mg orally), famotidine (20 mg orally), montelukast (10 mg orally) 
and acetaminophen (1000 mg orally) the morning of each pegloticase infusion and 
methylprednisolone (125 mg IV) given over an infusion duration between 10 and 30 minutes, 
prior to each pegloticase infusion. 
The risk of anaphylaxis and IRs is higher in patients whose sUA level increases to >6 mg/dL. 
Monitoring 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 (Keenan et al, 
2019).  
Refer to the current version of the FDA-approved KRYSTEXXA Full Prescribing Information 
and the KRYSTEXXA® 
ochure for detailed information.  
7.1.3 Methotrexate Overview and Risks 
MTX is a folic acid reductase inhibitor used as a disease-modifying, anti-rheumatic drug for the 
treatment of autoimmune diseases. MTX is a drug well-known to rheumatologists, has a 
well-established and understood safety profile and is known to prevent the formation of anti-drug 
antibodies (Strand et al, 2017). 
 
AEs that may be experienced by subjects treated with MTX include: 
 Gastrointestinal: nausea, vomiting, diarrhea, stomatitis; 
 Hematologic and oncologic: leukopenia, thrombocytopenia; 
 Hepatic: hepatotoxicity, increased serum alkaline phosphatase, increased serum bilirubin, 
increased serum transaminases; 
 Infection: increased susceptibility to infection; and 
 General: malaise, fatigue, dizziness, alopecia, photosensitivity.  
Additionally, MTX can cause fetal death or teratogenic effects. If either partner is receiving 
MTX, pregnancy should be avoided during therapy and for a minimum of 3 months after MTX 
therapy for the non-vasectomized male. For females of childbearing potential, pregnancy should 
be avoided for at least 1 ovulatory cycle after MTX therapy.  
Baseline assessment will include a complete blood count with differential, hepatic enzymes, 
renal function tests and a chest x-ray.  
MTX is available in both oral and injection formulations; however, subcutaneous (SC) 
administration may overcome some limitations of oral MTX therapy. In a trial of the PK profiles 
of MTX following oral and SC administration, the bioavailability of MTX was greater at all dose 
levels tested (10 mg, 15 mg, 20 mg, and 25 mg) for SC compared with oral administration, and a 


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dose-proportional increase in PK parameters was noted across all doses (Schiff and Sadowski 
2017).  
In addition, various clinical experiences suggest that SC MTX is more effective than oral MTX 
and may provide significant benefit even in patients in whom oral MTX proved to be inadequate. 
The increased efficacy of SC MTX resulting from higher drug exposure compared with oral 
MTX has been associated with a similar safety profile as oral MTX and in some reports even a 
lower frequency of gastrointestinal complaints (Vena et al, 2018). In a 6-month prospective, 
randomized, double-blind controlled trial of oral and SC MTX administration in 384 patients 
with active rheumatoid arthritis, SC administration was significantly more effective than oral 
administration at the same MTX dosage, with no difference in tolerability (Braun et al, 2008). 
This trial will use SC MTX to reduce and/or prevent the formation of anti-drug antibodies 
because subjects in this trial previously received pegloticase but did not maintain an sUA 
response, presumably due to anti-drug antibody formation.  
Refer to the current version of the FDA-approved RASUVO Full Prescribing Information for 
detailed information concerning the safety profile of MTX. 
7.2 
Rationale for This Trial 
Although pegloticase is highly effective, when administered without an immunomodulator, the 
formation of anti-drug antibodies results in a high non-responder rate. In Phase 3 trials in which 
pegloticase was administered without concomitant immunomodulation, 52% of subjects were 
non-responders, leaving many subjects with no alternative therapy options, since pegloticase is 
the last line of defense. Among patients who have previously failed pegloticase, there is an 
unmet need for treatment.  
Retreatment with an immunomodulator following loss of efficacy of other biologics has been 
shown to regain efficacy. In inflammatory bowel disease patients with loss of response due to 
immunogenicity, the addition of immunomodulators to therapy resulted in undetectable anti-drug 
antibody levels and was an effective approach to recapture clinical response (Ben-Horin et al, 
2013; Strik et al, 2017; Ungar et al, 2017).  
Prophylactic use of immunosuppressive therapy, such as MTX with pegloticase may enable 
sustained treatment and improve outcomes. In case reports of 2 subjects, MTX was used as an 
adjunct to pegloticase treatment for refractory tophaceous gout. In 1 subject, high sUA levels 
developed prior to the third infusion. Adjunctive MTX treatment restored pegloticase response 
and the patient s sUA levels decreased and remained low for the remainder of treatment. Oral 
MTX was initiated at the first infusion in a second subject. Following a lapse in MTX 
compliance, low sUA levels achieved initially were increased. Re-initiation of MTX restored 
pegloticase response and the patient tolerated subsequent infusions (Bessen et al, 2019a).  
Although there may be concerns for more severe IRs in this trial population upon retreatment 
with pegloticase due to relationship between anti-drug antibody development and IRs, analysis 
of IR severity among subjects treated with pegloticase every 2 weeks and who had more than 


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1 IR in the Phase 3 program showed that the majority (approximately 66%) had a second IR of 
the same or lower severity than the first IR.  
MTX is the most commonly used non-biological disease-modifying agent worldwide and is 
frequently used in combination with other biological therapies (Strand et al, 2017). An oral MTX 
dose of 15 mg is currently being studied in the randomized controlled trial to confirm if MTX 
can prevent anti-drug antibodies formation to increase responder rate and reduce risk of IR. In 
this trial, a higher SC dose of 25 mg (for subjects with estimated glomerular filtration rate 
[eGFR] 45 mL/min/1.73 m2 [15 mg for subjects with eGFR 
45 mL/min/1.73 m2) will 
be used to increase the likelihood of success in those who previously failed pegloticase.  
7.3 
Rationale for Dose Selection 
7.3.1 Pegloticase Dose Selection 
The dose of pegloticase and instructions for use are consistent with the current pegloticase 
prescribing information. Refer to the current version of the FDA-approved KRYSTEXXA Full 
Prescribing Information. 
7.3.2 Methotrexate Dose Selection 
MTX is among the most well-studied agents shown to reduce anti-drug antibodies in numerous 
trials (Strand et al, 2017). MTX as monotherapy for rheumatoid arthritis and psoriatic arthritis is 
generally administered at doses of 7.5 to 15 mg/week, with doses titrated up as necessary and 
tolerated to 25 to 30 mg/week (Visser and van der Heijde, 2009; Ceponis and Kavanaugh, 2010; 
Mouterde et al, 2011; Mease 2013). These dose levels have generally been both effective and 
safe. A similar dose range of MTX has been used in combination with biologic disease-
modifying antirheumatic drugs when the biologic disease-modifying antirheumatic drugs have 
been used as therapy for both rheumatoid and psoriatic arthritis, as well as other conditions 
(REMICADE Product Labeling, 2020; HUMIRA Product Labeling, 2018; CIMZIA Product 
Labeling, 2019). As discussed in Section 7.1.3, in the current trial, MTX will be administered 
SC, given its potential superior efficacy compared with oral administration.  
A retrospective chart review of the effect of MTX and pegloticase in 10 uncontrolled gout 
patients provides support for the safety of the SC MTX with pegloticase regimen. Nine patients 
began SC MTX (25 mg weekly) prior to initiating pegloticase 8 mg every 2 weeks; the 
remaining patient began oral MTX (12.5 mg weekly) 14 days after the first pegloticase infusion. 
When MTX was administered with pegloticase, either as SC or oral formulation, the majority of 
patients (80%; 8/10) received at least 12 pegloticase infusions, were considered responders and 
no new safety concerns emerged (Albert et al, 2019).  
The MTX dose in the current trial will be based on eGFR because renal excretion is the primary 
route of MTX elimination.  
Bressolle et al. (1998) have shown that in rheumatoid arthritis patients, the half-life of MTX is 
doubled when creatinine clearance decreases to <45 mL/min. The RASUVO Full Prescribing 
Information indicates that the dose of MTX should be reduced in patients who have renal 


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impairment. The 2008 American College of Rheumatology recommendations for use of MTX 
(Saag et al, 2008) indicate that MTX is contraindicated when the estimated creatinine clearance 
is <30 mL/min. Based on this literature, only subjects with an eGFR 
0 mL/min/1.73 m2 will be 
eligible for enrollment. In this trial, a higher SC dose of 25 mg (for subjects with eGFR 
45 mL/min/1.73 m2 [15 mg for subjects with eGFR 
45 mL/min/1.73 m2) will be used 
to increase the likelihood of success in those who previously failed pegloticase.  


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8 
TRIAL OBJECTIVES 
The overall objective of this trial is to evaluate the efficacy and safety of pegloticase and MTX 
co-administered in subjects with uncontrolled gout who previously received pegloticase without 
a concomitant immunomodulator but did not maintain an sUA response (i.e., unable to maintain 
sUA <6 mg/dL while being treated with pegloticase alone and/or stopped pegloticase treatment 
due to an IR).  
Primary Objective 
The primary objective is to demonstrate that the response rate during Month 6 (Weeks 20, 21, 
22, 23 and 24), as measured by the sustained normalization of sUA to <6 mg/dL for at least 80% 
of the time during Month 6, is greater than 20% in subjects receiving pegloticase with MTX.  
Secondary Objectives 
To evaluate the effect of pegloticase with MTX on the following: 
 The response rate during Month 3 (Weeks 10, 12 and 14), as measured by the sustained 
normalization of sUA to <6 mg/dL for at least 80% of the time during Month 3.  
 The proportion of subjects who experienced any of the following events from Day 1 to 
Week 24: IR leading to discontinuation of treatment, anaphylaxis or meeting Individual 
Subject sUA Discontinuation Criteria.  
 The change from Baseline in urate deposition volume, measured by dual-energy 
computed tomography (DECT) scan. 
 The change from Baseline in Health Assessment Questionnaire (HAQ) - Disability Index 
(HAQ-DI) score.  
 The change from Baseline in HAQ pain score.  
 The change from Baseline in HAQ health score. 
Exploratory Objectives 
To evaluate the effect of pegloticase with MTX on the following: 
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Safety and Tolerability Objectives 
To evaluate the effect of pegloticase with MTX on the following: 
 The AE/SAE profile overall for pegloticase and MTX and the incidence of adverse 
events of special interest (AESIs), including IRs, anaphylaxis, gout flares and major 
adverse cardiovascular events (MACE, defined as non-fatal stroke, non-fatal myocardial 
infarction, cardiovascular death and congestive heart failure).  
 The change from Baseline in safety laboratory test results, including high-sensitivity 
C-reactive protein (hs-CRP). 
 The change from Baseline in vital signs.  
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Trial Design and Plan 
This is a Phase 4, multicenter, open-label trial of pegloticase with MTX in adult subjects with 
uncontrolled gout who were previously treated with pegloticase without a concomitant 
immunomodulator and stopped pegloticase due to failure to maintain sUA response and/or a 
clinically mild IR. Approximately 30 subjects will be enrolled. The treatment period with 
pegloticase + MTX will be approximately 24 weeks, with optional extension up to 48 weeks. 
The trial design will include 5 distinct components:  
1) a Screening Period, lasting up to 42 days;  
2) a 6-week MTX Tolerability Assessment Period (hereafter referred to as the MTX Run-in 
Period);  
3) a 24-week Pegloticase + MTX Treatment Period, which will include a Week 24/End of 
Trial/Early Termination Visit (subjects that end MTX and pegloticase treatment prior to 
the Week 24 will remain on trial for follow up until the Week 24 visit);  
4) an Optional Pegloticase + MTX Extension Period from Week 24 to Week 48, if a subject 
may gain further benefit with additional pegloticase treatment per the discretion of the 
Principal Investigator, which will include a Week 48/Optional End of Trial/Optional Early 
Termination Visit and  
5) a 30-Day Post-Treatment Follow-up (Phone/Email) 30 days after the last pegloticase 
infusion or last dose of MTX (for subjects who are unable to tolerate MTX during the 
MTX Run-in Period and do not dose pegloticase). Subjects that end MTX and pegloticase 
treatment prior to Week 24 and remain on trial for at least 30 days prior to Week 24 will 
complete the 30-Day Post-Treatment Follow-Up as part of the visits following the End of 
Pegloticase visit. 
All subjects who meet eligibility criteria at Screening will begin titrating up to a once weekly SC 
MTX at a target dose of 25 mg 
45 mL/min/1.73 m2) or 15 mg 
<45 mL/min/1.73 m2) for 6 weeks prior to the first dose of pegloticase. Subjects will also take 
folic acid at a starting dose of 1 mg orally every day beginning at Week -6 (preferably 2 days 
prior to the first dose of MTX) continuing until prior to the End of Pegloticase Visit (if 
applicable) or until 1 week after the last pegloticase infusion for subjects who have not stopped 
pegloticase treatment. A higher folic acid dose or an alternative folate supplement will be 
allowed (see Section 9.4.1.3 for specific instructions). 
Subjects must be able to tolerate MTX at a minimum dose of 15 mg during the 6-week MTX 
Run-in Period to be eligible to participate in the Pegloticase + MTX Treatment Period, regardless 
of Baseline eGFR. Subjects who are unable to tolerate MTX 15 mg during the MTX Run-in 
Period will be considered MTX Run-in Screen Failures.  


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Female subjects of childbearing potential who inject at least 1 dose of MTX will receive a safety 
follow-up phone call/e-mail approximately 30 days after the last dose of MTX to verify that at 
least 1 ovulatory cycle has occurred since the last dose of MTX. If the subject has not ovulated, a 
urine pregnancy test will be performed. For those subjects who inject at least 1 dose of MTX and 
who are non-vasectomized males, an inquiry 
of MTX regarding partner pregnancy. 
All subjects who meet the inclusion/exclusion criteria and complete the MTX Run-in Period will 
be considered enrolled subjects and will receive the first pegloticase infusion on Day 1. All 
subsequent doses and trial visits will be scheduled based on the Day 1 Visit date. 
Prior to the Pegloticase + MTX Treatment Period, subjects will begin taking at least 1 standard 
gout flare prophylaxis regimen (i.e., colchicine and/or NSAIDs and/or low-dose prednisone 
 mg/day) per protocol 
at least 6 months per American College of Rheumatology guidelines (FitzGerald et al, 2020). For 
IR prophylaxis, fexofenadine (180 mg orally) and prednisone (50 mg orally) will be taken the 
night before each pegloticase infusion; fexofenadine (180 mg orally), famotidine (20 mg orally), 
montelukast (10 mg orally) and acetaminophen (1000 mg orally) will be taken the morning of 
each pegloticase infusion; methylprednisolone (125 mg IV), over an infusion duration between 
10 and 30 minutes, will be administered prior to each pegloticase infusion.  
During the Pegloticase + MTX Treatment Period, pegloticase 8 mg will be administered IV 
every 2 weeks from Day 1 through the Week 22/Week 46, after all predose trial visit assessments 
have been completed at each visit. The date, start and stop time of infusion will be recorded.  
During the Pegloticase + MTX Treatment Period, subjects will be instructed to inject MTX 
weekly on the same day each week, within 1 to 3 days prior to each pegloticase infusion (on the 
weeks when pegloticase is administered); however, if a subject does not do so, MTX must be 
be injected after the last pegloticase infusion for subjects who have not stopped pegloticase due 
to individual subject sUA discontinuation criteria. If the subject discontinues pegloticase due to 
the stopping rule or other reason, MTX and folic acid should also be discontinued.  
After Day 1, if a subject becomes unable to tolerate MTX, the folic acid dose can be increased, 
an alternative folate supplement may be used and/or the MTX dosage may be reduced or 
discontinued based on pre-defined criteria (see Section 9.4.6.3.2.2 for detailed instructions) and 
the subject may remain in the trial and continue pegloticase infusions. Every attempt should be 
made to re-start the MTX in subjects once their MTX-associated symptoms have improved or 
their laboratory tests have normalized.  
The Investigator will review the subject clinical status and 
 
(Appendix 17.8) at Week -6; prior to pegloticase infusion at the Week 24 and Week 36 Visits 
(subjects who may gain further benefit beyond 12 infusions and elect to receive pegloticase + 
MTX during the Optional Pegloticase + MTX Extension Period); and at the End of Pegloticase 
(if applicable) and Week 24 or 48/End of Trial/Early Termination Visits.  
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After the Week 24 or 48 Visit (or End of Pegloticase Visit [if applicable]) or upon pegloticase 
discontinuation, subjects should resume regular care for gout per the judgment of the treating 
physician, including resumption of urate-lowering therapy, if appropriate.  
Two sequential cohorts of subjects will be enrolled in this trial. Cohort 1 is targeted to enroll 
10 subjects who previously failed to maintain sUA response with pegloticase monotherapy and 
stopped pegloticase treatment without a history of pegloticase-related IR. After 7 and 10 subjects 
in Cohort 1 complete at least 6 infusion visits, safety assessments of IR and anaphylaxis from 
 will be performed by the Safety Review Team (comprising members of 
the Horizon Clinical Development and Patient Safety and Pharmacovigilance Teams) based on 
pre-determined tolerability criteria. If a subject discontinues treatment or discontinues the trial 
prior to the 6th infusion, their available data will be included in the safety assessment. If the 
safety assessment during Cohort 1 indicates that the pegloticase infusions are well tolerated 
based on the pre-determined criteria (see tolerability criteria), then the trial can begin enrolling 
Cohort 2. If the safety assessment indicates that the pegloticase infusions are not well tolerated 
based on the pre-determined tolerability criteria, then the trial will cease to screen and enroll new 
subjects. Subjects who are ongoing and benefitting from continued treatment, as determined by 
the Principal Investigator at the time of the termination of new subject screenings, will be 
permitted to continue treatment and trial visits.  
The aim is to enroll up to 20 subjects in Cohort 2; subjects who failed to maintain sUA response 
with pegloticase monotherapy and or experienced a pegloticase related clinically mild IR . After 
3, 6, 10, 15 and 20 subjects in Cohort 2 complete 6 infusion visits, safety assessments of IR and 
Team. If the 
safety assessment indicates that the pegloticase infusions are not well tolerated based on the pre-
determined tolerability criteria (see tolerability criteria) or in the absence of subjects with a 
history of pegloticase-related clinically mild IR, the trial will continue enrolling subjects without 
a history of pegloticase-related clinically mild IR to reach a total of 30 subjects enrolled for the 
trial.  
Depending on any potential safety signals reported (e.g., serious IR or any SAE related to 
pegloticase infusion), regular quarterly and/or ad hoc safety assessments will be conducted 
during the trial as specified in the Safety Management Plan and the Safety Review Team Charter. 
The regular quarterly reviews will include review of the database by the Safety Review Team 
and will be conducted as set out in the Safety Management Plan. The first safety review meeting 
will occur approximately after the first 3 subjects in Cohort 1 complete at least 12 weeks of the 
Pegloticase + MTX Treatment period (6 infusion visits). The Safety Review Team could stop the 
trial for other significant safety reasons.  
If 3 events of anaphylaxis (as assessed by PI)  occur, an Adjudication Committee (composed of 
independent experts external to Horizon) (Section 9.5.6) will be established for this trial to 
adjudicate the AESIs of Anaphylaxis at a frequency defined in the Adjudication Committee 
Charter. The AESI of IR, MACE and gout flare will not be adjudicated.  


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Samples for measurement of sUA levels will be collected at Screening, during the MTX Run-in 
Period, pre- each infusion, post-infusion on Day 1 and at the Week 10, 12, 14, 20, 22, 32, 34, 44 
and 46 Visits and on non-infusion visits on the 1st (~24 hours), 4th (~96 hours), 7th (~168 hours) 
and 10th (~240 hours) day after the first 4 infusions (Infusions 1, 2, 3, 4) and on the 1st (~24 
hours) and the 7th (~168 hours) day after the  5th , 6th   and 7th infusion; (i.e., Day 1 through prior 
to Week 14), Weeks 21 and 23, and at the End of Pegloticase (if applicable) or the Week 24 or 
48/End of Trial/Early Termination Visit. 
Samples will be collected for 
and 
 as indicated in Section 2.1 (Schedule of Assessments).  
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 and urine test, will be performed. 
The total blood volume to be collected from each subject during this trial is approximately 
450 mL.  
An overview of the trial design is presented in the schematic below, and details of trial activities 
are provided in Section 2.1.  
Figure 9.1 
Schematic of Trial Design 
 
D = Day; EOT = End of Trial; IV = intravenous; MTX = methotrexate; SC = subcutaneous; sUA = serum uric acid; 
W = Week 
1 
Individual subjects who meet the sUA discontinuation criteria will end pegloticase therapy, complete the End of 
Trial procedures and remain in the trial. 
2 
Key efficacy and safety assessments will be conducted during Weeks 10, 12, 14, 20, 21, 22, 23 and 24. 
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9.2 
Discussion of Trial Design 
This is a Phase 4, multicenter, open-label, efficacy and safety trial of pegloticase in combination 
with SC MTX in adult subjects with uncontrolled gout, who previously received pegloticase 
without a concomitant immunomodulator and stopped pegloticase due to a clinically mild 
pegloticase-related IR and/or failure to maintain sUA response.  
Immunogenicity (anti-pegloticase antibodies) in response to pegloticase therapy can lead to loss 
of therapeutic response and/or AEs, including IRs. For patients who previously lost therapeutic 
response to pegloticase treatment without a co-concomitant immunomodulator due to 
immunogenicity, a potential strategy to regain therapeutic efficacy with pegloticase is 
pretreatment followed by co-administration of immune-modulating therapy. MTX is the most 
commonly used non-biological disease-modifying agent worldwide and is frequently used in 
combination with other biological therapies (Strand et al, 2017), and has been shown to recapture 
clinical response of other biologic treatment after initial therapeutic efficacy is lost due to 
immunogenicity (Ben-Horin et al, 2013; Strik et al, 2017; Ungar et al, 2017). In the current trial, 
MTX given SC will be used as an immunomodulator co-administered with pegloticase to 
subjects who previously failed pegloticase alone.  
This trial will include up to a 6-week Screening Period, a 6-week MTX Run-in Period, a 
24-week Pegloticase + MTX Period, an Optional Pegloticase + MTX Extension Period from 
Week 24 to Week 48, if a subject may gain further benefit with additional pegloticase treatment 
per the discretion of the Principal Investigator and a Post-Treatment Follow-up Period.  
The Safety Review Team (Section 9.5.5) will assess the tolerability of pegloticase using the 
tolerability criteria (see Section 9.5.4.1.1.5).  
9.3 
Selection of Trial Population 
9.3.1 Inclusion Criteria 
Eligible subjects must meet/provide all of the following criteria: 
1. Willing and able to give informed consent. 
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the trial. 
3. 
 
4. Uncontrolled gout, defined by the following criteria: 
 Hyperuricemia during the Screening Period, 
6 mg/dL, and; 
 Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the 
maximum medically appropriate dose or with a contraindication to xanthine oxidase 
inhibitor therapy based on medical record review or subject interview, and; 
 Symptoms of gout, including at least 1 of the following: 
o Presence of at least 1 tophus 
o Recurrent flares, defined as 2 or more flares in the 12 months prior to 
Screening 
o Presence of chronic gouty arthritis 


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5. Subject was previously treated with pegloticase without concomitant immunomodulation 
>6 mg/dL within 2 weeks post pegloticase infusion) and did not experience an IR 
(Cohort 1) and/or stopped pegloticase treatment due to pegloticase-related clinically mild 
IR (Cohort 2) (see guidance on assessment of IR symptoms and severity in 
Appendix 17.9). A Sponsor Adjudication Committee will review the signs, symptoms 
and treatment administered for the prior IR associated with pegloticase infusion before 
subjects with history of mild IR are enrolled.  
6. Subject for whom the last pegloticase infusion occurred >6 months prior to Screening. 
7. Willing to discontinue any oral urate-lowering therapy for at least 7 days prior to Day 1 
and remain off other urate-lowering therapy during the Pegloticase + MTX Treatment 
Period.  
8. 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 
pregnancy tests during Screening. 
o Subjects must agree to use 2 reliable forms of contraception during the trial, 1 of 
which is recommended to be hormonal, such as an oral contraceptive. Hormonal 
Week -6 (start of MTX) and 
continue for 30 days after the last dose of pegloticase, or at least 1 ovulatory cycle 
after the last dose of MTX (whichever is the longer duration after the last dose 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. 
9. Men who are not vasectomized must agree to use appropriate contraception so as to not 
impregnate a female partner of reproductive potential during the trial, beginning with the 
initiation of MTX at Week -6 and continuing for at least 3 months after the last dose of 
MTX.  
10. Able to tolerate MTX at SC doses of at least 15 mg during the MTX Run-in Period, 
regardless of eGFR status. 
9.3.2 Exclusion Criteria 
Subjects will be ineligible for trial participation if they meet any of the following criteria: 
1. Known history of medically confirmed prior anaphylactic reaction.  
2. Known history of moderate or severe IR (including but not limited to difficulty in 
breathing, hypotension, generalized urticaria, generalized erythema, angioedema and/or 
required treatment with IV steroids or epinephrine; see guidance on assessment of 
anaphylaxis/IR symptoms and severity in Appendix 17.9) or other SAEs related to 
pegloticase or any other pegylated product treatment.  
3. Weight >160 kg (352 pounds) at Screening. 


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4. Any serious acute bacterial infection, unless treated and completely resolved with 
antibiotics at least 2 weeks prior to the Week -6 Visit.  
5. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic 
bronchiectasis. 
6. Current or chronic treatment with systemic immunosuppressive agents, such as MTX, 
azathioprine, cyclosporine, leflunomide, cyclophosphamide or mycophenolate mofetil. 
7. Current treatment with prednisone >10 mg/day or equivalent dose of another 
corticosteroid on a chronic basis (defined as 3 months or longer).  
8. Known history of any solid organ transplant surgery requiring maintenance 
immunosuppressive therapy. 
9. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA 
positivity, unless treated, viral load is negative and no chronic or active infection 
confirmed by hepatitis B virus serology. 
10. Known history of hepatitis C virus RNA positivity, unless treated and viral load is 
negative. 
11. Known history of human immunodeficiency virus positivity. 
12. G6PD deficiency (tested at the Screening Visit). 
13. Severe chronic renal impairment (eGFR <30 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. 
14. Non-compensated congestive heart failure, hospitalization for congestive heart failure or 
treatment for acute coronary syndrome (myocardial infarction or unstable angina) within 
3 months of the Screening Visit, current uncontrolled arrhythmia or current uncontrolled 
blood pressure (>160/100 mmHg) prior to Week -6. 
15. 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. 
16. Prior treatment with another recombinant uricase (rasburicase) or concomitant therapy 
with a PEG-conjugated drug (see Appendix 17.10 for a list of PEG-conjugated drugs). 
17. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant 
protein or porcine product. 
18. Contraindication to MTX treatment or MTX treatment considered inappropriate. 
19. Known intolerance to MTX. 
20. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, 
prior to MTX administration at Week -6 or plan to take an investigational drug during the 
trial. 
21. Current liver disease, as determined by alanine transaminase (ALT) or aspartate 
transaminase (AST) >1.25 × upper limit of normal (ULN) or albumin <lower limit of 
normal at the Screening Visit. 
22. Currently receiving systemic or radiologic treatment for ongoing cancer, excluding non-
melanoma skin cancer. 


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23. History of malignancy within 5 years other than non-melanoma skin cancer or in situ 
carcinoma of cervix. 
24. White blood cell count <4.0 × 109/L, hematocrit <32% or platelet count <75 × 109/L.  
25. Diagnosis of osteomyelitis. 
26. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as 
Lesch-Nyhan and Kelley-Seegmiller syndrome. 
27. Unsuitable candidate for the trial (e.g., cognitive impairment), based on the opinion of the 
Investigator, such that participation might create undue risk to the subject or interfere 
 
28. Alcohol use in excess of 3 alcoholic beverages per week. 
29. A known intolerance to all protocol standard gout flare prophylaxis regimen (i.e., unable 
to tolerate any of the following 3 agents: colchicine, NSAIDs or low dose prednisone 
 mg/day).  
30. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemed 
necessary by the Investigator, a chest x-ray may be performed during Screening.  
9.3.3 Removal of Subjects From Therapy or Trial 
All subjects are free to withdraw from trial participation at any time, for any reason and without 
prejudice to their further medical care. In addition, the Investigator may terminate a subject from 
the trial at any time. However, subjects who are removed from pegloticase therapy should remain 
in the trial unless they withdraw consent. 
9.3.3.1 Removal of Subjects From Pegloticase Therapy 
For subjects who do not complete therapy through Week 24 or 48, the reason for discontinuation 
from pegloticase therapy should be recorded on the eCRF using 1 of the following categories: 
 Lost to Follow-up. The subject does not return to the clinic for scheduled assessments 
e subject. 
 Lack of Efficacy. 
 AE
health (e.g., anaphylactic reaction), or the subject is unwilling to continue therapy 
because of an AE. Subjects who discontinue due to an AE should be followed until 
resolution or stabilization of the AE, or an adequate explanation for the event is obtained. 
 Physician Decision. The Investigator has determined that pegloticase administration 
poses an unacceptable risk to the subject (specify reason).  
 Withdrawal by Subject. Subject refusal of additional therapy (specify reason). 
 Trial Terminated by Sponsor. The Sponsor, IRB or regulatory agency terminates the trial.  
 Pregnancy. 
 Death. 


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9.3.3.1.1 Trial Considerations for Subjects Ending Pegloticase Infusions Prior to Week 24 
or Week 48 
 MTX, along with folic acid, will be discontinued at the time of cessation of pegloticase 
infusions prior to Week 24 or 48.  
 All subjects will complete the End of Pegloticase Visit and will remain in the trial 
through Week 24 (if End of Pegloticase Visit occurred before Week 24) regardless of 
whether they stop infusions due to sUA stopping rules or other reason (e.g., withdrawal 
of consent for pegloticase infusions). 
 Subjects are encouraged to continue to participate in all visits, including the 30-Day 
Post-Treatment Follow-up and Week 24/End of Trial/Early Termination Visits, but are 
especially encouraged to complete trial visits at the trial site for key efficacy and safety 
assessments at Weeks 10, 12, 14, 20, 21, 22, 23 and 24, so that sUA laboratory and other 
key assessments can be completed. During visits between these key efficacy and safety 
collection visits, in subjects who have stopped infusions, subjects may complete trial 
visits in person or via telephone to collect AE, concomitant medication and gout flare 
information.  
 Activities related to pre-/post-infusion monitoring or medication dispensation will not be 
completed once a subject has stopped pegloticase infusions. These activities include:  
o MTX compliance/reconciliation; 
o IR prophylaxis; 
o IR prophylaxis compliance; 
o Folic acid compliance; 
o Pegloticase infusion; 
o 
; 
o Pre-infusion 
 sampling; and  
o MTX drug/dispensation related items. 
 Re-introduction of oral urate-lowering therapies should not start until after the Week 24 
or 48/End of Trial/Early Termination Visit (or End of Pegloticase Visit [if applicable] 
laboratory tests are collected.  
If a subject discontinues treatment or discontinues the trial prior to the 6th infusion, their 
available data will be included in the safety assessment conducted by the Safety Review Team.  
Subjects who elect to receive pegloticase + MTX during the Optional Pegloticase + MTX 
Extension Period will complete the 30-Day Post-Treatment Follow-up after the final pegloticase 
infusion but are not required to return for biweekly visits.  
9.3.3.2 Removal of Subjects From Trial 
For subjects who discontinue from the trial prior to Week 24 or 48, the reason for 
discontinuation from the trial should be recorded on the eCRF using 1 of the following 
categories: 
CCI
CCI


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 Lost to Follow-up. The subject does not return to the clinic for scheduled assessments 
 
 Withdrawal of Subject. The subject withdraws from the trial. 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. 
 Trial Terminated by Sponsor. The Sponsor, IRB or regulatory agency terminates the trial.  
 Death. 
9.3.4 Replacement Policy 
9.3.4.1 Subjects 
In general, subjects who prematurely discontinue from the trial for any reason will not be 
replaced. An exception may be made for subjects who are unevaluable due to the impact of the 
coronavirus disease 2019 (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 trial to allow for the originally planned 
number to be evaluable for the primary efficacy analysis. 
9.3.4.2 Centers 
A center may be closed and/or replaced for the following administrative reasons:  
 Excessively slow recruitment. 
 Poor protocol adherence. 
9.3.4.3 Screen Failures 
Subjects who do not meet all of the inclusion criteria or meet any of the exclusion criteria will be 
considered screen failures.  
In addition, subjects who are unable to tolerate MTX at a SC dose of at least 15 mg weekly 
during the MTX Run-in Period will be considered MTX Run-in Screen Failures.  
Subjects who fail screening or are an MTX Run-in Screen Failure may be allowed to rescreen, or 
retest laboratories for the trial if both the Investigator and Sponsor are in agreement regarding 
rescreening/retesting and if the Investigator determines that the subject can satisfy all of the 
eligibility criteria. 
9.4 
Treatments 
9.4.1 Treatments Administered 
9.4.1.1 Methotrexate 
During the MTX Run-in Period, which begins 6 weeks prior to the first dose of pegloticase, 
subjects with 
45 mL/min/1.73 m2 will inject SC MTX weekly at a starting dose of 15 mg 


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at Weeks -6 and Week -5 increasing to 25 mg at Week -4 and continuing weekly throughout the 
45 mL/min/1.73 m2 will inject SC MTX weekly at a starting 
dose of 10 mg at Week -6 and Week -5 increasing to 15 mg at Week -4 and continuing weekly 
throughout the trial. If a subject becomes unable to tolerate MTX at 25 mg doses, the folic acid 
dose may be increased from 1 to 2 mg/day and/or the MTX dosage may be decreased to 20 or 
15 mg, but to no less than 15 mg. Subjects who cannot tolerate MTX at a minimum dose of 
15 mg during the MTX Run-in Period will be considered MTX Run-in Screen Failures, 
regardless of their Baseline eGFR.  
During the MTX Run-in Period, if a dose is missed, it should be injected 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. If a subject misses more 
than 2 doses of MTX during the 6-week Run-in Period, the Principal Investigator should contact 
the Sponsor to discuss eligibility of the subject for enrollment in the Pegloticase + MTX 
Treatment Period. 
During the Pegloticase + MTX Treatment Period, subjects will be instructed to inject MTX 
weekly on the same day each week, within 1 to 3 days prior to each pegloticase infusion (on the 
weeks when pegloticase is administered); however, if a subject does not do so, MTX must be 
be injected after the last pegloticase infusion for subjects who have not stopped pegloticase due 
to individual subject sUA discontinuation criteria. If the subject discontinues pegloticase due to 
the stopping rule or other reason, MTX should also be discontinued. 
After Day 1, if a subject becomes unable to tolerate MTX, the folic acid dose can be increased, 
an alternative folate supplement may be used and/or the MTX dosage may be reduced or 
discontinued based on pre-defined criteria and the subject may remain in the trial and continue 
pegloticase infusions (see Section 9.4.6.3.2.2 for detailed instructions). Every attempt should be 
made to re-start the MTX in subjects once their MTX-associated symptoms have improved or 
their laboratory tests have normalized.  
MTX for SC injection in auto-injectors (7.5, 10, 15, 20, 25 mg) will be provided to all subjects 
(RASUVO Full Prescribing Information). For each subject, the MTX dose will be based on their 
Baseline eGFR value. 
Refer to Section 9.4.12 for contraception requirements.  
9.4.1.2 Pegloticase 
All subjects who meet the entry criteria and tolerate SC MTX at a minimum dose of 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 Treatment Period) or a total of 24 infusions from Day 1 through Week 46, inclusive 
(Pegloticase + MTX Treatment Period and Optional Pegloticase + MTX Extension Period), for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
. Subjects will not be fasting on the day of 


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infusion and will be encouraged to have a snack or normal meal before or after the infusion. On 
Day 1, pre- and post-infusion sUA results must be reported by the central laboratory. For the 
remainder of the trial beginning at Week 2, 2 sUA samples will be collected within 48 hours 
PRIOR to pegloticase infusion and results reported by the local laboratory and central laboratory 
(see Section 9.5.1.1). 
After the Week 24 or 48 Visit (or End of Pegloticase Visit [if applicable]) or upon pegloticase 
discontinuation, subjects should resume regular care for gout per the judgment of the treating 
physician, including resumption of urate-lowering therapy, if appropriate.  
Pegloticase will be administered as an admixture of 8 mg in 250 mL of 0.45% or 0.9% Sodium 
Chloride Injection, United States Pharmacopeia (USP) for IV infusion by gravity feed or infusion 
pump, generally over 120 minutes. Pegloticase will not be administered as an IV push or bolus. 
If using tubing with no in-line filter, the pegloticase preparation will be infused over 
approximately 120 ±15 minutes while the subject is under close observation for any signs of 
distress. If an in-line filter is used, it should be 0.2 µm or larger. At the end of the infusion, the 
IV line will be flushed with 10 mL of normal saline to ensure the full dose is administered. The 
date and time of infusion start and stop and time of the start and stop time of the flush will be 
recorded.  
9.4.1.3 Folic Acid 
Subjects will also take folic acid at a starting dose of 1 mg orally every day beginning at Week -6 
(preferably 2 days prior to the first dose of MTX) until prior to the End of Pegloticase Visit (if 
applicable) or until 1 week after the last pegloticase infusion for subjects who have not stopped 
pegloticase treatment.  
During the MTX Run-in Period, if minor clinical symptoms emerge, such as mild stomatitis, 
mild gastrointestinal discomfort or fatigue, the Investigator may increase the folic acid dose from 
1 mg/day to 2 mg/day.  
During the Pegloticase + MTX Treatment Period after Day 1, if MTX toxicity-related laboratory 
findings or symptoms (such as nausea, fatigue) occur, the Investigator may increase the folic acid 
dose from 1 mg/day to 2 mg/day. If after more than 1 week of taking 2 mg/day folic acid, the 
sign/symptom or laboratory abnormalities do not resolve or improve, the subject is allowed to 
switch to oral leucovorin at 10 mg/week, given 10 to 24 hours POST each MTX injection, at the 
discretion of the Investigator. In this case, the Investigator should discuss the timing of oral 
leucovorin administration relative to the MTX injection with the Medical Monitor to ensure 
subject compliance. Leucovorin taken before, at the time of or too soon (<8 hours) after MTX 
injection will likely reduce the efficacy of MTX. 
If the subject discontinues pegloticase due to the stopping rule or other reason, folic acid should 
also be discontinued.  


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Prescriptions are to be filled at a local pharmacy, as needed. At trial visits, the subject will be 
asked whether folic acid was taken per protocol. 
9.4.1.4 Gout Flare Prophylaxis 
All subjects will receive standardized prophylactic treatment to reduce the risk of acute gout 
flares, beginning 
, continuing for at least 6 months 
per American College of Rheumatology guidelines (FitzGerald et al, 2020). Before a subject 
begins the Pegloticase + MTX Treatment Period, he or she must have been taking at least 
1 standard gout flare prophylaxis regimen (i.e., colchicine and/or NSAIDs and/or low-dose 
prednisone 10 mg/day) per protocol. Gout flare prophylaxis is optional from Week 26 to the 
end of the trial if needed at the discretion of the Principal Investigator.  
Prescriptions are to be filled at a local pharmacy, as needed. At trial visits, the subject will be 
asked whether gout flare prophylaxis was taken per protocol. 
9.4.1.5 Infusion Reaction Prophylaxis 
Since IRs can occur with pegloticase, all subjects will receive IR prophylaxis prior to each 
pegloticase infusion, consisting of antihistamines, acetaminophen, a leukotriene inhibitor and 
corticosteroids. To standardize this regimen, fexofenadine (180 mg orally) and prednisone 
(50 mg orally) will be taken the night before each pegloticase infusion. Fexofenadine (180 mg 
orally), famotidine (20 mg orally), montelukast (10 mg orally) and acetaminophen (1000 mg 
orally) will be taken the morning of each pegloticase infusion. Methylprednisolone (125 mg IV), 
given over an infusion duration between 10 and 30 minutes prior to each pegloticase infusion 
will be administered. 
Substitution of the corticosteroid is generally 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. IR medications administered prior to each pegloticase infusion will be supplied by the 
site.  
Prescriptions are to be filled at a local pharmacy, as needed. At trial visits, the subject will be 
asked 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 used to treat an anaphylactic reaction. Personnel 
trained in managing IRs and in the use of the emergency equipment will be readily available 
during and for 1 hour after the infusion. As IRs can occur after the completion of the infusion, 
subjects will be observed for 1-hour post infusion. 
9.4.2 Identity of Investigational Products 
9.4.2.1 Pegloticase 
Pegloticase is a clear, colorless, sterile solution in phosphate-buffered saline intended for IV 
infusion after dilution. Each mL of pegloticase contains 8 mg of uricase protein conjugated to 


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24 mg of 10 kDa mPEG. Excipients include disodium hydrogen phosphate dihydrate, sodium 
chloride, sodium dihydrogen phosphate dihydrate and water for injection.  
9.4.2.2 Methotrexate 
MTX for SC injection in auto-injectors (7.5, 10, 15, 20, 25 mg) will be provided to all subjects. 
For each subject, the MTX dose will be based on their Baseline eGFR value. 
See RASUVO Full Prescribing Information for additional detail.  
9.4.3 Labeling 
Pegloticase (KRYSTEXXA®) and MTX will be supplied by PCI Pharma Services.  
Pegloticase (KRYSTEXXA®) is commercially available in the United States and will be 
packaged in sterile, single-use 2-mL glass vials with a Teflon®-coated (latex-free) rubber 
injection stopper to deliver pegloticase as 8 mg of uricase protein in 1 mL volume. An ancillary 
label will be fixed to the vial and carton that identifies the trial, 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 in auto-injectors. An ancillary label will be fixed to the auto-injector and 
carton that identifies the trial, allows subject information to be entered and contains the 
investigational use caution statement according to the FDA Title 21 CFR Part 312 requirements. 
Each auto-injector and carton label will have a unique number. Auto-injectors will be provided 
to trial subjects at the Week -6 Visit for weekly dosing after visit procedures and 
inclusion/exclusion criteria are confirmed. 
9.4.4 Storage 
Before preparation for use, pegloticase will be stored in the carton, maintained under 
refrigeration between 2ºC and 8ºC (36ºF and 46ºF), protected from light and will not be shaken 
or frozen. Pegloticase diluted in infusion bags is stable for 4 hours at 2°C to 8°C (36°F to 46°F) 
and for 4 hours at room temperature (20°C to 25°C, 68°F to 77°F). 
MTX will be stored between 20° and 25°C (68° and 77°F), protected from light and will not be 
frozen; excursions to 15° to 30°C (59° to 86°F) will be permitted.  
9.4.5 Drug Accountability 
Clinical supplies will be dispensed only in accordance with this protocol. Accurate records of the 
clinical supplies received, the amount dispensed for each subject and the amount remaining at 
the conclusion of the trial will be maintained. Each trial site will also maintain individual subject 
drug logs/electronic logs to account for MTX auto-injectors and subject compliance will be 
monitored by the site at each visit (see Section 9.4.11). 


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Investigational clinical supplies will be received by a designated person at the trial site, handled 
and stored safely and properly and kept in a secured location to which only the Investigator and 
designated assistants have access.  
The Trial Pharmacy Manual contains more detailed information on MTX and pegloticase 
packaging, labeling, storage and destruction. 
9.4.6 Trial Drug Administration and Timing of Dose for Each Subject 
9.4.6.1 Description of Clinical Supplies 
PCI Pharma Services will supply trial drugs (pegloticase and MTX) to clinical sites. Ancillary 
supplies for dosing will be provided by the trial site (i.e., infusion bags containing saline, 
syringes, needles, alcohol swabs, gauze pads, bandages and biohazard containers for safe storage 
of used needles and syringes).  
9.4.6.2 Determination of Dose Volume 
Pegloticase will be administered as an admixture of 8 mg in 250 mL of 0.45% or 0.9% Sodium 
Chloride Injection, USP for IV infusion.  
In the event of any potential safety signals reported (e.g., serious IR or any SAE related to 
pegloticase infusion), additional IR mitigation approaches, such as a slower pegloticase infusion 
rate, can be implemented. 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. 
9.4.6.3 Details Concerning Timing and Dose Administration 
9.4.6.3.1 Preparation 
Vials of pegloticase will be visually inspected for particulate matter and discoloration before 
administration, whenever solution and container permit. Vials will not be used if either 
particulate matter or discoloration is present. Using appropriate aseptic technique, 1 mL of 
pegloticase will be withdrawn from the vial into a sterile syringe. Any unused portion of product 
remaining in the vial will be discarded. Syringe contents will be injected into a single 250 mL 
bag of 0.45% or 0.9% Sodium Chloride Injection, USP for IV infusion and will not be mixed or 
diluted with other drugs. The infusion bag containing the dilute pegloticase solution will be 
inverted a number of times to ensure thorough mixing but will not be shaken. In accordance with 
good pharmacy practice, gloves will be worn during preparation of the dose. 
Pegloticase infusion must be started within 4 hours of dilution. Before administration, the diluted 
solution of pegloticase should be allowed to reach room temperature. Pegloticase must never be 
subjected to artificial heating. 


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9.4.6.3.2 Dose Modifications, Interruptions and Delays 
9.4.6.3.2.1 Pegloticase Modifications 
In the event of potential IR safety signals identified during the pegloticase infusion, or when the 
pre-infusion sUA level is >6mg/dL, additional IR mitigation approaches, such as a slower 
pegloticase infusion rate, can be implemented.  
Infusion of pegloticase will be immediately held if the subject experiences any significant IR 
such as respiratory distress, agitation, chest or back pain, urticaria or another clinically 
significant event occurring during infusion. If the AE meets the definition of an SAE for IR, the 
infusion should not be restarted unless the site Investigator determines it is safe to do so. 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 at a slower infusion rate. An 
example of an ~150-minute infusion procedure in 250 mL volume (relative to the standard 
steady rate over 120 minutes) that can be implemented at the discretion of the Investigator is 
presented in Table 9.1.  
Table 9.1 
Sample Pegloticase Infusion Rate Modification Following an Infusion 
Reaction 
Time Interval 
Staggered Rate (Over ~150 Minutes) 
Standard Steady Rate (Over 120 Minutes) 
First 30 minutes 
1.0 mL/min (30 mLs) 
2.08 mL/min 
Second 30 minutes 
1.5 mL/min (45 mLs) 
2.08 mL/min 
Third 30 minutes 
2.0 mL/ min (60 mLs) 
2.08 mL/min 
Fourth 30 minutes 
2.0 mL/min (60 mLs) 
2.08 mL/min 
Last 27.5 minutes 
2.0 mL/min (55 mLs) 
Done 
 
Alternatively, a larger volume of diluent, not to exceed 500 mL can be used. In this case, the 
infusion duration will be extended to a minimum of 3 hours. The total volume and duration of 
infusion will be captured in the medical record and eCRF. 
Infusion of pegloticase may be held or delayed if the subject has an ongoing SAE or AE/SAE 
that occurs prior to the infusion. The status of subjects with skipped infusions will be discussed 
-by-case basis to determine 
whether the subject should continue to the next scheduled infusion or proceed to the End of 
Pegloticase Visit.  
If a confirmed anaphylaxis event occurs in any subject, further dosing with pegloticase for that 
subject will be discontinued. 


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9.4.6.3.2.2 MTX Dose Titration Algorithm and Intolerance Criteria 
During the MTX Run-in Period, a subject will be considered an MTX Run-in Screen Failure if 
any of the following new laboratory findings (repeat laboratory tests may be needed to confirm 
the findings) or symptoms reflecting MTX intolerance occur:  
1. Abnormal hematology findings: 
a. White blood cell count <3.5 × 109/L; 
b. Platelet count <75 × 109/L; and 
c. Hematocrit <32%. 
2. Abnormal hepatic function findings: 
a. AST/ALT >1.5 × upper limit of reference range and  
b. Albumin <lower limit of reference range. 
3. Abnormal renal function: eGFR <30 mL/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; and 
e. Severe headaches, fatigue and problems concentrating.  
In addition, during the MTX Run-in Period, if minor clinical symptoms emerge, such as mild 
stomatitis or mild gastrointestinal discomfort, the Investigator may increase the folic acid dose 
from 1 mg/day to 2 mg/day and/or reduce the MTX dose (but to no less than 15 mg/week). If 
symptoms improve, the subject will not be considered a screen failure on the basis of that 
symptom. 
During the Pegloticase + MTX Treatment Periods, MTX dose guidance based on new laboratory 
findings or new symptoms will be as follows: 




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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 Principal 
Investigator. 
Guidance for increasing MTX back towards 15 or 25 mg/week after dose reduction, based on 
improvement or resolution of abnormal liver enzymes (>2 × ULN): 
1. 
higher dose provided (i.e., 7.5 to 10 mg, 10 to 15 mg, 15 to 20 mg or 20 to 25 mg) and 
reassess in 2 weeks. 
2. If liver 
dose provided (i.e., 10 to 15 mg, 15 to 20 mg or 20 to 25 mg) and reassess in 2 weeks. 
Improvement of other laboratory abnormalities potentially attributed to MTX may also warrant 
titration back up to 15 or 25 mg weekly, based on Principal Investigator judgement and in 
discussion with the Sponsor Medical Monitor. 
9.4.7 Method of Assigning Subjects to Treatment Groups 
All subjects will receive the same trial drugs (i.e., SC MTX and pegloticase).  
Two sequential cohorts of subjects will be enrolled in this trial. Subjects who previously failed to 
maintain sUA response with pegloticase monotherapy and stopped pegloticase treatment without 
a history of pegloticase-related IR will be enrolled in Cohort 1.  
The Safety Review Team will use the tolerability criteria to determine if Cohort 1 enrollment can 
continue, Cohort 2 enrollment can begin and whether subjects without a history of pegloticase-
related clinically mild IR can enroll in Cohort 2.  
Based on the safety assessment during Cohort 1, the trial can begin enrolling Cohort 2 if the 
pegloticase infusions are well tolerated or the trial will cease to screen and enroll new subjects if 
the pegloticase infusions are not well tolerated.  
Subjects with a history of pegloticase-related clinically mild IR will be enrolled in Cohort 2. If 
the safety assessment during Cohort 2 indicates that the pegloticase infusions are not well 
tolerated based on pre-determined tolerability criteria or in the absence of subjects with a history 
of pegloticase-related clinically mild IR, the trial will continue with enrolling subjects without a 
history of pegloticase-related clinically mild IR.  
9.4.8 Blinding 
All trial drugs will be administered in an open-label fashion.  
9.4.9 Prior and Concomitant Therapy  
Medication history (i.e., prior medications) will include all prior gout medications, starting at the 
time of diagnosis and up to the Screening Visit and all other medications taken from 1 year prior 


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to the Screening Visit. Detailed pegloticase use history, including reason for discontinuation and 
associated reactions, if any, will be collected.  
Concomitant medications are defined as drug or biological products other than the trial drugs (or 
prior gout medications) taken by a subject from Screening through the Post-Treatment Follow-up 
Visits. This includes other prescription medications (including preventive vaccines), 
over-the-counter medications, herbal medications, vitamins and food supplements. If a subject is 
treated with antibiotics, refer to Section 9.4.6.3.2.2 for monitoring guidelines. 
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.  
Other than restricted medications (Section 9.4.10), other medications used at the time of trial 
initiation may be continued at the discretion of the Investigator.  
9.4.9.1 Gout Flare Treatment 
An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, 
including pegloticase. Subjects will be instructed to contact the site within 12 hours of the onset 
of symptoms. Gout flares will be confirmed through questioning or direct observation, as 
detailed in Section 9.5.4.8. All subjects who experience a gout flare during the trial will be 
prescribed anti-inflammatory treatment (e.g., NSAID, colchicine, corticosteroids and 
intra-articular steroid injections), as clinically indicated or deemed necessary on an individual 
basis at the discretion of the Investigator. Pain medications for gout flare should be administered 
according to standard of care, as clinically indicated or deemed necessary on an individual basis 
at the discretion of the Investigator. All medications should be documented on the concomitant 
medication eCRF. 
Colchicine will be prescribed in a medically appropriate dose range of 0.6 to 1.8 mg/day, usually 
dosed as 0.6 mg orally twice per day unless reduced dosing is necessitated by renal insufficiency 
or gastrointestinal intolerance. The precise dose and regimen of colchicine will be individualized 
for each subject by the Investigators and documented on the concomitant medication eCRF.  
9.4.9.2 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 
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If a subject experiences an AE suspected to be an IR:  
 A physical examination will be performed to capture medically relevant details, 
including, but not limited to, a thorough dermatologic examination for detection of 
erythema, urticaria (hives) or peri-oral or lingual edema; a chest examination for breath 
sounds, stridor or wheezing; and a cardiac examination with attention to irregular 
heartbeat. 
 Vital signs (sitting or supine blood pressure, heart rate, respiratory rate and body 
temperature) will be captured at least every 30 minutes until the resolution or 
stabilization of the AE. 
 A serum sample will be collected in a serum-separator tube at that time or at the 
subsequent visit. The sample will be centrifuged, frozen at -20°C or colder and stored for 
the batch shipment to a Horizon designated laboratory for evaluation of pegloticase 
antibodies at a future date.  
 When possible, a 12-lead electrocardiogram (ECG) will also be performed at the time of 
IR.  
Section 9.5.4.1.1.5), pegloticase should be immediately discontinued. Any incidence of 
anaphylaxis should be reported as an SAE. 
The Investigator may administer any medically indicated pharmacologic agent or procedure 
intended to relieve symptoms (CAUTION: no other drugs can be mixed in the pegloticase 
infusion bag). Signs and symptoms of the AE and drugs given for treatment are to be recorded in 
the medical record and in the eCRF. 
After the first incidence of an IR that does not meet the anaphylaxis criteria (see 
Section 9.5.4.1.1.5) or does not meet serious criteria, the Investigator may elect to initiate the 
next infusion at a slower rate. All changes to infusion rate or dilution are to be recorded in the 
medical record and in the eCRF. 
9.4.10 Restricted Medications 
Subjects will be directed to discontinue current urate-lowering therapy at least 7 days prior to 
Day 1.  
Subjects should not receive the following medications from Screening through the end of 
pegloticase and MTX during the trial:  
 Concomitant therapy with allopurinol, febuxostat, probenecid or other urate-lowering 
medications or a PEG-conjugated drug (see Appendix 17.10); 
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 Any MTX other than the trial approved investigational product, azathioprine, 
mycophenolate mofetil or other systemic immunosuppressants aside from glucocorticoids 
for gout flare or IR prophylaxis or intermittent gout flare treatment; 
 Systemic or radiologic treatment for ongoing cancer, excluding non-melanoma skin 
cancer; and 
 Current or chronic treatment with systemic immunosuppressive agents. 
9.4.11 Treatment Compliance 
A dosing calendar will be provided to subjects at the Week -6 Visit for recording the MTX dose 
and the date, time and mg dose of each dose. The dosing calendar and MTX auto-injector should 
be brought to each trial visit for assessment of compliance. At the end of the trial or if the subject 
prematurely discontinues the trial, the subjects will return any unused or partially used trial drugs 
to the site. Adherence to the MTX regimen will also be recorded by the trial coordinator at trial 
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 injected at least 80% of the protocol-specified amount 
of MTX will be considered compliant. Noncompliant subjects will be re-educated on 
compliance.  
At trial visits, the subject will be asked whether folic acid, gout flare and IR prophylaxis were 
administered. 
Pegloticase will be administered at the trial site by trained personnel. The date and time of 
infusion start and stop and the stop and start time of the flush will be recorded. 
9.4.12 Contraception Requirements 
Women of childbearing potential (including those with an onset of menopause <2 years prior to 
Screening, non-therapy-induced amenorrhea for <12 months prior to Screening or not surgically 
sterile [absence of ovaries and/or uterus]) must agree to use 2 reliable forms of contraception 
during the trial, 1 of which is recommended to be hormonal, such as an oral contraceptive.  
cle prior to Week -6 (start of MTX) and 
continue for 30 days after the last dose of pegloticase, or at least 1 ovulatory cycle after the last 
dose of MTX (whichever is the longer duration after the last dose 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.  
Men who are not vasectomized must agree to use appropriate contraception so as to not 
impregnate a female partner of reproductive potential during the trial, beginning with the 
initiation of MTX at Week -6 and continuing for at least 3 months after the last dose of MTX. 
Appropriate contraception methods include condom use and abstinence. 


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9.5 
Efficacy, Quality-of-Life, Pharmacokinetic and Safety Variables 
The Schedule of Assessments is provided in Section 2.1. 
9.5.1 Efficacy Variables 
Efficacy will be assessed based on measurement of sUA levels, urate deposition and 
 
 
and the HAQ-DI, HAQ pain scale and HAQ health scale.  
9.5.1.1 Serum Uric Acid 
Serum samples for measurement of sUA levels will be collected at the Screening Visit, the 
Week -6 Visit (prior to the first dose of MTX) and the Week -2 Visit. On Day 1, a pre- and 
post-infusion sUA will be collected to be shipped to the central laboratory. For the remainder of 
trial visits beginning at Week 2 during the Pegloticase + MTX Treatment Period; 2 sUA samples 
will be collected within 48 hours PRIOR to each pegloticase infusion. One sample will be for 
testing at the 
 local laboratory and the second sample will be sent to the central laboratory 
(the central laboratory sample may be drawn separately from the local collection). The local 
laboratory or central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be drawn on 
different days or times so long as both samples are drawn within 48 hours PRIOR to the infusion 
and the results of at least 1 sample are available prior to the infusion. Additional serum samples 
for sUA levels will be collected after the end of each pegloticase infusion prior to discharge at 
Weeks 10, 12, 14, 20, 22, 32, 34, 44 and 46; at Weeks 21 and 23; and at the End of Pegloticase 
(if applicable) or the Week 24 or 48/End of Trial/Early Termination Visit.  
Serum for sUA analysis will also be collected following the first 7 pegloticase infusions at 
Day 1, Week 2, Week 4, Week 6, Week 8, Week 10 and Week 12, respectively. The sUA will be 
collected at the following non-infusion days: 1st (~24 hours), 4th (~96 hours), 7th (~168 hours) 
and 10th (~240 hours) day after each of the first 4 infusions, Day 1 to Week 6.  Following Week 
8, Week 10, Week 12, sUA will be collected at the following non-infusion days:  1st (~24 hours) 
and 7th (~168 hours). If infusion intervals of less than 2 weeks should occur due to scheduling 
issues, less than 4 sUA measurements between infusions are acceptable. The 1st day (~24hours) 
samples must be obtained at a minimum. If there are restrictions in relation to obtaining the 
interim samples also obtain 7th day (~168 hours) if feasible. 
To ease the on-site visit burden for subjects, for non infusion visit sUA collection, a Home 
Health Care nurse may collect sUA samples, AE data and concomitant medication information if 
the subject consents 
Prior to Week 22, subjects whose lowest available interim sUA value (typically the 1st day 
[~24 hours] after infusion) after the pegloticase infusion at Week 2, 4, 6, 8, 10 or 12 is less than a 
50% reduction from the highest sUA value measured between Screening and pre-infusion on 
Day 1 will discontinue treatment and complete the End of Pegloticase Visit within 2 weeks of the 
last infusion, but remain in the trial for biweekly visits, including the Week 24/End of Trial/Early 
Termination and 30-Day Post-Treatment Follow-up Visits.  
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9.5.2 
 
 
9.5.2.1 
 
9.5.2.2 
 
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9.5.2.3 
 
9.5.3 
 
Serum samples for 
 will be collected after the end of infusion on Day 1 
(prior to discharge); prior to the pegloticase infusion and after the end of infusion (prior to 
discharge) at the Weeks 2, 6, 14 and 22 Visits (Pegloticase + MTX Treatment Period); prior to 
the pegloticase infusion and after the end of infusion at the Week 36 Visit (subjects who may 
gain further benefit beyond 12 infusions and elect to receive pegloticase + MTX during the 
Optional Pegloticase + MTX Extension Period); and at the End of Pegloticase (if applicable) or 
Week 24 or 48/End of Trial/Early Termination Visit. 
Serum samples for evaluation of 
 will be collected at 
the Week -6 Visit (prior to the first dose of MTX); prior to the pegloticase infusion on Day 1 and 
at the Weeks 2, 6, 14 and 22 Visits (Pegloticase + MTX Treatment Period); prior to the 
pegloticase infusion and after the end of infusion at the Week 36 Visit (subjects who may gain 
further benefit beyond 12 infusions and elect to receive pegloticase + MTX during the Optional 
Pegloticase + MTX Extension Period); and at the End of Pegloticase (if applicable) or Week 24 
or 48/End of Trial/Early Termination Visit.  
Blood samples for 
 analysis will be collected prior to the pegloticase 
infusion on Day 1 and at the Weeks 14 and 22 Visits (Pegloticase + MTX Treatment Period) and 
prior to the pegloticase infusion at the Weeks 24, 36 and 46 Visits (subjects who may gain 
further benefit beyond 12 infusions and elect to receive pegloticase + MTX during the Optional 
Pegloticase + MTX Extension 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.  
9.5.3.1 Additional Sample Collection for Future Use 
Optional serum and urine samples will be collected from each consenting subject at the Week -6 
Visit (prior to the first dose of MTX); prior to pegloticase infusion at the Day 1 and Week 14 
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Visits (Pegloticase + MTX Treatment Period); prior to pegloticase infusion at the Week 24 and 
Week 36 Visits (subjects who may gain further benefit beyond 12 infusions and elect to receive 
pegloticase + MTX during the Optional Pegloticase + MTX Extension Period); and at the End of 
Pegloticase (if applicable) and Week 24 or 48/End of Trial/Early Termination Visits.  
Subjects may still participate in the trial even if they decline to provide consent for the optional 
future use of serum and urine samples.  
Samples will be retained for potential future analyses, which may include biomarkers relevant to 
gout (e.g., inflammatory markers), gout co-morbidities in response to pegloticase or other 
potential treatments for gout.  
The samples will be retained no longer than 15 years after trial completion or as required by 
applicable law. The samples will be stored in a secured storage space with adequate measures to 
protect confidentiality. 
Detailed instructions regarding blood sample timing and handling are provided in the Laboratory 
Manual.  
9.5.4 Safety Variables 
Safety assessments will include monitoring and recording of all AEs, whether or not drug 
related, measurement of vital signs, physical examinations and monitoring of hematology and 
blood chemistry and urine test. 
9.5.4.1 Adverse Events 
9.5.4.1.1 Definitions 
9.5.4.1.1.1 Adverse Event Definition 
As defined by the ICH, an AE is any untoward medical occurrence in a clinical trial subject 
administered a medicinal (investigational or non-investigational) product, whether or not the 
event is considered related to the trial drug. An AE is therefore any unfavorable and unintended 
sign (including an abnormal laboratory finding, except for an abnormal sUA result), symptom, or 
disease (new or exacerbated) temporally associated with the use of the trial drug. This includes 
any occurrence that is new in onset or aggravated in severity or frequency from the Baseline 
condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities.  
Examples of an AE include:  
 Conditions newly detected or diagnosed after the signing of the ICF, including conditions 
that may have been present but undetected prior to the start of the trial;  
 Conditions known to have been present prior to the start of the trial that worsen after the 
signing of the ICF; 
 Signs, symptoms or the clinical sequelae of a suspected drug interaction; and  


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 Signs, symptoms or the clinical sequelae of a suspected overdose of either investigational 
product or a concomitant medication (overdose per se should not be reported as an AE). 
Issues that will not be considered an AE include: 
 Conditions present at the start of the trial should be recorded as medical history; 
  Medical or surgical procedures (e.g., endoscopy, appendectomy; however, a condition 
that leads to a procedure is an AE if it qualifies according to the definitions above); 
 Situations where an untoward medical occurrence did not occur (e.g., social, diagnostic, 
elective or convenience admission to a hospital); 
 Fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of 
the trial that do not represent a clinically significant change from Baseline; and 
 Abnormal laboratory or test findings that are not assessed by the Investigator as a 
clinically significant change from Baseline. 
-
that must be used to report/document the AE. 
9.5.4.1.1.2 Serious Adverse Event Definition 
Based on ICH guidelines, an SAE is any untoward medical occurrence that at any dose: 
a. Results in death. 
b. Is life threatening.  
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 
 
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. 
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 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 
 
9.5.4.1.1.3 Non-Serious Adverse Event Definition 
AEs that do not result in any of the outcomes listed in Section 9.5.4.1.1.2 are considered 
non-serious. 
9.5.4.1.1.4 Unexpected Adverse Event Definition 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the Reference 
Safety Information section of the 
 (for pegloticase) or United States 
Prescribing Information (for MTX) or is not listed with the specificity or severity that has been 
observed. Unexpected, as used in this definition, also refers to AEs or suspected adverse 
reactions that are mentioned in the Reference Safety Information as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
9.5.4.1.1.5 Adverse Events of Special Interest 
AESIs include IRs, anaphylaxis, gout flares and MACE. If 3 events of Anaphylaxis (as assessed 
by PI) occur an Adjudication Committee (composed of independent experts external to Horizon) 
Anaphylaxis. The AESI of IR, MACE 
and gout flare will not be adjudicated.  
  


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Tolerability Criteria 
Safety assessments of IR and anaphylaxis will be conducted after 7and 10 subjects in Cohort 1 
complete 6 infusions and after 3, 6, 10,15 and 20 subjects in Cohort 2 complete 6 infusions. If 
more than one-third of subjects experience a severe IR and/or anaphylaxis related to pegloticase 
infusion, the pegloticase infusions will be considered not tolerated. 
The signs and symptoms of 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 be limited to:  
 Respiratory: difficulty breathing with wheezing or stridor; respiratory distress 
manifested as at least 2 or more of the following: tachypnoea, increased use of 
accessory respiratory muscles, cyanosis, recession or grunting; 
 Upper airway swelling (lip, tongue, throat, uvula or larynx); 
 Cardiovascular: hypertension, tachycardia, measured hypotension, a decreased level 
of consciousness or loss of consciousness; 
 Dermatological or mucosal: generalized urticaria (hives), generalized erythema, 
angioedema or generalized pruritus with skin rash 
The Safety Review Team must confirm that the tolerability criteria are not met in Cohort 1, prior 
to Screening subjects with history of pegloticase-related mild IR for Cohort 2. The Safety 
Review Team could stop the trial for other significant safety concerns.  
If an anaphylaxis event occurs in any subject, further dosing with pegloticase for that subject will 
be discontinued. Anaphylaxis events will be adjudicated using the Sampson criteria (see 
Appendix Error! Reference source not found. for guidance on anaphylaxis and IR symptoms 
and assessment). 
Infusion Reaction 
An IR will be defined as any infusion-related AE or cluster of temporally-related AEs, not 
attributable to another cause, which occur during the pegloticase infusion and for up to 2 hours 
post infusion. Other AEs that occur outside of the 2-hour window following the infusion may 
also be categorized as an IR at the Principal 
IR and treatments administered will be documented in the medical record and in the eCRF and 
will be adjudicated.  
Examples of AEs not considered possible IRs include, but are not limited to: laboratory 
abnormalities that are unlikely to have occurred during or within 1 hour following the infusion 
(e.g., anemia), gout flares, most infectious diseases or the recurrence or worsening of a known 
ry.  
In the event of any potential or suspected IR, the procedures in Section 9.4.9.2 will be 
performed. 


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


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9.5.4.1.2 Documentation of Adverse Events 
AE and SAE monitoring will begin from the signing of the ICF until the 30-Day Post-Treatment 
Follow-up Visit. 
Subjects will be questioned about AEs at each trial visit, using nonspecific questions, such as 
trial visit
and documented in the source record after the signing of the ICF.  
9.5.4.1.3 Intensity of Adverse Events 
All AEs, both serious and non-serious, will be assessed for severity using the Rheumatology 
Common Toxicity Criteria v2.0 (Woodworth et al, 2007). The scale displays Grades 1 through 4 
with unique clinical descriptions of severity for each AE (including abnormal laboratory values) 
based on this general guideline.  
 Grade 1 (mild)  asymptomatic or transient, short duration (<1 week), no change in 
lifestyle, no medication or over-the-counter. 
 Grade 2 (moderate)  symptomatic, duration 1 to 2 weeks, alter lifestyle occasionally, 
medications give relief (may be prescription), trial drug continued. 
 Grade 3 (severe)  prolonged symptoms, reversible, major functional impairment, 
prescription medications/partial relief, hospitalized <24 hours, temporary trial drug 
discontinuation or/and dose reduced. 
 Grade 4 (includes life-threatening)  at risk of death, substantial disability, especially if 
permanent, hospitalized >24 hours, permanent trial drug discontinuation. 
9.5.4.1.4 Relationship to Trial 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: 
 Not related: There is no plausible temporal relationship or there is another explanation 
that unequivocally provides a more plausible explanation for the event. 
 Related: There is evidence in favor of a causal relationship (i.e., there is a plausible time 
cour
 
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. 


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The assessment of causality will be based on the information available and may change based 
upon receipt of additional information. 
9.5.4.1.5 Reporting and Documenting SAEs and Product Complaints 
9.5.4.1.5.1 Serious Adverse Events 
Any death, life-threatening event, or other SAE experienced by a subject during the course of the 
trial, whether or not judged drug-related, must be reported within 24 hours of knowledge of the 
event by entering the information into the eCRF. If unable to access the eCRF, the event must be 
reported by submitting the completed SAE form via email or fax to the contacts provided below.  
Fax 
 
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 as outlined above. 
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 Spon
 
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 safety letters to the FDA and Investigators according to 21 CFR 312.32 by Horizon). 
9.5.4.1.5.2 Product Complaints 
A product complaint process will be described in the Trial Reference Manual. Any product 
complaint must be reported to the Sponsor using this process. 
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9.5.4.1.6 Follow-up of Adverse Events 
After the initial recording of an AE, the Investigator should proactively follow the subject. Any 
non-serious AEs that are still ongoing at the 30-Day Post-Treatment Follow-up Visit should be 
reviewed to determine if further follow up is required. The Investigator will document on the AE 
eCRF all ongoing non-serious AEs that will not be followed further after the 30-Day 
Post-Treatment Follow-up Visit. If in doubt, the Investigator sh
Medical Monitor. 
All SAEs should be followed until resolution, until the condition stabilizes, or until the subject is 
lost to follow-up. Once the SAE is resolved, the corresponding AE eCRF page should be 
updated. 
9.5.4.1.7 Medication Error and Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational drug 
to or by a trial subject, at a dose above that which is assigned to that individual subject according 
to the trial protocol. 
All cases of medication errors and overdose (with or without associated AEs) will be 
documented on the eCRF in order to capture this important safety information consistently in the 
database. AEs associated with an overdose and SAEs of overdose are to be reported according to 
the procedures outlined in Section 9.5.4.1.2 and Section 9.5.4.1.5, respectively. 
In the event of drug overdose, the subject is to be treated as appropriate. 
9.5.4.1.8 Review of Adverse Events and Emerging New Safety Information 
The Sponsor will notify all Investigators involved in the clinical investigation of important safety 
information regarding the trial drug, as required by the applicable regulations. Investigators will 
notify their IRB of all such notifications, as required. 
9.5.4.1.9 Reporting of Investigational New Drug Safety Reports 
The Sponsor will notify the United States FDA and all Investigators on any new serious risks 
associated with the drug. 
9.5.4.1.10 Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to competent authorities. 
9.5.4.2 Pregnancy Reporting 
Women of childbearing potential (including those with an onset of menopause <2 years prior to 
the Screening, non-therapy-induced amenorrhea for <12 months prior to the Screening, or not 
surgically sterile [absence of ovaries and/or uterus]) will have a serum pregnancy test at the 
Screening Visit. Urine pregnancy tests will also be performed at all other time points, as 


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indicated in Section 2.1. Pregnancy will not be considered an AE in this trial; however, any 
pregnancy complications, including an elective termination for medical reasons, should be 
reported as an AE.  
Information must be obtained and reported if a female subject suspects that she has become 
pregnant during the trial (including the MTX Run-in Period) up to 30 days after the last dose of 
trial treatment (either pegloticase or MTX), or if a female partner of male subject suspects that 
she has become pregnant during the trial (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 trial 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, the female subject 
will be removed from pegloticase therapy and should remain in the trial unless she withdraws 
consent for trial participation. Pregnancy will be followed until the outcome of pregnancy is 
available. 
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-trial pregnancy and considered 
reasonably related to the trial drug by the Investigator should be reported to the Sponsor. 
Women who are breastfeeding are not eligible to participate in the trial. 
9.5.4.3 Medical History 
Medical history, including gout history (e.g., time of first diagnosis and history of tophi, 
collected on a gout-specific eCRF) and symptom severity, will be recorded at the Screening 
Visit.  
9.5.4.4 Vital Signs, Height and Weight 
Routine vital signs, including blood pressure, respiratory rate, temperature and heart rate will be 
measured at Screening, Weeks -6, -4 and -2 (MTX Run-in Period), Day 1, Weeks 2, 4, 6, 8, 10, 
12, 14, 16, 18, 20 and 22 (Pegloticase + MTX Treatment Period), Weeks 24, 26, 28, 30, 32, 34, 
36, 38, 40, 42, 44 and 46 (for subjects who participate in the Optional Pegloticase + MTX 
Extension Period) and the End of Pegloticase (if applicable), Week 24 or 48/End of Trial/Early 
Termination Visits. Heart rate and blood pressure measurements should be taken after the subject 
has been in a sitting position in a rested and calm state with proper positioning, including back 
heart level and the 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 trial visit. The Korotkoff phase V will be 


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used to determine diastolic blood pressure. During the Pegloticase + MTX Treatment Period 
visits, vital signs should be taken before the pegloticase infusion and any time after the end of the 
 
When possible, the same staff member should take all blood pressure measurements for a given 
subject. 
Weight should be measured in kilograms or pounds when the subject is not wearing shoes and 
recorded at the Screening Visit, prior to pegloticase infusion on Day 1, prior to pegloticase 
infusion at the Week 24 (subjects who may gain further benefit beyond 12 infusions and elect to 
receive pegloticase + MTX during the Optional Pegloticase + MTX Extension Period) and at the 
End of Pegloticase (if applicable) or Week 24 or 48/End of Trial/Early Termination Visits.  
Height will be collected at the Screening Visit only. 
Vital sign monitoring during IR is described in Section 9.4.9.2.  
9.5.4.5 Physical Examinations 
A complete physical examination will be performed at the Screening Visit, including head, eyes, 
ears, nose and throat; heart; lungs; abdomen; skin; extremities; neurological status and 
musculoskeletal system. The examination will include assessment for presence of tophi, as well 
as gout history and symptom severity.  
A targeted physical examination per Investigator judgement will be conducted at the Week -2 
Visit and prior to administration of pegloticase on Day 1 and at the Weeks 4, 8, 12, 16 and 20 
Visits (Pegloticase + MTX Treatment Period); prior to pegloticase infusion at the Weeks 24 and 
36 Visits (subjects who may gain further benefit beyond 12 infusions and elect to receive 
pegloticase + MTX during the Optional Pegloticase + MTX Extension Period); and at the End of 
Pegloticase (if applicable) or Week 24 or 48/End of Trial/Early Termination Visits; at a 
minimum the targeted physical examination should include heart, lungs and abdominal 
examination (Section 2.1).  
Physical examination findings at Screening will be recorded on the appropriate eCRF. 
Clinically significant findings from the targeted physical examinations will be recorded as AEs.  
9.5.4.6 Electrocardiogram 
A 12-lead ECG will be performed at Screening and will be read at the site. 
When possible, a 12-lead ECG will also be performed at the time when a select AESI (see 
Section 9.5.4.1.1.5) is suspected.  


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9.5.4.7 Clinical Laboratory Safety Tests 
A blood sample for G6PD analysis will be collected at the Screening Visit. G6PD testing should 
be performed by the central laboratory; however, if performed by the local laboratory, normal 
ranges should be provided. 
Blood samples (for hematology and clinical chemistry) will be collected at the Screening Visit; 
at the Week -2 Visit; prior to the pegloticase infusion on Day 1 and at the Weeks 2, 6 and 14 
Visits (Pegloticase + MTX Treatment Period); prior to pegloticase infusion at the Week 24 and 
36 Visits (subjects who may gain further benefit beyond 12 infusions and elect to receive 
pegloticase + MTX during the Optional Pegloticase + MTX Extension Period); and at the End of 
Pegloticase (if applicable) or Week 24 or 48/End of Trial/Early Termination Visits. 
Urine samples (for albumin:creatinine ratio) will be collected at the Screening Visit; prior to the 
pegloticase infusion on Day 1 and at the Weeks 2, 6 and 14 Visits (Pegloticase + MTX 
Treatment Period); prior to pegloticase infusion at the Week 24 and 36 Visits (subjects who may 
gain further benefit beyond 12 infusions and elect to receive pegloticase + MTX during the 
Optional Pegloticase + MTX Extension Period); and at the End of Pegloticase (if applicable) and 
Week 24 or 48/End of Trial/Early Termination Visits.  
Women of childbearing potential (as defined in Section 9.5.4.2) will have a serum pregnancy test 
at the Screening Visit; urine samples (for human chorionic gonadotropin) will be collected at all 
other visits.  
Safety laboratory assessments will include:  
 Hematology: complete blood count (hemoglobin concentration, hematocrit, erythrocyte 
count, platelet count, leukocyte count, and differential leukocyte count) with differential;  
 Chemistry: albumin, transaminases (AST, ALT), alkaline phosphatase, total bilirubin, 
creatinine (including calculation for eGFR calculated by the MDRD equation: 175 × 
(standardized serum creatinine [mg/dL])-1.154 × (age)-0.203 × (0.742 if female) × (1.212 if 
African American) or 175 × (standardized serum creatinine [µmol/L]/88.4)-1 154 × (age)-0.203 
× (0.742 if female) × (1.212 if African American), glucose, sodium, potassium, calcium, 
chloride, total protein and blood urea nitrogen; and  
 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 hs-CRP will be collected at the Screening Visit; prior to the pegloticase 
infusion on Day 1 and at the Week 14 Visits (Pegloticase + MTX Treatment Period); prior to 
pegloticase infusion at the Week 24 and 36 Visits (subjects who may gain further benefit beyond 
12 infusions and elect to receive pegloticase + MTX during the Optional Pegloticase + MTX 


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Extension Period); and at the End of Pegloticase (if applicable) and Week 24 or 48/End of 
Trial/Early Termination Visits.  
9.5.4.8 Assessment of Gout Flare 
There is no validated instrument to assess gout flares. Gout flares will be assessed at the time 
points specified in Section 2.1. Investigators will assess gout flares based on subject 
self-reporting, with Investigator confirmation of flare based on subject questioning and/or direct 
observation. All gout flares will be recorded as AEs with the required AE reporting information. 
Investigators will also ask the subject a series of questions related to each gout flare, to document 
subject report of swollen joints, joints that are warm to touch, and level of joint pain (Gaffo et 
al, 2012).  
9.5.5 Safety Review Team 
S
Safety Review Team (comprising members of the Horizon Clinical Development and Patient 
Safety and Pharmacovigilance Teams) based on pre-determined tolerability criteria.  
Depending on any potential safety signals reported (e.g., serious IR or any SAE related to 
pegloticase infusion), regular quarterly and/or ad hoc safety assessments will be conducted 
during the trial as specified in the Safety Management Plan and the Safety Review Team Charter.  
9.5.6 Adjudication Committee 
An Adjudication Committee (composed of independent experts external to Horizon) will be 
established for this trial to adjudicate the AESIs of anaphylaxis, if 3 events of Anaphylaxis (as 
assessed by PI) occur (see Section 9.5.4.1.1.5).  The AESI of IR, MACE and gout flare will not 
be adjudicated. The AESIs of anaphylaxis will be adjudicated at a frequency defined in the 
Adjudication Committee Charter. The committee will be comprised of physicians with 
experience in immunology, allergic reactions, rheumatology and cardiovascular diseases. Details 
outlining the responsibilities of the Adjudication Committee will be included in the Adjudication 
Committee Charter.  
9.5.7 Appropriateness of Measurements 
The trial assessments are appropriate for a trial in subjects with gout and consistent with those 
used in registrational trials.  
9.5.8 Trial Procedures 
Subjects who provide informed consent and who meet all the entry criteria for participation in 
this trial will be enrolled. 
9.5.8.1 Screening Visit (Within 42 Days Prior to the First Dose of MTX at Week -6) 
During the Screening Period, trial candidates will be evaluated for eligibility according to the 
stated inclusion and exclusion criteria (Section 9.3). The following procedures will be performed 
during S
participation into the trial. 


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 Obtain signed, written informed consent. Refusal to provide this permission excludes an 
individual from eligibility for trial participation. Record date informed consent was given 
and who conducted the process on the appropriate source documentation. 
 Determine trial eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3). 
 Obtain demographic information. 
 Chest x-ray for subjects who have not had a chest x-ray within 2 years prior to Screening 
if deemed necessary by the Investigator. 
 Perform a complete physical examination, including assessment of head, eyes, ears, nose 
and throat; heart; lungs; abdomen; skin; extremities; neurological status and 
musculoskeletal system including an assessment for the presence of tophi as well as gout 
history and symptom severity (on gout-specific case report form). 
 Collect prior pegloticase treatment history on pegloticase treatment case report form. 
 Collect complete gout history (on gout-specific CRF), other relevant medical/surgical 
history, and medication history, including gout medications starting at the time of 
diagnosis and up to the screening, substance use history, and all other medications 
currently be taken at screening (see Section 9.4.10 for restrictions regarding medications).  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  
 Record height and weight.  
 Perform 12-lead ECG. 
 Obtain blood samples for hematology and clinical chemistry analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for urine albumin:creatinine ratio. 
 Obtain a serum sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain blood samples to evaluate sUA (only 1 sUA sample for central laboratory). 
  Obtain a blood sample for hs-CRP.   
 Obtain a blood sample for G6PD. 


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 Inquire about AEs and concomitant medication use. 
9.5.8.2 MTX Run-in Period 
 A DECT scan will be obtained. The initial DECT scan will be performed after the 
Screening Visit, during the MTX Run-in Period and prior to the Day 1 Visit. 
9.5.8.2.1 Week -6 
 Confirm trial eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3).  
 Principal Investigator review of subject clinical status and treatment goals.  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain blood samples to evaluate sUA (only 1 sample for central laboratory). 
 
 
 Administer HAQ-DI, 
 
 Record 
. 
 Obtain optional serum and urine samples from subjects who consent for future analysis. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Fill folic acid prescription.  
 Dispense MTX with instructions to take it weekly (see Section 9.4.1 for dosing 
instructions). 
 Obtain blood samples for 
 prior to the first dose 
of MTX. 
 Inquire about AEs and concomitant medication use. 
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9.5.8.2.2 Week -4 
 Confirm trial eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3).  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX (see Section 9.4.1 for dosing instructions). 
 Ask Yes/No question regarding folic acid compliance. 
 Fill folic acid prescriptions, as needed.  
 Inquire about AEs and concomitant medication use. 
 Subjects who inject MTX during Week -6 or Week -5 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 that at least 1 ovulatory cycle has occurred since the last 
dose of MTX. If the subject has not ovulated, a urine pregnancy test will be performed. 
For subjects who are non-vasectomized males, an inquiry will be conducted 
approximately 3 months after MTX discontinuation regarding partner pregnancy.  
9.5.8.2.3 Week -2 
 Confirm trial eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3).  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  
 Obtain blood samples for hematology and clinical chemistry analysis.  


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 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain a blood sample for measurement of sUA (only 1 sample for central laboratory). 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX (see Section 9.4.1 for dosing instructions). 
 Ask Yes/No question regarding folic acid compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Inquire about AEs and concomitant medication use. 
 Subjects who inject MTX during Week -4 or Week -3 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 that at least 1 ovulatory cycle has occurred since the last 
dose of MTX. If the subject has not ovulated, a urine pregnancy test will be performed. 
For subjects who are non-vasectomized males, an inquiry will be conducted 
approximately 3 months after MTX discontinuation regarding partner pregnancy.  
9.5.8.3 Pegloticase + MTX Treatment Period 
9.5.8.3.1 Day 1 
Pre-infusion Day 1 
On Day 1, subjects will return to the clinic for the following assessments prior to the 1st dose of 
pegloticase.  
 Confirm trial eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3). 
 Enroll subjects without a history of pegloticase-related IR in Cohort 1 (see Section 9.4.7).  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  


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 Record weight. 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 
. 
 Administer HAQ-DI, 
 
 Record 
. 
 Obtain optional serum and urine samples from subjects who consent for future analysis. 
 Obtain blood samples for hematology and clinical chemistry analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain blood samples to evaluate sUA (only 1 sample for central laboratory). 
 Obtain blood samples to evaluate hs-CRP. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Obtain blood samples for 
.  
 Obtain blood samples for 
. 
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Subjects who inject MTX during Week -2 or Week -1 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 that at least 1 ovulatory cycle has occurred since the last 
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dose of MTX. If the subject has not ovulated, a urine pregnancy test will be performed. 
For subjects who are non-vasectomized males, an inquiry will be conducted 
approximately 3 months after MTX discontinuation regarding partner pregnancy. 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 1st dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and start/stop times of the 10 ml flush. 
Post-infusion Day 1 
On Day 1, the following assessments will be performed after the pegloticase infusion.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
 Obtain blood sample for 
 after the end of the infusion, prior to 
discharge from the site. 
 Obtain 1 blood sample for measurement of sUA after the end of the pegloticase infusion 
for shipment to the central laboratory. 
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 1st day 
(~24 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 4th day 
(~96 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 7th day 
(~168 hours) after the pegloticase infusion.  
9.5.8.3.2 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 10th 
day (~240 hours) after the pegloticase infusion. Week 2 
Pre-infusion Week 2 
At Week 2, subjects will return to the clinic for the following assessments prior to the 2nd dose of 
pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 2 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
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Horizon Therapeutics Ireland DAC 
 
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Protocol: HZNP-KRY-407
 
 
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drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1).  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain blood samples for hematology and clinical chemistry analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Obtain blood samples for 
. 
 Obtain blood sample for 
 analysis.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 2nd dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
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Post-infusion Week 2 
At Week 2, the following assessments will be performed after the pegloticase infusion.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
 Obtain blood sample for 
 after the end of the infusion, prior to 
discharge from the site. 
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 1st day 
(~24 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 4th day 
(~96 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 7th day 
(~168 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 10th 
day (~240 hours) after the pegloticase infusion.  
o Stopping rule: Subjects whose lowest available interim sUA value (typically the 
1st day [~24 hours] after infusion) after the pegloticase infusion at Week 2 is less 
than a 50% reduction from the highest sUA value measured between Screening 
and pre-infusion on Day 1 will discontinue treatment and complete the End of 
Pegloticase Visit within 2 weeks of the last infusion, but remain in the trial for 
biweekly visits, including the Week 24/End of Trial/Early Termination and 30-
Day Post-Treatment Follow-up Visits. 
9.5.8.3.3 Week 4 
Pre-infusion Week 4 
At Week 4, subjects will return to the clinic for the following assessments prior to the 3rd dose of 
pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 4 
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
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Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 99 of 168 
 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 3rd dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 4 
At Week 4, the following assessment will be performed after the pegloticase infusion.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 1st day 
(~24 hours) after the pegloticase infusion.  


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 100 of 168 
 
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 4th day 
(~96 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 7th day 
(~168 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 10th 
day (~240 hours) after the pegloticase infusion.  
o Stopping rule: Subjects whose lowest available interim sUA value (typically the 
1st day [~24 hours] after infusion) after the pegloticase infusion at Week 4 is less 
than a 50% reduction from the highest sUA value measured between Screening 
and pre-infusion on Day 1 will discontinue treatment and complete the End of 
Pegloticase Visit within 2 weeks of the last infusion, but remain in the trial for 
biweekly visits, including the Week 24/End of Trial/Early Termination and 30-
Day Post-Treatment Follow-up Visits. 
9.5.8.3.4 Week 6 
Pre-infusion Week 6 
At Week 6, subjects will return to the clinic for the following assessments prior to the 4th dose of 
pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 6 
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 
. 
 Administer HAQ-DI. 
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 101 of 168 
 
 Obtain blood samples for hematology and clinical chemistry analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Obtain blood samples for 
. 
 Obtain blood sample for 
 analysis.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 4th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 6 
At Week 6, the following assessments will be performed after the pegloticase infusion.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
 Obtain blood sample for 
 after the end of the infusion, prior to 
discharge from the site. 
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 1st day 
(~24 hours) after the pegloticase infusion.  
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 102 of 168 
 
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 4th day 
(~96 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 7th day 
(~168 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 10th 
day (~240 hours) after the pegloticase infusion.  
o Stopping rule: Subjects whose lowest available interim sUA value (typically the 
1st day [~24 hours] after infusion) after the pegloticase infusion at Week 6 is less 
than a 50% reduction from the highest sUA value measured between Screening 
and pre-infusion on Day 1 will discontinue treatment and complete the End of 
Pegloticase Visit within 2 weeks of the last infusion, but remain in the trial for 
biweekly visits, including the Week 24/End of Trial/Early Termination and 30-
Day Post-Treatment Follow-up Visits. 
9.5.8.3.5 Week 8 
Pre-infusion Week 8 
At Week 8, subjects will return to the clinic for the following assessments prior to the 5th dose of 
pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 8 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 103 of 168 
 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 5th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 8 
At Week 8, the following assessment will be performed after the pegloticase infusion.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 1st day 
(~24 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 7th day 
(~168 hours) after the pegloticase infusion.  
o Stopping rule: Subjects whose lowest available interim sUA value (typically the 
1st day [~24 hours] after infusion) after the pegloticase infusion at Week 8 is less 
than a 50% reduction from the highest sUA value measured between Screening 
and pre-infusion on Day 1 will discontinue treatment and complete the End of 
Pegloticase Visit within 2 weeks of the last infusion, but remain in the trial for 
biweekly visits, including the Week 24/End of Trial/Early Termination and 30-
Day Post-Treatment Follow-up Visits. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 104 of 168 
 
9.5.8.3.6 Week 10 
Pre-infusion Week 10 
At Week 10, subjects will return to the clinic for the following assessments prior to the 6th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 10 
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1).  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 6th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 105 of 168 
 
Post-infusion Week 10 
At Week 10, the following assessment will be performed after the pegloticase infusion.  
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 1st day 
(~24 hours) after the pegloticase infusion.  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 7th day 
(~168 hours) after the pegloticase infusion.  
o Stopping rule: Subjects whose lowest available interim sUA value (typically the 
1st day [~24 hours] after infusion) after the pegloticase infusion at Week 10 is less 
than a 50% reduction from the highest sUA value measured between Screening 
and pre-infusion on Day 1 will discontinue treatment and complete the End of 
Pegloticase Visit within 2 weeks of the last infusion, but remain in the trial for 
biweekly visits, including the Week 24/End of Trial/Early Termination and 30-
Day Post-Treatment Follow-up Visits. 
9.5.8.3.7 Week 12 
Pre-infusion Week 12 
At Week 12, subjects will return to the clinic for the following assessments prior to the 7th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 12 
pegloticase infusion. One sample will be tested for sUA a
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 106 of 168 
 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 7th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 12 
At Week 12, the following assessment will be performed after the pegloticase infusion.  
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 1st day 
(~24 hours) after the pegloticase infusion 
 Obtain blood sample to evaluate sUA (only 1 sample for central laboratory) on the 7th day 
(~168 hours) after the pegloticase infusion.  


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 107 of 168 
 
o Stopping rule: Subjects whose lowest available interim sUA value (typically the 
1st day [~24 hours] after infusion) after the pegloticase infusion at Week 12 is less 
than a 50% reduction from the highest sUA value measured between Screening 
and pre-infusion on Day 1 will discontinue treatment and complete the End of 
Pegloticase Visit within 2 weeks of the last infusion, but remain in the trial for 
biweekly visits, including the Week 24/End of Trial/Early Termination and 30-
Day Post-Treatment Follow-up Visits. 
9.5.8.3.8 Week 14 
Pre-infusion Week 14 
At Week 14, subjects will return to the clinic for the following assessments prior to the 8th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 14 
pegloticase infusion. One sample will be tested for sUA at the 
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1).  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain blood samples for hematology, clinical chemistry and hs-CRP analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 
 
. 
 Administer HAQ-DI, 
 
 Record 
. 
 Obtain optional serum and urine samples from subjects who consent for future analysis. 
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 108 of 168 
 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Obtain blood samples for 
 analysis.  
 Obtain blood samples for 
. 
 Obtain blood sample for 
.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 A DECT scan will be obtained. DECT may be completed within ±10 days of the 
scheduled visit.  
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 8th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 14 
At Week 14, the following assessments will be performed after the pegloticase infusion.  
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
 (see 
Section 9.5.4.4).  
 Obtain blood sample for 
 after the end of the infusion, prior to 
discharge from the site.  
CCI
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 109 of 168 
 
9.5.8.3.9 Week 16 
Pre-infusion Week 16 
At Week 16, subjects will return to the clinic for the following assessments prior to the 9th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 16 
pegloticase infusion. One sample will be tested for sUA at the 
 and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 110 of 168 
 
INFUSION: Following completion of the above procedures, administer the 9th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 16 
At Week 16, the following assessment will be performed after the pegloticase infusion.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
from the site (see 
Section 9.5.4.4).  
9.5.8.3.10 Week 18 
Pre-infusion Week 18 
At Week 18, subjects will return to the clinic for the following assessments prior to the 10th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 18 
pegloticase infusion. One sample will be tested for sUA 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1).  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 111 of 168 
 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 10th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 18 
At Week 18, the following assessment will be performed after the pegloticase infusion.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
 (see 
Section 9.5.4.4).  
9.5.8.3.11 Week 20 
Pre-infusion Week 20 
At Week 20, subjects will return to the clinic for the following assessments prior to the 11th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 20 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4).  


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 112 of 168 
 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 
. 
 Administer HAQ-DI. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis, and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 11th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 20 
At Week 20, the following assessment will be performed after the pegloticase infusion.  
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
 (see 
Section 9.5.4.4).  
9.5.8.3.12 Week 21 
At Week 21, subjects will return to the clinic for the following assessments.  
 Obtain a blood sample for measurement of sUA by the central laboratory.  
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 113 of 168 
 
 Document gout flares and intensity. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Inquire about AEs and concomitant medication use. 
9.5.8.3.13 Week 22 
Pre-infusion Week 22 
At Week 22, subjects will return to the clinic for the following assessments prior to the 12th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 22 
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1).  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis and IR prophylaxis 
compliance. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
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 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed for subjects 
who may gain further benefit beyond 12 infusions and elect to receive pegloticase + 
MTX during the Optional Pegloticase + MTX Extension Period.  
 Obtain blood samples for 
 analysis.  
 Obtain blood samples for 
. 
 Obtain blood sample for 
.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 12th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 22 
At Week 22, the following assessments will be performed after the pegloticase infusion.  
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
after the end of the infusion, but prior to 
 (see 
Section 9.5.4.4).  
 Obtain blood sample for 
 after the end of the infusion, prior to 
discharge from the site. 
9.5.8.3.14 Week 23 
At Week 23, subjects will return to the clinic for the following assessments.  
 Obtain a blood sample for measurement of sUA by the central laboratory.  
 Document gout flares and intensity. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX. 
 Inquire about AEs and concomitant medication use. 
CCI
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 115 of 168 
 
At the discretion of the Principal Investigator, subjects who may gain further benefit may elect to 
receive pegloticase + MTX during the Optional Pegloticase + MTX Extension Period and will 
receive additional infusions at Weeks 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44 and 46.  
9.5.8.3.15 Week 24/1st Infusion of Optional Pegloticase + MTX Extension Period 
Week 24 is the final visit of the Pegloticase + MTX Treatment Period.  Subjects who may not 
gain further benefit beyond 12 infusions 
 and 
decide to complete the study at Week 24 (see Section 9.5.1.1) or who discontinue treatment prior 
to Week 22 will complete the End of Pegloticase Visit (see Section 9.5.8.4). Trial drug is not 
administered for subjects who may not gain further benefit beyond 12 infusions based on the 
.  
For subjects who may gain further benefit beyond 12 infusions and elect to receive trial drug, the 
infusion will be performed at Week 24. 
Pre-infusion Week 24 
At Week 24, subjects will return to the clinic for the following assessments prior to the 13th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 14 
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1).  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Principal Investigator review of subject clinical status and treatment goals.  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Record weight. 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 116 of 168 
 
 Obtain blood samples for hematology, clinical chemistry and hs-CRP analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 
 
. 
 Administer HAQ-DI, 
 
 Record 
. 
 Obtain optional serum and urine samples from subjects who consent for future analysis. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis and IR prophylaxis 
compliance. 
 Fill gout prophylaxis, IR prophylaxis and folic acid prescriptions, as needed.  
 Obtain blood samples for 
. 
 Obtain blood sample for 
.  
 Obtain blood samples for 
 analysis.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 A DECT scan will be obtained. DECT may be completed within ±10 days of the 
scheduled visit.  
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 13th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
CCI
CCI
CCI
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 117 of 168 
 
Post-infusion Week 24 
At Week 24, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
 (see 
Section 9.5.4.4).  
9.5.8.4 End of Pegloticase Visit 
Subjects who end pegloticase infusions prior to Week 22 will complete the End of Pegloticase 
Visit procedures within 2 weeks of their final infusion. Subjects are especially encouraged to 
complete trial visits at the trial site for key efficacy and safety assessments at Weeks 10, 12, 14, 
20, 21, 22, 23 and 24/End of Trial/Early Termination, so that sUA and other key assessments can 
be completed. During visits between these key efficacy and safety collection visits, in subjects 
who have stopped infusions, subjects may complete trial visits in person or via a telephone visit 
to collect AE, concomitant medication and gout flare information (see Section 9.3.3.1.1).  
For subjects who agree to continue trial visits after the End of Pegloticase Visit, the 30-Day Post 
Treatment Follow-up Visit will be captured as part of the continued visits; however, if the last 
trial visit is <30 days posttreatment, the 30-Day Post-Treatment Follow-up phone call/email will 
still be required. 
The following procedures will be completed at the End of Pegloticase Visit:  
 Principal Investigator review of subject clinical status and treatment goals.  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) prior to 
discharge (see Section 9.5.4.4).  
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain optional serum and urine samples from subjects who consent for future analysis. 
 Obtain blood samples for hematology, clinical chemistry and hs-CRP analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 118 of 168 
 
 Obtain a blood sample (1 sample) for measurement of sUA. 
 Administer MTX (subjects who have not stopped pegloticase due to individual subject 
sUA discontinuation criteria).  
 Assess MTX compliance/reconciliation. 
 
. 
 Administer HAQ-DI, 
 
 Record 
. 
 If handheld uric acid device is provided, assess Investigator or subject user experience 
with uric acid device questionnaire at any time during the visit prior to discharge from the 
site. 
 Assess MTX compliance. 
 Ask Yes/No question regarding folic acid compliance. 
 Ask Yes/No question regarding gout flare prophylaxis compliance.  
 A DECT scan may be performed ±10 days from the scheduled visit date. Subjects who 
end pegloticase infusions prior to Week 24 should follow the scheduled time points and 
have a DECT scan at the Week 24/End of Trial/Early Termination Visits. 
 Obtain blood samples for 
. 
 Obtain blood sample for 
.  
 Inquire about AEs and concomitant medication use. 
9.5.8.5 Optional Pegloticase + MTX Extension Period Visits After Week 24 - Subjects 
Who May Gain Further Benefit Beyond 12 Infusions 
9.5.8.5.1 Week 26 
Pre-infusion Week 26 
At Week 26, subjects will return to the clinic for the following assessments prior to the 14th dose 
of pegloticase.  
CCI
CCI
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 119 of 168 
 
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 26 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 14th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 120 of 168 
 
Post-infusion Week 26 
At Week 26, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
scharge/release from the site (see 
Section 9.5.4.4).  
9.5.8.5.2 Week 28 
Pre-infusion Week 28 
At Week 28, subjects will return to the clinic for the following assessments prior to the 15th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 28 
pegloticase infusion. One sample will be tested for sUA 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 121 of 168 
 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 15th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush.  
Post-infusion Week 28 
At Week 28, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
rge/release from the site (see 
Section 9.5.4.4).  
9.5.8.5.3 Week 30 
Pre-infusion Week 30 
At Week 30, subjects will return to the clinic for the following assessments prior to the 16th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 30 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 122 of 168 
 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 16th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 30 
At Week 30, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
rge/release from the site (see 
Section 9.5.4.4).  


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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9.5.8.5.4 Week 32 
Pre-infusion Week 32 
At Week 32, subjects will return to the clinic for the following assessments prior to the 17th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 32 
pegloticase infusion. One sample will be tested for sUA at the 
 and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 124 of 168 
 
INFUSION: Following completion of the above procedures, administer the 17th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 32 
At Week 32, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
after the end of the infusion, but 
 (see 
Section 9.5.4.4).  
9.5.8.5.5 Week 34 
Pre-infusion Week 34 
At Week 34, subjects will return to the clinic for the following assessments prior to the 18th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 34 
pegloticase infusion. One sample will be tested for sUA 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 .  
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 125 of 168 
 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 18th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 34 
At Week 34, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
after the end of the in
Section 9.5.4.4).  


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 126 of 168 
 
9.5.8.5.6 Week 36 
Pre-infusion Week 36 
At Week 36, subjects will return to the clinic for the following assessments prior to the 19th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 36 
pegloticase infusion. One sample will be tested for sUA 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1).  
 Principal Investigator review of subject clinical status and treatment goals.  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain blood samples for hematology, clinical chemistry and hs-CRP analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 
 
. 
 Administer HAQ-DI, 
 
 Record 
. 
 Obtain optional serum and urine samples from subjects who consent for future analysis. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 127 of 168 
 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Obtain blood samples for 
 analysis.  
 Obtain blood samples for 
. 
 Obtain blood sample for 
.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 19th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 36 
At Week 36, the following assessments will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
 (see 
Section 9.5.4.4).  
 Obtain blood sample for 
 after the end of the infusion, prior to 
discharge from the site.  
CCI
CCI
CCI
CCI


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 128 of 168 
 
9.5.8.5.7 Week 38 
Pre-infusion Week 38 
At Week 38, subjects will return to the clinic for the following assessments prior to the 20th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 38 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
Version 2.0, amendment 1, admin change1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 129 of 168 
 
INFUSION: Following completion of the above procedures, administer the 20th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 38 
At Week 38, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
9.5.8.5.8 Week 40 
Pre-infusion Week 40 
At Week 40, subjects will return to the clinic for the following assessments prior to the 21st dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 40 
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 


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 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 21st dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 40 
At Week 40, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
rge/release from the site (see 
Section 9.5.4.4).  
9.5.8.5.9 Week 42 
Pre-infusion Week 42 
At Week 42, subjects will return to the clinic for the following assessments prior to the 22nd dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 42 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 


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 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 22nd dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 42 
At Week 42, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
ischarge/release from the site (see 
Section 9.5.4.4).  


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9.5.8.5.10 Week 44 
Pre-infusion Week 44 
At Week 44, subjects will return to the clinic for the following assessments prior to the 23rd dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 44 
pegloticase infusion. One sample will be tested for sUA 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 
 Re-dispense MTX. 
 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 


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INFUSION: Following completion of the above procedures, administer the 23rd dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 44 
At Week 44, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
Section 9.5.4.4).  
9.5.8.5.11 Week 46 
Pre-infusion Week 46 
At Week 46, subjects will return to the clinic for the following assessments prior to the 24th dose 
of pegloticase.  
 Obtain 2 blood samples for measurement of sUA within 48 hours prior to the Week 46 
pegloticase infusion. One sample wi
local laboratory and 
1 sample will be shipped to the central laboratory for testing. The local laboratory or 
central laboratory pre-infusion sUA results should be reported prior to pegloticase 
infusion. Note:  It is allowable for the local and central laboratory sUA samples to be 
drawn on different days or times so long as both samples are drawn within 48 hours prior 
to the infusion and the results of at least 1 sample are available prior to the infusion (see 
Section 9.5.1.1). 
 Document gout flares and intensity. 
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) (see 
Section 9.5.4.4). 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Provide dosing calendar for subjects to record the date and time they inject MTX. 
Additional calendar pages will be provided at future visits as needed. 
 Assess MTX compliance/reconciliation. 


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 If subject has not injected MTX within the previous 1 to 3 days, administer MTX 
 minutes prior to pegloticase infusion. 
 Ask Yes/No question regarding folic acid, gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis) and IR prophylaxis compliance. 
 Fill gout prophylaxis (at the discretion of the Principal Investigator), IR prophylaxis and 
folic acid prescriptions, as needed.  
 Obtain blood samples for 
 analysis.  
 Administer IR prophylaxis (see Section 9.4.1.5). 
 Inquire about AEs and concomitant medication use. 
INFUSION: Following completion of the above procedures, administer the 24th dose of 
pegloticase and record date, volume and duration of infusion and start/stop (IV infusion 
120 ±15 minutes) times of dosing and the start/stop times of the 10 ml flush. 
Post-infusion Week 46 
At Week 46, the following assessment will be performed after the pegloticase infusion (for 
subjects who may gain further benefit with additional pegloticase treatment beyond 12 infusions 
based on the 
 
 Obtain a blood sample (1 sample) for measurement of sUA by the central laboratory after 
the end of pegloticase infusion, prior to discharge.  
 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) any time 
 (see 
Section 9.5.4.4).  
9.5.8.6 Week 24 or 48/End of Trial/Early Termination Visit 
Subjects who may not gain further benefit beyond 12 infusions based on the Principal 
will complete the 
procedures outlined below.  
The following procedures will be completed at the Week 24 or 48/End of Trial/Early 
Termination Visit.  
 Principal Investigator review of subject clinical status and treatment goals.  
 Perform a targeted physical examination (at a minimum this should include heart, lungs 
and abdominal examination). 
 Document gout flares and intensity. 
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 Record vital signs (blood pressure, respiratory rate, temperature and heart rate) prior to 
discharge (see Section 9.5.4.4).  
 Record weight. 
 Obtain a urine sample for pregnancy testing from female subjects of childbearing 
potential. 
 Obtain optional serum and urine samples from subjects who consent for future analysis 
 Obtain blood samples for hematology, clinical chemistry and hs-CRP analysis and eGFR 
calculation (calculated by the central laboratory).  
 Obtain a urine sample for albumin:creatinine ratio. 
 Obtain a blood sample (1 sample) for measurement of sUA. 
 Administer MTX (subjects who have not stopped pegloticase due to individual subject 
sUA discontinuation criteria).  
 Assess MTX compliance/reconciliation. 
 
. 
 Administer HAQ-DI, 
 
 Record 
. 
 Assess MTX compliance. 
 Ask Yes/No question regarding folic acid and gout flare prophylaxis (for subjects who 
receive gout flare prophylaxis in the Optional Pegloticase + MTX Extension Period) 
compliance. 
 Subjects who end pegloticase infusions prior to Week 24 or 48 should follow the 
scheduled time points and have a DECT scan at the Week 24 or 48/End of Trial/Early 
Termination Visits. 
 Obtain blood samples for 
. 
 Obtain blood sample for 
.  
 Obtain blood samples for 
 analysis.  
 Inquire about AEs and concomitant medication use. 
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9.5.8.7 30-Day Post-Treatment Follow-up Phone/Email Visit 
Thirty (30) days after the last MTX dose or pegloticase infusion (whichever is later), subjects 
will be contacted by telephone or email to review AEs, SAEs and concomitant medications. 
Subjects who receive at least 1 dose of MTX and are females of childbearing potential, will 
receive a safety follow-up phone call/e-mail approximately 4 weeks/30 days after the last dose of 
MTX to verify at least 1 ovulatory cycle has occurred after the last dose of MTX. If the subject 
has not ovulated, the subject will be requested to return to the site for a urine pregnancy test.  
9.5.8.8 MTX Partner Pregnancy Follow-up 
Male subjects who are non-vasectomized will be asked 3 months after MTX discontinuation 
regarding partner pregnancy.  
9.6 
Statistical Methods and Determination of Sample Size 
9.6.1 Endpoints 
9.6.1.1 Primary Endpoint 
The primary efficacy endpoint is the proportion of Month 6 (Weeks 20, 21, 22, 23 and 24) 
responders, defined as subjects achieving and maintaining sUA <6 mg/dL for at least 80% of the 
time during Month 6. 
9.6.1.2 Secondary Endpoints 
The secondary endpoints are:  
 The proportion of Month 3 (Weeks 10 to 14) responders, defined as subjects achieving 
and maintaining sUA <6 mg/dL for at least 80% of the time during Month 3. 
 The proportion of subjects who experienced any of the following events from Day 1 to 
Week 24: IR leading to discontinuation of treatment, anaphylaxis or meeting Individual 
Subject sUA Discontinuation Criteria. 
 The mean change from Baseline in urate deposition volume (measured by DECT) to 
Week 24. 
 The mean change from Baseline in HAQ-DI score at Weeks 14 and 24. 
 The mean change from Baseline in HAQ pain score at Weeks 14 and 24. 


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 The mean change from Baseline in HAQ health score at Weeks 14 and 24. 
9.6.1.3 Exploratory Endpoints 
The exploratory endpoints are:  
9.6.1.4 
 
The 
 are:  
 The concentrations of 
 over time. 
 The incidence and titer of 
 over time. 
 The concentrations of 
 over time. 
9.6.1.5 Safety and Tolerability Endpoints 
Safety and tolerability endpoints are: 
 The incidence of IRs, anaphylaxis, gout flares, MACE and the AE/SAE profile overall 
and potentially attributed to the combination of pegloticase and MTX. 
 The mean change from Baseline in laboratory test results, including hs-CRP.  
 The mean change from Baseline in vital sign results. 
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9.6.2 Analysis Sets 
The following analysis sets will be defined for this trial:  
 MTX treated analysis set: all subjects 
 dose of MTX.  
 Intent-to-treat (ITT) analysis set: all enrolled subjects who receive 
 dose of pegloticase 
with MTX. 
 Safety analysis set: all enrolled subjects who receive 
 dose of pegloticase with MTX. 
 
 
 
  
. 
9.6.3 Demographic Variables 
Demographic data, including age, race, gender, medical history and other disease characteristics, 
will be summarized using descriptive statistics.  
9.6.4 Subject Disposition 
The number of subjects in each analysis set and the number and percentage of subjects who 
complete the trial, who discontinue the trial prematurely, who complete pegloticase treatment 
and who discontinue treatment prematurely, along with the reasons for discontinuation will be 
summarized.  
9.6.5 Efficacy Analysis 
Data will be summarized descriptively. 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.  
9.6.5.1 Primary and Secondary Endpoint Analysis 
The estimand for the primary analysis will use the Treatment Policy Strategy for most 
intercurrent events; selected intercurrent events leading to data that are missing completely at 
random may be addressed with a While-on-Treatment Strategy (e.g., if site closures due to 
COVID-19).  
The primary efficacy endpoint is the proportion of responders during Month 6. The proportion of 
21, 22, 
23 and 24. The amount of time that sUA is <6 mg/dL (using linear interpolation, if necessary) 
will be calculated and divided by the total amount of time from the first to the last observed sUA 
value in this time range (missed values in this time range will be ignored for purposes of this 
calculation). Subjects who have no available sUA value in this time range will be imputed as 
non-responders unless the data are missing completely at random, in which case they will be 
omitted from the analysis. Two-sided exact 95% confidence intervals (CIs) will be calculated. 
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The primary analysis will be performed on all enrolled subjects who receive 
pegloticase with MTX (i.e., the ITT analysis set).  
The proportion of Month 3 responders will be summarized similarly to the Month 6 responders. 
All sUA results collected between infusions from Week 10 through Week 14 of the trial will be 
used in the calculation of the Month 3 responders.  
The mean change from Baseline in in urate deposition volume (measured by DECT) to Week 24 
will be summarized along with the corresponding 95% CI for subjects with DECT assessments. 
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. For this composite endpoint, each individual component of the 
composite will be analyzed overall with a summary of the incidence and the corresponding 
95% CI. 
The primary and secondary endpoints will be summarized overall and by cohort. If Cohort 2 
enrolls both subjects with previous mild IR and those with no previous IR, then the data will be 
summarized by IR category (no IR, mild IR) within Cohort 2 and for Cohorts 1 and 2 combined. 
No adjustments to CIs will be made for multiple endpoints or multiple time points.  
9.6.5.2 Exploratory Endpoint Analysis 
Exploratory endpoints (see Section 9.6.1.3) for 
 will be summarized 
using descriptive statistics.  
9.6.6 
 
Concentrations for 
 will be summarized by time point using 
descriptive statistics for the 
and ITT analysis sets, respectively.  
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Incidence of 
 will be summarized using the ITT analysis set.  
The impact of 
 will be 
explored. 
9.6.7 Safety Analysis 
Treatment-emergent AEs (TEAEs) during the MTX 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 Periods 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 will be summarized separately for the Run-in Period and the Pegloticase + MTX 
Treatment Period (inclusive of the  Optional Pegloticase + MTX Extension Period). TEAEs in 
the Pegloticase + MTX Treatment Period will be summarized overall and by cohort. If Cohort 2 
enrolls both subjects with previous mild IR and those with no previous IR, then the data will be 
summarized by IR category (no IR, mild IR) within Cohort 2 and for Cohorts 1 and 2 combined. 
AEs that occur more than 30 days after the last dose of pegloticase and/or MTX through the 
30-Day Post-Treatment Follow-up Visit will also be summarized.  
The number and percentage of subjects with at least 1 AE, at least 1 SAE, at least 1 severe AE 
and with an AE that leads to discontinuation of pegloticase and/or MTX will be summarized. 
Adverse events will be listed. 
The number and percentage of subjects experiencing AEs will be summarized by system organ 
class and preferred term. Summaries by maximum severity and relationship to MTX and/or 
pegloticase will also be provided. SAEs and AEs leading to discontinuation of MTX and/or 
pegloticase will be presented by system organ class and preferred term. 
The proportion of subjects with SAEs and each AESI will also be summarized.  
Laboratory test results will be summarized by trial visit and change from Baseline. Shift tables 
for laboratory parameters by Common Terminology Criteria for Adverse Events grade will be 
presented. Laboratory test results will also be classified relative to the normal reference range 
(normal, low or high). 
Vital signs, including blood pressure, respiratory rate, temperature and heart rate, will be 
summarized by trial visit and change from Baseline.  
Prior and concomitant medications will be summarized and/or included in the data listings. 
9.6.8 Interim Analyses 
Safety data will be summarized for safety assessments conducted after 7and 10 subjects in 
Cohort 1 complete 6 infusions and after 3, 6,10,15, and 20 subjects in Cohort 2 complete 
6 infusions. The results of these analyses will determine if enrollment will continue in each 
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cohort. Efficacy and safety data may be summarized periodically throughout the trial to support 
scientific publications. Additionally, safety data will be summarized regularly for safety 
monitoring. Final analysis will occur when all subjects have completed the trial. No Type 1 error 
rate adjustments will be made due to multiple summaries.  
9.6.9 Sample Size and Power Considerations 
A sample size of 30 subjects is planned for this trial to provide a sizeable number of subjects to 
support the following projections. The primary efficacy endpoint will be demonstrated to be 
statistically greater than 20% if at least 12/30 (40%) responders are observed. In that case, the 
lower bound of a 95% CI for the proportion of responders will be approximately 23%. 
9.7 
Changes in the Conduct of the Trial 
If any modifications in the experimental design, dosages, parameters, subject selection or any 
other sections of the protocol are indicated or required, the Investigator will consult with the 
Sponsor before any such changes are instituted. Modifications will be accomplished through 
formal amendments to this protocol by the Sponsor and approved from the appropriate IRB. 
All protocol deviations and the reasons for such deviations must be documented in the eCRF.  
The Sponsor has a legal responsibility to report fully to regulatory authorities all results of 
administration of investigational drugs to humans. No investigational procedures other than those 
described in this protocol will be undertaken on the enrolled subjects without the agreement of 
the IRB and Sponsor. 


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10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
The Investigator must maintain adequate and accurate records to document fully the conduct of 
the trial and to ensure that trial data can be subsequently verified. These documents should be 
classified in 2 separate categories: (1) Investigator trial 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 
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 trial center: 
 Medical history/physical condition and diagnosis of the subject before involvement in the 
trial sufficient to verify that the subject meets protocol entry criteria.  
 Trial number, assigned subject number and verification that written informed consent was 
obtained (each recorded in dated and signed progress notes). 
 Progress notes for each subject visit (each dated and signed). 
 Records of each trial visit including each trial assessment and the identity of the staff 
member performing the assessment. 
 Trial drug dispensing and return. 
 Review by the Investigator or qualified personnel on the 1572 of laboratory test results. 
 AEs (start and stop date, description, action taken and resolution). 
 Investigator or sub-
AEs. 
 Concomitant medications (start and stop dates, reason for use). 
 Condition of subject upon completion of, or premature withdrawal from, the trial. 


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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 trial 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. 


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12 TRIAL MONITORING 
The Investigator will ensure that the trial is conducted in accordance with all regulations 
governing the protection of human subjects. The Investigator will adhere to the basic principles 
ibilities of Sponsors 
and Investigators,
ice: Consolidated Guidance.  Additionally, 
this trial 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 trial protocol and 
 to all Sub-Investigators, pharmacists and 
other staff responsible for trial conduct. 
All aspects of the trial will be monitored by qualified individuals designated by the Sponsor. The 
Sponsor will ensure that the trial is monitored adequately in accordance with GCP guidelines. 
Prior to initiation of the trial
trial center 
personnel information regarding the investigational drug, protocol requirements, monitoring 
requirements and reporting of SAEs. 
At intervals during the trial, as well as after the completion of subject enrollment, the trial center 
will be monitored by the Sponsor or designee for compliance. During these visits, the monitor 
will discuss trial 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 trial 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 trial 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 trial 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 trial. 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 trial and to 
have direct access to inspect, for purposes of verification, the hospital or clinical records of all 
subjects enrolled in this trial. A statement to this effect should be included in the ICF. 


Horizon Therapeutics Ireland DAC 
 
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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 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 and 
AE/medical history/surgery/non drug therapy terms will be coded using the Rheumatology 
Common Toxicity Criteria v2.0. 


Horizon Therapeutics Ireland DAC 
 
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14 RETENTION OF RECORDS 
No trial documents at the trial site should be destroyed without prior written agreement between 
the Sponsor and the Investigator. All subjects
eCRF, other supporting data, records of drug dispensing and accountability, signed ICFs, IRB 
correspondence and correspondence with the Sponsor must be kept by the Investigator for at 
least 2 years and/or as required by the local law following the date of the last approval of a 
marketing application in an ICH region (including the United States) and until there are no 
pending or contemplated marketing applications in any other ICH region. If an application is not 
filed or not approved for the indication under study, all trial-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 trial-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 trial was conducted.  


Horizon Therapeutics Ireland DAC 
 
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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. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
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Protocol: HZNP-KRY-407
 
 
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16 REFERENCES 
Albert J, Hosey T, LaMoreaux B. Subcutaneous or oral methotrexate exposure and response to 
pegloticase in uncontrolled gout patients in a community rheumatology practice [abstract]. 
Arthritis Rheumatol. 2019;71:2131-2.  
Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab 
therapy eliminates antidrug antibodies in serum and restores clinical response of patients with 
inflammatory bowel disease. Clin Gastro Hepatol. 2013:11:444-7. 
Berhanu AA, Krasnokutsky S, Keenan RT, Pillinger MH. Pegloticase failure and a possible 
solution: Immunosuppression to prevent intolerance and inefficacy in patients with gout. Semin 
Arthritis Rheum. 2017;46:754-8. 
Bessen SY, Bessen MY, Yung CM. Recapture and improved outcome of pegloticase response 
with methotrexate-A report of two cases and review of the literature. Semin Arthritis Rheum. 
2019a;49:56-61. 
Bessen MY, Bessen SY, Yung CM. Concomitant immunosuppressant use with pegloticase in 
patients with tophaceous gout - a case series. Int J Clin Rheumatol. 2019b;14:238-45. 
Botson J, Peterson J. Pretreatment and co-administration with methotrexate improved durability 
of pegloticase response: a prospective observational, proof-of-concept, case series [abstract]. 
Ann Rheum Dis. 2019;78:A1289. 
Botson JK, Tesser JRP, Bennett R, et al. Pegloticase in combination with methotrexate in 
patients with uncontrolled gout: A multicenter, open-label study (MIRROR). J Rheum. 
2020 Sep 15. doi:10.3899/jrheum.200460.  
Braun J, Kästner P, Flaxenberg P, et al. Comparison of the clinical efficacy and safety of 
subcutaneous versus oral administration of methotrexate in patients with active rheumatoid 
arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. 
Arth Rheum. 2008;58:73-81. 
Bressolle F, Bologna C, Kinowski JM, Sany J, Combe B. Effects of moderate renal insufficiency 
on pharmacokinetics of methotrexate in rheumatoid arthritis patients. Ann Rheum Dis. 
1998;57(2):110-3. 
Brook RA, Forsythe A, Smeeding JE, Lawrence Edwards N. Chronic gout: epidemiology, 
disease progression, treatment and disease burden. Curr Med Res Opin. 2010;26(12):2813 21. 
Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: dimensions and practical 
applications. Health Qual Life Outcomes. 2003;1:20. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
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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;74(6):1037-44. 
Ceponis A, Kavanaugh A. Use of methotrexate in patients with psoriatic arthritis. Clin Exp 
Rheumatol. 2010;28(5 Suppl 61):S132-7. 
CIMZIA (UCB Inc.). Certolizumab pegol for injection, for subcutaneous use. United States 
Prescribing Information. September 2019. 
https://www.cimzia.com/themes/custom/cimzia/docs/CIMZIA full prescribing information.pdf 
FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline 
for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72:744-60. 
Freyne B. A case report of immunosuppressant medication associated polyarticular tophaceous 
gout successfully treated using the polyethylene glycol-conjugated uricase enzyme pegloticase. 
Transplant Proc. 2018;50:4099-101. 
Gaffo AL, Schumacher RH, Saag KG, et al. Developing a provisional definition of flare in 
patients with established gout. Arthritis Rheum. 2012;65(5):1508-17. 
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:R63. 
HUMIRA (AbbVie Inc.). Adalimumab injection, for subcutaneous use. United States Prescribing 
Information. October 2018. https://www.rxabbvie.com/pdf/humira.pdf 
Keenan RT, Baraf HSB, LaMoreaux B. Use of pre-infusion serum uric acid levels as a biomarker 
for infusion reaction risk in patients on pegloticase. Rheumatol Ther. 
2019;https://doi.org/10.1007/s40744-019-0151-9. 
Khanna P, Khanna D, Storgard C, Baumgartner S, Morlock R. A world of hurt: failure to achieve 
treatment goals in patients with gout requires a paradigm shift. Postgrad Med. 
2016;128(1):34 40. 
Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in 
adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 
2012;71:1914-5. 
KRYSTEXXA Full Prescribing Information.  
KRYSTEXXA® Pegloticase (polyethylene glycol-
Pharma, edition 10.0, 25 July 2018. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
Protocol: HZNP-KRY-407
 
 
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Lie E, Kristensen LE, Forsblad-d'Elia H, et al. The effect of comedication with conventional 
synthetic disease modifying antirheumatic drugs on TNF inhibitor drug survival in patients with 
ankylosing spondylitis and undifferentiated spondyloarthritis: results from a nationwide 
prospective study. Ann Rheum Dis 2015;74:970-8. 
Masri K, Winterling K, LaMoreaux B. Leflunomide co-therapy with pegloticase in uncontrolled 
gout. Ann Rheum Dis. 2020;79:450. 
Mease P. Methotrexate in psoriatic arthritis. Bull Hosp Jt Dis. 2013;71 Suppl 1:S41-5. 
Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher HR, Saag KG. Gout epidemiology: 
results from the UK General Practice Research Database, 1990 1999. Ann Rheum Dis. 
2005;64(2):267 72. 
Mouterde G, Baillet A, Gaujoux-Viala C, et al. Optimizing methotrexate therapy in rheumatoid 
arthritis: a systematic literature review. Joint Bone Spine. 2011;78(6):587-92. 
Rainey H, Baraf HSB, Yeo A, Lipsky P. Companion immunosuppression with azathioprine 
increases the frequency of persistent responsiveness to pegloticase in patients with chronic 
refractory gout. Ann Rheum Dis. 2020;79:438. 
REMICADE (Janssen Biotech, Inc.). Infliximab for injection, for intravenous use. United States 
Prescribing Information. May 2020. http://www.janssenlabels.com/package-insert/product-
monograph/prescribing-information/REMICADE-pi.pdf. 
Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. 2010;12(6):223. 
Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res 
Ther. 2006;8 Suppl 1:S2. 
Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology. American College of 
Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying 
antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762-84. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 
2006;117(2):391-7. 
Sattui SE, Singh JA, Gaffo AL. Comorbidities in patients with crystal diseases and 
hyperuricemia. Rheum Dis Clin North Am. 2014;40(2):251 78. 
Schiff MH, Sadowski P. Oral to subcutaneous methotrexate dose-conversion strategy in the 
treatment of rheumatoid arthritis. Rheumatol Int. 2017;37:213-8. 


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
Date: 02 May 2022
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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. 
Strik 
anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in 
patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128-34. 
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. 
Ungar B, Kopylov U, Engel T, et al. Addition of an immunomodulator can reverse antibody 
formation and loss of response in patients treated with adalimumab. Aliment Pharmacol Ther. 
2017;45:276-82. 
Vena GA, Cassano N, Iannone F. Update on subcutaneous methotrexate for inflammatory 
arthritis and psoriasis. Ther Clin Risk Management. 2018;14:105-16. 
Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in 
rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68(7):1094-9. 
Wertheimer A, Morlock R, Becker A. A revised estimate of the burden of illness of gout. Curr 
Ther Res Clin Exp. 2013;75:1 4. 
Woodworth T, Furst DE, Alten R, et al. Standardizing assessment and reporting of adverse 
effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v2.0. 
J Rheumatol. 2007;34(6):1401-14. 
Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general 
population: the National Health and Nutrition Examination Survey 2007 2008. Arthritis Rheum. 
2011;63(10):3136 41. 
 


Horizon Therapeutics Ireland DAC 
 
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17 APPENDICES 
17.1 Administrative Appendix 
This appendix provides names and contact information for the trial 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. 
Clinical Monitor                               
 
                                                          
                                                            
                                                          Horizon Therapeutics U.S.A., Inc. 
                                                          Two Tower Place, 12th Floor  
    South San Francisco, CA 94080 
 
 
Mobile telephone number: 
        
 
 Office telephone number: 
 
 
 Fax number: 
 
 
Email: 
 
 
Sponsor 
 
Representative                                   
 
 
Horizon Therapeutics Ireland DAC, 
 
 
 
Dublin, Ireland  D02E2X4 
 
Mobile telephone number: 
 
 
Fax number: 
 
 
Email:
  
 
Sponsor Contact for 
ICON 
Serious Adverse Event Reporting 
 Fax number: 
 
 
Email: clinicalsafety@horizontherapeutics.com 
 
24-hour Phone Contact for 
Med Communications 
Safety Coverage 
Phone number: 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA® IND: 010122 
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Protocol: HZNP-KRY-407
 
 
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17.2 Health Assessment Questionnaire (Disability Index, Pain and Health Scales) 
Example HAQ-DI below. This page not for subject use. Horizon will supply the site with copies 
for subject use. 
 






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17.4 
 
 
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17.9 Infusion Reaction and Anaphylaxis Assessment Guidance 
1. Infusion Reaction Criteria and Severity Assessment Guidance 
An infusion reaction (IR) will be defined as any infusion-related adverse event or cluster of 
temporally related adverse events, not attributable to another cause, which occur during the 
pegloticase infusion and for up to 2 hours post infusion. Other adverse events that occur outside 
of the 2-hour window and up to 24 hours following the infusion may also be categorized as an IR 
 
In general, the severity assessment should follow the following Infusion Reaction Severity 
definition in the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 (Nov. 2017). 
CTCAE 
term 
Grade 1  
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Life-threatening) 
Grade 5 
Infusion 
related 
reaction 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated 
but responds promptly 
to symptomatic 
treatment 
(e.g., antihistamines, 
nonsteroidal 
anti-inflammatory 
drugs, narcotics, 
intravenous fluids)  
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for clinical 
sequelae 
Life-threatening 
consequences; urgent 
intervention 
indicated 
Death 
A Sponsor Adjudication Committee will review the signs, symptoms and treatment administered 
for the prior IR associated with pegloticase infusion before subjects with history of mild IR are 
enrolled in Cohort 2. 
2. Anaphylaxis Criteria  
Based on NIAID/FAAN (National Institute of Allergy and Infectious Disease/Food 
Allergy and Anaphylaxis Network) criteria by Sampson et al, 2006, anaphylaxis is likely 
when any 1 of the following 3 criteria are fulfilled: 
 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, swollen  
lips tongue uvula) with at least 1of the following 
o Respiratory compromise (e.g., dyspnea, wheeze
bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)  


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o Reduced blood pressure or associated symptoms of end
organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence) 
 Two or more of the following that occur rapidly after exposure to a likely allergen for 
that subject (minutes to several hours) 
o Involvement of the skin mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)  
o Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)  
o Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], 
syncope, incontinence)  
o Persistent gastrointestinal symptoms (e.g., crampy, abdominal pain, 
vomiting).  
 The subject experiences a reduced blood pressure after exposure to a known allergen 
for that subject (minutes to several hours) 
o Systolic blood pressure of less than 90 mmHg or greater than 30% decrease 
from that 
 Baseline.  
 


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17.10 Polyethylene Glycol-Conjugated Drug List 
Concomitant use of other PEG-conjugated drugs including but not limited to those outlined 
below is prohibited from Screening through the end of pegloticase and MTX during the trial.  
Brand Name 
Generic name or Parent protein 
ADAGEN® 
Pegademase bovine 
ADYNOVATE® 
Factor VIII 
CIMZIA® 
Certolizumab pegol 
DOXIL® 
Doxorubicin 
JIVI® 
Factor VIII 
MACUGEN® 
Pegaptanib  
MIRCERA® 
Epoietin beta 
MOVANTIK® 
Naloxegol 
NEULASTA® 
Pegfilgrastim 
OMONTYS® 
Peginesatide 
ONCASPAR® 
Asparaginase 
ONIVYDE 
Irinotecan liposome 
PALYNZIQ® 
Pegvaliase-pqpz 
PEGASYS® 
PegInterferon alfa-2a 
PEGINTRON® 
PegInterferon alfa-2b 
PLEGRIDY® 
PegInterferon beta-1a 
REBINYN® 
Coagulation Factor IX 
SOMAVERT® 
Pegvisomant 
SYLATRON® 
PegInterferon alfa-2b 
 

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Statistical Analysis Plan
Horizon Therapeutics Ireland DAC
HZNP-KRY-407
A Phase 4, Multicenter, Open-label, Efficacy and Safety Trial of Pegloticase
and Methotrexate Co-administered in Patients with Uncontrolled Gout who
have Previously Received Pegloticase Monotherapy but did not Maintain a 
Serum Uric Acid Response (ADVANCE)
Protocol Version: Version 2.0
Sponsor:
Horizon Therapeutics Ireland DAC
1 Burlington Road
Connaught House, 1st Floor
Dublin Ireland D04 C5Y6
Prepared by:
Version
Date
1.0
20 SEP 2021
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS .....................................................................................................................................5
1.
INTRODUCTION..............................................................................................................................................7
2.
STUDY DOCUMENTS .....................................................................................................................................7
3.
STUDY OBJECTIVES......................................................................................................................................7
3.1
PRIMARY OBJECTIVE .......................................................................................................................................7
3.2
SECONDARY OBJECTIVES.................................................................................................................................7
3.3
EXPLORATORY OBJECTIVES.............................................................................................................................8
3.4
SAFETY AND TOLERABILITY OBJECTIVES ........................................................................................................8
4.
STUDY DESIGN AND PLAN ..........................................................................................................................8
5.
DETERMINATION OF SAMPLE SIZE ......................................................................................................11
6.
GENERAL ANALYSIS CONSIDERATIONS..............................................................................................12
7.
VISIT WINDOWS ...........................................................................................................................................12
8.
ANALYSIS SETS.............................................................................................................................................17
9.
STUDY POPULATION...................................................................................................................................18
9.1
SUBJECT DISPOSITION....................................................................................................................................18
9.2
PROTOCOL DEVIATIONS.................................................................................................................................18
9.3
ELIGIBILITY ...................................................................................................................................................19
9.4
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................................................................................19
9.5
PRIOR AND CONCOMITANT MEDICATIONS.....................................................................................................20
10.
EFFICACY ANALYSES.................................................................................................................................21
10.1 EFFICACY VARIABLES....................................................................................................................................21
10.1.1
Primary Efficacy Endpoint..............................................................................................................21
10.1.2
Secondary Efficacy Endpoints.........................................................................................................21
10.1.3
Exploratory Efficacy Endpoints ......................................................................................................22
10.2 BASELINE VALUES.........................................................................................................................................24
10.3 ADJUSTMENTS FOR COVARIATES ...................................................................................................................24
10.4 HANDLING OF DROPOUTS OR MISSING DATA ................................................................................................24
10.5 INTERIM ANALYSIS AND DATA MONITORING ................................................................................................24
10.6 EXAMINATION OF SUBGROUPS.......................................................................................................................25
10.7 MULTIPLE COMPARISON/MULTIPLICITY ........................................................................................................25
10.8 MULTICENTER STUDIES .................................................................................................................................25
11.
METHODS OF EFFICACY ANALYSIS ......................................................................................................25
11.1 HANDLING RULES FOR SUA VALUES.............................................................................................................25
11.2 PRIMARY EFFICACY ENDPOINT AND ANALYSIS .............................................................................................26
11.3 ADDITIONAL ANALYSES OF SUA ...................................................................................................................27
11.4 ANALYSES OF PROPORTION OF SUBJECTS WITH INFUSION REACTIONS, ANAPHYLAXIS, AND MEETING 
INDIVIDUAL SUBJECT SUA DISCONTINUATION CRITERIA .......................................................................................28
11.5 ANALYSES OF DECT SCANS..........................................................................................................................28
11.6 ANALYSES OF 
 
 
..................................28
11.7 ANALYSES OF HEALTH ASSESSMENT QUESTIONNAIRE..................................................................................29
11.8 ANALYSES OF 
...............................................................................................................................29
11.9 ANALYSES OF
......................................................................................................................................29
11.10ANALYSES OF 
............................................................................................................................29
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11.11
 
 
 
 
............................................................................29
11.12
 
 
 
...............................................................................29
11.13
 
 
......................................................................................................................................30
12.
............................................................................................................30
12.1
...........................................................................................................................................30
12.2
 
 
.........................................................................30
12.3
 
 
.....................................................................31
13.
...............................................................................................................31
14.
SAFETY ANALYSES......................................................................................................................................32
14.1 EXTENT OF EXPOSURE ...................................................................................................................................32
14.2 ADVERSE EVENTS..........................................................................................................................................34
14.3 ADVERSE EVENTS OF SPECIAL INTEREST.......................................................................................................36
14.4 CLINICAL LABORATORY EVALUATION ..........................................................................................................39
14.5 VITAL SIGNS ..................................................................................................................................................39
14.6 PHYSICAL EXAMINATION...............................................................................................................................40
14.7 ELECTROCARDIOGRAM ..................................................................................................................................40
15.
CHANGES TO PROTOCOL-SPECIFIED ANALYSES.............................................................................40
16.
REFERENCES.................................................................................................................................................41
17.
APPENDICES..................................................................................................................................................42
APPENDIX A: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS...........................42
APPENDIX B: DETAILS ON 
VALUE SET........................................................................................46
APPENDIX C: LIST OF TABLES, LISTINGS, AND FIGURES ........................................................................54
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LIST OF ABBREVIATIONS
Abbreviation
Full Notation
ADA
Anti-drug antibodies
AE
Adverse event
AESI
Adverse event of special interest
ATC
Anatomical Therapeutic Chemical
BLQ
Below limit of quantification
BMI
Body mass index 
CI
Confidence interval
COVID-19
Coronavirus Disease 2019
CS
Clinically significant
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CTC
Common Toxicity Criteria
CV
Coefficient of variation
DECT
Dual-energy computed tomography
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
estimated glomerular filtration rate
ET
Early termination
HAQ
Health Assessment Questionnaire 
HAQ-DI
Health Assessment Questionnaire Disability Index
hs-CRP
high-sensitivity C-reactive protein
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IR
Infusion reaction
ITT
Intent-to-treat
IV
Intravenously 
MACE
Major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
MCS
Mental composite summary
MTX
Methotrexate
NCS
Not clinically significant
PCS
Physical composite summary
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Abbreviation
Full Notation
PT
Preferred term
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SMQ
Standard MedDRA query
SOC
System organ class
sUA
Serum uric acid
TLFs
Tables, listings, and figures
VAS
Visual analog scale
CCI
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1.
INTRODUCTION
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Horizon Therapeutics Ireland DAC protocol HZNP-KRY-407 [A 
Phase 4, Multicenter, Open-label, Efficacy and Safety Trial of Pegloticase and Methotrexate 
Co-administered in Patients with Uncontrolled Gout who have Previously Received Pegloticase 
Monotherapy but did not Maintain a Serum Uric Acid Response (ADVANCE)]. The purpose of 
this plan is to provide specific guidelines for the statistical analyses. Any deviations from this 
plan will be documented in the clinical study report (CSR).
2. STUDY DOCUMENTS
The following study documents are used for the preparation of the statistical analysis plan (SAP):
Protocol Version 2.0, 10 AUG 2021
Annotated electronic case report form (eCRF), Version 1.054, 29 JAN 2021
3. STUDY OBJECTIVES
3.1
Primary Objective
The primary objective is to demonstrate that the response rate during Month 6 (Weeks 20, 21, 
22, 23 and 24), as measured by the sustained normalization of serum uric acid (sUA) to <6 
mg/dL for at least 80% of the time during Month 6, is greater than 20% in subjects receiving 
pegloticase with methotrexate (MTX). 
3.2
Secondary Objectives
To evaluate the effect of pegloticase with MTX on the following: 
The response rate during Month 3 (Weeks 10, 12 and 14), as measured by the sustained 
normalization of sUA to <6 mg/dL for at least 80% of the time during Month 3. 
The proportion of subjects who experienced any of the following events from Day 1 to 
Week 24: infusion reaction (IR) leading to discontinuation of treatment, anaphylaxis or 
meeting Individual Subject sUA Discontinuation Criteria. 
The change from Baseline in urate deposition volume, measured by dual-energy 
computed tomography (DECT) scan. 
The change from Baseline in Health Assessment Questionnaire (HAQ) - Disability Index 
(HAQ-DI) score. 
The change from Baseline in HAQ pain score. 
The change from Baseline in HAQ health score. 
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3.3
Exploratory Objectives
To evaluate the effect of pegloticase with MTX on the following: 
3.4
Safety and Tolerability Objectives
To evaluate the effect of pegloticase with MTX on the following: 
The adverse event (AE)/serious adverse event (SAE) profile overall for pegloticase and 
MTX and the incidence of adverse events of special interest (AESIs), including IRs, 
anaphylaxis, gout flares and major adverse cardiovascular events (MACE, defined as 
non-fatal stroke, non-fatal myocardial infarction, cardiovascular death and congestive 
heart failure). 
The change from Baseline in safety laboratory test results, including high-sensitivity C-
reactive protein (hs-CRP).
The change from Baseline in vital signs.
4. STUDY DESIGN AND PLAN
This is a Phase 4, multicenter, open-label trial of pegloticase with MTX in adult subjects with
uncontrolled gout who were previously treated with pegloticase without a concomitant
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immunomodulator and stopped pegloticase due to failure to maintain sUA response and/or a
clinically mild IR. Approximately 30 subjects will be enrolled. The treatment period with
pegloticase + MTX will be approximately 24 weeks, with optional extension up to 48 weeks.
The trial design will include 5 distinct components:
1) a Screening Period, lasting up to 42 days;
2) a 6-week MTX Tolerability Assessment Period (hereafter referred to as the MTX Run-in 
Period);
3) a 24-week Pegloticase + MTX Treatment Period, which will include a Week 24/End of 
Trial/Early Termination Visit (subjects that end MTX and pegloticase treatment prior to 
Week 24 will remain on trial for follow-up until the Week 24 visit);
4) an Optional Pegloticase + MTX Extension Period from Week 24 to Week 48, if a subject 
may gain further benefit with additional pegloticase treatment per the discretion of the 
Principal Investigator, which will include a Week 48/Optional End of Trial/Optional 
Early Termination Visit and
5) a 30-day post-treatment follow-up (phone/email) 30 days after the last pegloticase 
infusion or last dose of MTX (for subjects who are unable to tolerate MTX during the 
MTX Run-in Period and do not dose pegloticase.) Subjects that end MTX and pegloticase 
treatment prior to Week 24 and remain on trial for at least 30 days prior to Week 24 will 
complete the 30-day Post-Treatment Follow-up as part of the visits following the End of 
Pegloticase visit.
All subjects who meet eligibility criteria at Screening will begin titrating up to a once weekly 
subcutaneous MTX at a target dose of 25 mg (if estimated glomerular filtration rate (eGFR) is 
45 mL/min/1.73 m2) or 15 mg (if eGFR is 30 and <45 mL/min/1.73 m2) for 6 weeks prior to 
the first dose of pegloticase. Subjects will also take folic acid at a starting dose of 1 mg orally 
every day beginning at Week -6 (preferably 2 days prior to the first dose of MTX) continuing 
until prior to the End of Pegloticase Visit (if applicable) or until 1 week after the last pegloticase 
infusion for subjects who have not stopped pegloticase treatment. A higher folic acid dose or an 
alternative folate supplement will be allowed.
Subjects must be able to tolerate MTX at a minimum dose of 15 mg during the 6-week MTX 
run-in period to be eligible to participate in the Pegloticase + MTX Treatment Period, regardless 
of baseline eGFR. Subjects who are unable to tolerate MTX 15 mg during the MTX run-in
period will be considered MTX run-in screen failures.  
All subjects who meet the inclusion/exclusion criteria and complete the MTX run-in period will 
be considered enrolled subjects and will receive the first pegloticase infusion on Day 1. All
subsequent doses and trial visits will be scheduled based on the Day 1 visit date. During the 
Pegloticase + MTX Treatment Period, pegloticase 8 mg will be administered intravenously (IV)
every 2 weeks from Day 1 through the Week 22/Week 46 visit, after all predose trial visit 
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assessments have been completed at each visit. The date, start and stop time of infusion will be 
recorded.  
Individual subject sUA will be measured locally within 48 hours prior to each pegloticase 
infusion throughout the trial and by the central laboratory on infusion visit days. In addition, 
sUA will be collected between infusions for the first 12 weeks of the trial. These interim sUA 
values will be measured at the 1st (~24 hours), 4th (~96 hours), 7th (~168 hours) and 10th (~240
hours) day after each infusion at Day1, Week 2, Week 4, Week 6 and at the 1st (~24 hours) and 
7th (~168 hours) day after infusion at Week 8, Week 10, and Week 12.
Pegloticase treatment will continue if there is a meaningful sUA reduction from the Baseline, at 
the discretion of the Principal Investigator, even if sUA<6 mg/dL is not maintained consistently 
over the 2-week interval between infusions during this 12-week period. However, pegloticase 
treatment should be stopped if the lowest available interim sUA value (typically the 1st day [~24 
hours] after infusion) after the pegloticase infusion at Week 2, 4, 6, 8, 10 or 12 is less than a 50% 
reduction from the highest sUA value measured between Screening and pre-infusion on Day 1. 
Prior to Week 22, subjects who discontinue treatment due to individual subject sUA levels, as 
evaluated by the Principal Investigator, will remain in the trial for biweekly visits, including the
Week 24/End of Trial/Early Termination and 30-Day Post-Treatment Follow-up Visits if not
captured as part of post treatment follow-up. 
Two sequential cohorts of subjects will be enrolled in this trial. Cohort 1 is targeted to enroll 10 
subjects who previously failed to maintain sUA response with pegloticase monotherapy and
stopped pegloticase treatment without a history of pegloticase-related IR. After 7 and 10 subjects 
in Cohort 1 complete at least 6 infusion visits, safety assessments of IR and anaphylaxis from 
will be performed by the Safety Review Team (comprising members of 
the Horizon Clinical Development and Patient Safety and Pharmacovigilance Teams) based on 
pre-determined tolerability criteria. If a subject discontinues treatment or discontinues the trial 
prior to the 7th infusion, their available data will be included in the safety assessment. If the 
safety assessment during Cohort 1 indicates that the pegloticase infusions are well tolerated 
based on the pre-determined tolerability criteria (no more than one-third of subjects experience a 
severe IR and/or anaphylaxis) then the trial can begin enrolling Cohort 2. If the safety assessment 
indicates that the pegloticase infusions are not well tolerated based on the predetermined
tolerability criteria, then the trial will cease to screen and enroll new subjects. Subjects who are
ongoing and benefitting from continued treatment, as determined by the Principal Investigator at
the time of the termination of new subject screenings, will be permitted to continue treatment and
trial visits.
The aim is to enroll up to 20 subjects with or without a history of pegloticase-related clinically 
mild IR in Cohort 2. After 3, 6, 10, 15 and 20 subjects in Cohort 2 complete at least 6 infusion 
by the Safety Review Team. If the safety assessment indicates that the pegloticase infusions are 
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not well tolerated based on the pre-determined tolerability criteria or in the absence of subjects 
with a history of pegloticase-related clinically mild IR, the trial will continue enrolling subjects 
without a history of pegloticase-related clinically mild IR to reach a total of 30 subjects enrolled 
for the trial.  
Depending on any potential safety signals reported (e.g., serious IR or any SAE related to 
pegloticase infusion), regular quarterly and/or ad hoc safety assessments will be conducted 
during the trial as specified in the Safety Management Plan and the Safety Review Team Charter. 
The regular quarterly reviews will include review of the database by the Safety Review Team 
and will be conducted as set out in the Safety Management Plan. The first safety review meeting 
will occur approximately after the first 3 subjects in Cohort 1 complete at least 12 weeks of the 
Pegloticase + MTX Treatment period (6 infusion visits). The Safety Review Team could stop the 
trial for other significant safety reasons.  
If 3 events of anaphylaxis (as assessed by PI) occur, an Adjudication Committee (composed of 
independent experts external to Horizon) will be established for this trial to adjudicate the AESI 
Anaphylaxis at a frequency defined in the Adjudication Committee Charter. The AESI of IR, 
MACE and gout flare will not be adjudicated.  
Samples for measurement of sUA levels will be collected at Screening, during the MTX run-in
period, pre- each infusion, post-infusion on Day 1 and at the Week 10, 12, 14, 20, 22, 32, 34, 44
and 46 Visits and on non-infusion days on the 1st (~24 hours), 4th (~96 hours), 7th (~168 hours) 
and 10th (~240 hours) day after the first 4 infusions (Infusions 1, 2, 3, 4) and on the 1st (~24 
hours) and the 7th (~168 hours) day after the  5th , 6th   and 7th infusion, Weeks 21 and 23, and at 
the End of Pegloticase (if applicable) or the Week 24 or 48/End of Trial/Early Termination Visit.
Samples will be collected for 
 and
. 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 and urine test, will be performed.
All sites and subjects will be provided with FDA-approved handheld sUA devices to
measure subject uric acid levels based on capillary samples. Results will be collected in the
eCRF at non-infusion visits and pre- and post-infusion during pegloticase infusion visits.
Subjects may also use the device to measure uric acid at home. Results will be collected for
exploratory uses only. No in-trial treatment decisions will be made based upon the data 
generated with the handheld device.
5. DETERMINATION OF SAMPLE SIZE
A sample size of 30 subjects is planned for this trial to provide a sizeable number of subjects to 
support the following projections. The primary efficacy endpoint will be demonstrated to be 
statistically greater than 20% if at least 12/30 (40%) responders are observed. In that case, the 
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lower bound of a 95% confidence interval (CI) for the proportion of responders will be 
approximately 23%.  
6. GENERAL ANALYSIS CONSIDERATIONS
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs. 
Unless otherwise noted, all statistical testing will be 2-sided and will be performed at the 0.05 
significance level. 
Continuous variables will be summarized by presenting the number of observations, means, 
standard deviations (SDs), medians, quartiles, minimums, and maximums. 
Categorical variables will be summarized by presenting counts and percentages of subjects in
corresponding categories. All possible categories as defined in the CRF should be populated,
even if they have zero counts. Percentages are based on the total number of subjects unless 
otherwise specified.
All summary tables will be presented by cohort and with an overall column. If Cohort 2
enrolls both subjects with previous mild IR and those with no previous IR, then the data will be 
summarized by IR category (no IR, mild IR) within Cohort 2 and for Cohorts 1 and 2 no IR 
subjects combined.
Individual subject data obtained from the eCRFs, external vendors, and any derived data will be 
presented by subject in data listings.
The analyses described in this plan are considered a priori, in that they have been defined before
database lock.
Any analyses performed after database lock will be considered post hoc and exploratory. Post
hoc analyses will be labeled as such on the output and identified in the CSR.
All analyses and tabulations will be performed using SAS software Version 9.4 or higher. 
Tables, listings, and figures will be presented in RTF format. 
7. VISIT WINDOWS
For all analyses, data will be summarized according to the scheduled visit and time points as 
outlined in the protocol and by the visit denoted on the eCRF. The reference date associated with 
each visit is collected on the Visit Date eCRF page. Further, the End of Study/Early Termination 
(ET) visit and the End of Pegloticase Infusion Visit will be windowed to a visit based on the 
study day of occurrence relative to the target day of each scheduled visit according to Table 1, 
Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, and Table 8 below. If an End of Study/ET 
or End of Pegloticase Infusion visit is reassigned to a visit for which the subject has scheduled 
data collected, the data from the nominal scheduled visit will take precedence and the data from 
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the End of Study/ET or End of Pegloticase Infusion visit will not be summarized. Table 1 shows 
windows for the vital sign assessments. Table 2 shows windows for the hematology, chemistry, 
and urinalysis clinical laboratory assessments. Table 3 shows the windows for the hsCRP 
laboratory assessments. Table 4 shows the windows for the DECT scans. Table 5 shows the 
windows for HAQ and 
 count assessments. Table 6 shows the windows for 
 
, and 
. Table 7 shows the windows 
for 
 and 
 assessments. Table 8 shows the windows for 
sUA assessments. Unscheduled sUA visits, assessed by the central or local laboratory, will also 
be assigned to an analysis visit according to the windows in Table 8. These unscheduled 
assessments will only be used for the determination of sUA responder status. For all assessments, 
the study day in the Pegloticase + MTX period will be calculated relative to the first dose of 
pegloticase.
Table 1: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (Vital Signs)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
Week 2
15
2 
22
Week 4
29
23 
36
Week 6
43
37 
50
Week 8
57
51 
64
Week 10
71
65 
78
Week 12
85
79 
92
Week 14
99
93 
106
Week 16
113
107 
120
Week 18
127
121 
134
Week 20
141
135 
148
Week 22
155
149 
162
Week 24
169
163 
176
Week 26
183
177 
190 
Week 28
197
191 
204
Week 30
211
205 
218
Week 32
225
219 
232
Week 34
239
233 
246
Week 36
253
247 
260
Week 38
267
261 
274
Week 40
281
275 
288
Week 42
295
289 
302
Week 44
309
303 
316
Week 46
323
317 
330 
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Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Week 48
337
Table 2: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (Hematology and Chemistry Laboratory Assessments, eGFR, urine 
albumin:creatinine ratio)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
Week 2
15
2 
29
Week 6
43
30
71
Week 14
99
72 
134
Week 24
169
135 
211
Week 36
253
212 - 295
Week 48
337
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Table 3: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (hsCRP)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
Week 14
99
2 
134 
Week 24
169
135 
211 
Week 36
253
212 
295 
Week 48
337
Table 4: Visit Windows for Assigning End of Study/ET and End of Pegloticase Visits to a 
Scheduled Visit (DECT)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
Week 14
99
2 
134 
Week 24
169
135 
253
Week 48
337
Table 5: Visit Windows for Assigning ET and End of Pegloticase Visits to a Scheduled Visit 
(HAQ, 
)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
Week 6
43
2 
71
Week 14
99
72 
120
Week 20
141
121 
155
Week 24
169
156 
211
Week 36
253
212 
295
Week 48
337
Table 6: Visit Windows for Assigning ET and End of Pegloticase Visits to a Scheduled Visit 
(
, 
)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
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Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Week 14
99
2 
134
Week 24
169
       135 
211
Week 36
253
            212 
295
Week 48
337
          
Table 7: Visit Windows for Assigning ET and End of Pegloticase Visits to a Scheduled Visit 
(
, 
)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
Week 2
15
2 
29
Week 6
43
30 
71
Week 14
99
72 
127
Week 22
155
128 
162
Week 24
169
163 
211
Week 36
253
212 
295
Week 48
337
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Table 8: Visit Windows for Assigning ET and End of Pegloticase Visits to a Scheduled Visit 
(sUA Assessments)
Study Period
Visit
Target Day  
Window for 
Reassignment to 
Scheduled Visit (days)
Pegloticase + MTX
Day 1
1
1
Week 2
15
2 
22
Week 4
29
23 
36
Week 6
43
37 
50 
Week 8
57
51 
64
Week 10
71
65 
78 
Week 12
85
79 
92 
Week 14
99
93 
106 
Week 16
113
107 
120 
Week 18
127
121 
134 
Week 20
141
135 
144
Week 21
148
145 
151
Week 22
155
152 
158 
Week 23
162
159 
165 
Week 24
169
166 
176
Week 26
183
177 
190 
Week 28
197
191 
204 
Week 30
211
205 
218 
Week 32
225
219 
232 
Week 34
239
233 
246 
Week 36
253
247 
260 
Week 38
267
261 
274 
Week 40
281
275 
288 
Week 42
295
289 
302 
Week 44
309
303 
316
Week 46
323
317
330 
Week 48
337
31
8. ANALYSIS SETS
The following subject analysis sets will be used for safety analyses: 
The safety analysis set will include all enrolled subjects who receive at least 1 dose of 
pegloticase + MTX.
The MTX analysis set will include all subjects who receive at least 1 dose of MTX.
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The following subject analysis set will be used for efficacy analyses: 
The intent-to-treat (ITT) analysis set will include all enrolled subjects who receive at 
least 1 dose of pegloticase + MTX.
The following analysis set will be used for
.
Note that the safety analysis set and ITT analysis set are defined the same for this protocol.
9. STUDY POPULATION
9.1
Subject Disposition
The number of subjects screened, the number of screen failures, the number of subjects who 
entered the MTX Run-in period and the number of subjects who discontinued the MTX Run-in 
period will be summarized. The number of subjects in each analysis set, the number of subjects 
who entered the Pegloticase + MTX treatment period, the number of subjects who completed and 
discontinued from the Pegloticase + MTX treatment period (separately for Weeks 1-24 and the 
optional period Weeks 24-48), and the number of subjects who completed and discontinued the 
study, along with the reasons for discontinuation for Week 24 and Week 48 respectively will be 
summarized.
Subject study duration in weeks will be summarized for subjects in the ITT analysis set. The 
number of subjects with results for each scheduled visit will also be presented. A subject will be 
considered to have completed a visit if they had any results recorded in the eCRF for the visit. 
Subject study duration will be calculated from the first visit in the MTX Run-in Period (Week -6) 
to the end of trial visit date, on which the end of study assessment (i.e., Week 48) is performed.
9.2
Protocol Deviations
Major protocol deviations that could potentially affect the efficacy or safety conclusions of the 
study will be identified before database lock. Major protocol deviations are detailed in the 
Protocol Deviation Management Plan and may include, but are not limited to:
Subjects who did not satisfy selected key inclusion and exclusion criteria;
Subjects who developed withdrawal criteria during the study but were not withdrawn;
Subjects who received an incorrect dose;
Subjects who received an excluded concomitant treatment.
The number of subjects experiencing any minor protocol deviation, any major protocol deviation
and any deviation related to COVID-19, along with the number of protocol deviations, will be 
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presented for subjects in the ITT analysis set. Major protocol deviations will be further 
summarized by deviation category. 
All protocol deviations, including the deviation designation (major or minor), category, 
subcategory, and indication of whether the deviation was related to COVID-19 will be presented 
in a data listing.
9.3
Eligibility
A listing of subjects not fulfilling all eligibility criteria will be created.
9.4
Demographic and Baseline Characteristics
Demographic and baseline data and gout history will be summarized using descriptive statistics. 
Demographic variables include age (in years), sex, ethnicity and race.  
Other baseline characteristics include height (in cm), weight (in kg), body mass index (BMI in 
kg/m2), childbearing potential (for females only), and substance use history.
Descriptive statistics will be presented for age, height, weight, BMI, sex, ethnicity, race, 
childbearing potential (for females only), tobacco use, alcohol use, and other substance use. 
Demographic and baseline characteristics will be summarized for the ITT analysis set.
Gout history variables will include time since first gout attack (in years), time since first gout 
diagnosis (in years), presence of uric acid crystals confirming diagnosis, number of acute flares 
in past 12 month, number of acute flares in past 6 months, pattern of flares, typical severity of 
acute flares, chronic gout synovitis/arthropathy, prior or current tophi, history of overnight 
hospital stay for gout, history of surgery for gout (excluding arthrocentesis), history of kidney 
stones,  kidney function impacted by gout, number of episodes of renal colic in the past year, and 
urate lowering therapy history (allopurinol, febuxostat, and other urate lowering therapy for 
gout).
Time since first gout attack will be calculated as: (informed consent date - date of first gout 
attack + 1) / 365.25, rounded to two decimal places. In the event of a partial first gout attack 
date, the earliest possible date implied by the data provided will be imputed.
Time since first gout diagnosis will be calculated as: (informed consent date - date of first 
diagnosis + 1) / 365.25, rounded to two decimal places. In the event of a partial diagnosis date, 
the earliest possible date implied by the data provided will be imputed.
Gout history will be summarized for the ITT analysis set.
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Medical/Surgical history
The verbatim term of the medical/surgical history condition/event will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) 23.1. 
Medical/surgical history will be summarized in the ITT analysis set and will be ordered 
alphabetically by system organ class (SOC) and by preferred term (PT) within system organ 
class. 
Medical/surgical history terms and tobacco and alcohol history will be listed.
Pegloticase History
Pegloticase use history will be summarized in the ITT analysis set using descriptive statistics. 
Pegloticase history variables will include: time since last dose to screening, duration of 
treatment, dosing frequency, total number of infusions, reason for stopping pegloticase 
treatment, sUA stopping rule met (if applicable), and infusion reaction severity (if applicable). 
9.5
Prior and Concomitant Medications
Prior and concomitant medication verbatim terms in the eCRFs will be mapped to Anatomical 
Therapeutic Chemical (ATC) level 4 and preferred names using the WHODRUG Global B3 
Sep2020.
Partial dates will be imputed. For details on imputation rules, refer to Appendix A: Presentation 
of Data and Programming Specifications. Imputed dates are only used for classification of 
medication into prior or concomitant medication; no other calculation such as durations will be 
done.
Prior medications are defined as any medication with a start date prior to the date of first dose of 
treatment in the MTX Run-in Period. 
Concomitant medications during the MTX Run-in Period are defined as:
Medications with a start prior to the first dose of MTX in the MTX Run-in Period that are 
ongoing or with a stop date after the first dose of MTX in the MTX Run-in Period.
Medications with a start date after the first dose of MTX in the MTX Run-in Period but 
before the first dose of pegloticase and before 30 days after the last MTX dose, for 
subjects who did not receive an infusion of pegloticase.
Concomitant medications during the Pegloticase + MTX Period are defined as:
Medications with a start prior to the first dose of pegloticase that are ongoing or with a 
stop date after the first dose of pegloticase.
Medications with a start date after the first dose of pegloticase but before 30 days after 
the last dose of pegloticase.
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Medications with a partial start date where month and year of start match the month and year of 
first MTX date and match the month and year of first Pegloticase infusion will be classified as 
being concomitant in both the MTX Run-in Period and in the Pegloticase + MTX Period. In 
general, medications can be classified in one or more of prior, concomitant during the MTX 
Run-in Period, and concomitant during the Pegloticase + MTX Period categories.
Summaries will be presented separately for prior medications, concomitant medications during 
the MTX Run-in Period, and concomitant medications during the Pegloticase + MTX Period. 
Summaries will be presented by ATC Level 4 term and preferred drug name. Medication 
summaries will be sorted alphabetically by ATC Level 4 and by preferred drug name within 
ATC Level 4. Subjects will be counted only once for each medication class and each preferred 
drug name. 
Concomitant procedures and prior and concomitant medications will be presented in a listing.
10. EFFICACY ANALYSES
The ITT analysis set will be used to assess efficacy endpoints. The estimand for the primary 
analysis will use the Treatment Policy Strategy (data will be used regardless of whether an 
intercurrent event occurred) for most intercurrent events; the intercurrent event of treatment or 
study discontinuation related to COVID-19 (leading to data that are missing completely at 
random) will be addressed with a While-on Treatment Strategy (only values prior to occurrence 
of intercurrent event will be used).
10.1 Efficacy Variables
10.1.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the Month 6 responder rate, defined as the proportion of 
subjects achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 6.
The Month 6 responder rate will consider pre and post infusion results at Week 20, results at 
Week 21, pre and post infusion results at Week 22, results at Week 23, and pre-infusion results at 
Week 24. The amount of time that sUA is < 6 mg/dL (using linear interpolation if necessary) will 
be calculated and divided by the total amount of time from the first to the last observed sUA 
value in corresponding time range (missed values in this time range will be ignored for purposes 
of this calculation). If the amount of time that sUA is < 6 mg/dL is
80%, then the subject will 
be considered a responder. 
10.1.2 Secondary Efficacy Endpoints
Month 3 responder rate defined as the proportion of subjects achieving and maintaining 
sUA < 6 mg/dL for at least 80% of the time during Month 3. The Month 3 responder rate 
will consider pre and post infusion results at Week 10, Week 12, and Week 14 and also 
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the between-visit non-infusion results at ~24 hours and ~168 hours after doses at Week 
10 and 12.
The proportion of subjects who experienced any of the following events from Day 1 to 
Week 24: IR leading to discontinuation of treatment, anaphylaxis or meeting Individual 
Subject sUA Discontinuation Criteria (defined as the lowest available interim sUA value
after the pegloticase infusion at Week 2, 4, 6, 8, 10 or 12 is less than a 50% reduction 
from the highest sUA value measured between Screening and pre-infusion on Day 1). 
The change from Baseline in urate deposition volume, measured by dual-energy
computed tomography (DECT) scan. The DECT will include, at a minimum, hands, feet 
and knees and other anatomical areas as clinically indicated.
Change from baseline to each postbaseline assessment in HAQ-DI score. The HAQ-DI 
functional ability and includes questions of fine movements 
of the upper extremity, locomotor activities of the lower extremity and activities that 
involve both upper and lower extremities.  There are 20 questions in 8 categories of 
functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual 
activities [Cole, 2006]. The
is indicated as: without any difficulty, with some difficulty, with much difficulty and 
unable to do.  Any devices that are usually used to complete activities and any categories 
for which help from another person is needed is also assessed. See details on scoring of 
HAQ-DI in Appendix A.  
Change from baseline to each postbaseline assessment in HAQ Pain Score. The HAQ 
-100 
where 0 represents no pain and 100 represents severe pain.
Change from baseline to each postbaseline assessment in HAQ Health score. The HAQ 
Health question asks,
10.1.3 Exploratory Efficacy Endpoints
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10.2 Baseline Values
Unless otherwise noted, baseline is defined as the last non missing value recorded before the first 
infusion of pegloticase.
10.3 Adjustments for Covariates
Analyses of the efficacy endpoints will not include adjustments for covariates.
10.4 Handling of Dropouts or Missing Data
No imputations will be made for missing values. In general, summaries will be based on 
observed data only. See further details on missing data for the primary endpoint in Section 11.2.
10.5 Interim Analysis and Data Monitoring
No formal interim analysis is planned for this study.
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Safety data will be summarized for safety assessments conducted after 7 and 10 subjects in 
Cohort 1 complete 6 infusions and after 3, 6, 10, 15 and 20 subjects in Cohort 2 complete 6 
infusions. The results of these analyses will determine if enrollment will continue in each cohort. 
Efficacy and safety data may be summarized periodically throughout the trial to support
scientific publications. Additionally, safety data will be summarized regularly for safety 
monitoring. Final analysis will occur when all subjects have completed the trial. No Type 1 error
rate adjustments will be made due to multiple summaries. 
10.6 Examination of Subgroups
No subgroup analysis is planned for this study.
10.7 Multiple Comparison/Multiplicity
No Type 1 error rate adjustments will be made due to multiple comparisons. 
10.8 Multicenter Studies
Data from all sites will be summarized together for analyses.
11. METHODS OF EFFICACY ANALYSIS
11.1 Handling Rules for sUA Values 
Serum samples for measurement of sUA levels will be collected at the Screening, Week -6 (prior 
to the first dose of MTX) and Week -2 Visits. On Day 1, a pre- and post-infusion sUA will be 
collected to be shipped to the central laboratory. For the remainder of trial visits beginning at 
Week 2 during the Pegloticase + MTX Treatment Period, 2 sUA samples will be collected within 
local 
laboratory and the second sample will be sent to the central laboratory (the central laboratory 
sample may be drawn separately from the local collection). Additional serum samples for sUA 
levels will be collected after the end of each pegloticase infusion prior to discharge at Weeks 10, 
12, 14, 20, 22, 32, 34, 44 and 46. Single serum samples for measurement of sUA will also be 
collected at non-infusion visits at Weeks 21 and 23 and at the End of Pegloticase (if applicable) 
or the Week 24 or 48/End of Trial/ET Visit. Serum for sUA analysis will also be collected at 
Day 1 (~24 hours) post-infusion, Day 4 (~96 hours) post-infusion, Day 7 (~168 hours) post-
infusion, and Day 10 (~ 240 hours) post-infusion following the first 4 pegloticase infusions at 
Day 1, Weeks 2, 4, 6. , Serum for sUA analysis will also be collected at Day 1 (~24 hours) post-
infusion, and Day 7 (~168 hours) post-infusion following the Week 8, 10 and 12 infusions. If 
infusion intervals of less than 2 weeks should occur due to scheduling issues, the 1st day 
(~24hours) samples must be obtained at a minimum and also the 7th day (~168 hours) if feasible.  
Prior to Week 22, subjects whose lowest available interim sUA value (typically the 1st day [~24 
hours] after infusion) after the pegloticase infusion at Week 2, 4, 6, 8, 10 or 12 is less than a 50% 
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reduction from the highest sUA value measured between Screening and pre-infusion on Day 1 
will discontinue treatment and complete the End of Pegloticase Visit within 2 weeks of the last 
infusion, but remain in the trial for biweekly visits, including the Week 24/End of Trial/Early 
Termination and 30-Day Post-Treatment Follow-up Visits. 
Samples that result in discordant results between local and central laboratories will be evaluated 
-by-case basis 
to determine whether the subject should continue on trial or proceed to the End of Pegloticase 
Visit. 
For the determination of sUA responder endpoints, scheduled assessments of sUA and 
unscheduled assessments of sUA, reported by the central laboratory, will be used. Local 
laboratory-processed pre-infusion sUA results will be used only when the central laboratory-
processed value at a time point is not available, but the local lab-processed pre-infusion value, 
collected at the same time point, is available. 
When the central laboratory or local laboratory reports a value for sUA as being lower than the 
zero will be used as the numeric value for the 
purpose of determining response and for summaries of observed values and the change from 
baseline. When the central laboratory or local laboratory reports a value for sUA as being higher 
for the purpose of determining response and for summaries of observed values and the change 
from baseline.
11.2 Primary Efficacy Endpoint and Analysis
The primary efficacy endpoint is the proportion of Month 6 (Weeks 20, 21, 22, 23 and 24) 
responders, defined as subjects achieving and maintaining sUA < 6 mg/dL for at least 80% of the 
time during Month 6.
The sUA concentrations vs. time (collected to the nearest minute in the CRF) curve will be used 
to estimate the proportion of time that the sUA is < 6 mg/dl using the available pre-infusion, 
non-infusion, and post-infusion samples with non-missing sUA values. Central laboratory results 
from visits at which an infusion was not performed (e.g., subject discontinued pegloticase but 
remained in study or unscheduled visits) will be used when available. 
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responder for the primary efficacy endpoint. A subject with the proportion of hours, P, less than 
80% will be counted as a non-responder. Any subject who meets the individual subject sUA 
discontinuation criteria or
prior to 
Week 24 will be counted as a non-responder.
For subjects who postponed or missed visits due to COVID-19, only visits occurring prior to any 
disruption of treatment (> 21 days between infusions) or cessation in treatment will be used for 
the primary analysis. Any results following the disruption in treatment will be set to missing. 
Subjects with disrupted treatment due to COVID-19 at any point prior to the Month 6 period will 
not be included in the primary analysis. 
The proportion of hours during the period during which the sUA was less than 6 mg/dL will be 
proportion of hours will not be calculated. The number and proportion of subjects that 
discontinued treatment due to the stopping rule will be summarized. The number and proportion 
of responders will be summarized along with a 95% exact (Clopper-Pearson) confidence interval
(CI) for the proportion. In addition, the number and proportion of subjects missing all data in the
analysis period, subjects with only one measurement above the cutoff in the analysis period, and
subjects with only one measurement below the cutoff in the analysis period will be summarized.
11.3 Additional Analyses of sUA
The proportion of time sUA < 6 mg/dL between first infusion and Week 24 will be calculated 
similarly to the primary endpoint but based on all available sUA values (from central and local 
labs (if central unavailable)) collected between the first infusion and Week 24.  The proportion of 
time will be summarized with descriptive statistics by Month 6 responder groups (non-
responders vs. responders).
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The Month 3 responder rate will be summarized similar to Month 6 responder rates described 
above. The Month 3 responder rate will consider pre and post infusion results at Week 10, Week 
12, and Week 14 and also the between-visit non-infusion results at ~24 hours and ~168 hours 
after doses at Week 10 and 12. The number and proportion of responders along with the two-
sided 95% exact Clopper-Pearson CIs for the responder rates will be presented. The proportion 
of hours during Month 3 where the sUA < 6 mg/dL will be summarized using descriptive
statistics.
Observed values and change from baseline at each scheduled time point, including pre-infusion 
and post-infusion results for sUA will be summarized using descriptive statistics. A two-sided 
95% Wald CI will be presented for the mean observed value and mean change from baseline for 
each visit. The proportion of subjects with sUA < 6 mg/dL at each scheduled time point will be 
summarized, along with the two-sided 95% exact Clopper-Pearson CIs.
Line plots of the observed mean pre-infusion sUA values at each scheduled visit will be 
presented by cohort and Cohort 1 and 2 combined. By-subject plots of sUA values by time will 
also be presented and will include a reference line at 6 mg/dL.
11.4 Analyses of Proportion of Subjects with Infusion Reactions, Anaphylaxis, and Meeting 
Individual Subject sUA Discontinuation Criteria
The proportion of subjects who experience an IR leading to pegloticase discontinuation, 
anaphylaxis, or meet individual subject sUA discontinuation criteria will be presented along with 
the two-sided 95% exact Clopper-Pearson CIs. The proportion of subjects meeting each criteria 
separately will also be presented.
11.5 Analyses of DECT Scans
The observed values and the change from baseline for urate deposition volume, hand erosion 
score, foot erosion score, and total bone erosion score at each scheduled time point will be 
summarized using descriptive statistics. A two-sided 95% Wald CI for the changes from baseline 
will be presented.
11.6
 
 
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11.7 Analyses of Health Assessment Questionnaire
Observed values and change from baseline in the HAQ-DI, HAQ-Pain, and HAQ-Health score at 
each scheduled time point will be summarized using descriptive statistics. A two-sided 95% 
Wald CI for the changes from baseline will be presented.
11.8 Analyses of 
11.9 Analyses of 
11.10 Analyses of 
11.11 Analyses of 
11.12 Analyses of 
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11.13 Analyses of 
Subjects will be assessed for the presence of 
. The number of 
 will be recorded 
for the 
 
 
For subjects with 
 at baseline, the mean number of 
 and change from 
baseline will be presented by visit. A two-sided 95% 
 for the changes from baseline will 
be presented.
12.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.3
 
 
 
 
 
 
 
 
13.
 
 
 
 
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14. SAFETY ANALYSES
Safety analyses for the MTX Run-in Period will be based on the MTX Analysis Set. Safety 
analyses for the Pegloticase + MTX Treatment Period and Optional Pegloticase + MTX 
Extension Period will be based on the Safety Analysis Set.
14.1 Extent of Exposure
Study drug exposure will be summarized for both MTX and pegloticase using the duration of 
treatment (in days), number of doses, total dosage received, and average doses received.
For the MTX Run-in Period, the following will be summarized using descriptive statistics: 
Duration of treatment defined as the last dose of MTX prior to the Day 1 visit date first 
dose date of MTX + 1 
Total MTX dosage (prescribed dose) taken between the first and last dose dates in the 
MTX Run-in Period, inclusive (in mg) 
Average MTX dose (in mg) (total dosage for the MTX Run-in Period divided by number 
of doses taken during the MTX Run-in Period) 
Number of subjects with any dose reduction (reduction in prescribed dose for reason of 
abnormal labs, AE, or titration down).
For the Pegloticase + MTX Period, the following will be summarized:
Separately for the Pegloticase + MTX Treatment Period, Optional Pegloticase + MTX 
Extension Period, and overall
o
Number of pegloticase infusions received 
o
Duration in days between first and last pegloticase infusion in the given period, 
defined as last infusion date first infusion date + 1 
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o
Number of incomplete infusions received 
o
Number of interrupted infusions 
At each scheduled Pegloticase infusion visit
o
Number of subjects receiving a complete infusion (i.e., full dose administered)
o
Number of infusions administered without interruption
o
Number of subjects with an interrupted infusion
o
Number of subjects not receiving MTX between previous infusion and current 
infusion
MTX
o
Duration of MTX dosing during the Pegloticase + MTX Treatment Period, 
defined as the last MTX date prior to Week 24
first MTX dosing date (on or 
after the date of the Day 1 visit) + 1
o
Total MTX dosage (in mg) received during the Pegloticase + MTX Treatment 
period 
o
Average MTX dose (in mg) (total dosage for the Pegloticase + MTX Treatment 
Period divided by number of doses taken during the Pegloticase + MTX 
Treatment Period) 
o
Number of subjects with any dose reduction (reduction in prescribed dose for 
reason of abnormal labs, AE, or titration down) in the Pegloticase + MTX 
Treatment Period.
o
Duration of MTX dosing during the Optional Pegloticase + MTX Extension 
Period, defined as the last MTX date Week 24 MTX dosing date + 1
o
Total MTX dosage (in mg) received during the Optional Pegloticase + MTX 
Extension period 
o
Average MTX dose (in mg) (total dosage for the Optional Pegloticase + MTX 
Extension Period divided by number of doses taken during the Optional
Pegloticase + MTX Extension Period) 
o
Number of subjects with any dose reduction (reduction in prescribed dose for 
reason of abnormal labs, AE, or titration down) in the Optional Pegloticase + 
MTX Extension Period.
For the overall study, the following will be summarized:
MTX
o
Duration of MTX dosing, defined as the last MTX date first MTX dosing date + 
1
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o
Total MTX dosage (in mg) received
o
Number of subjects with any dose reduction (reduction in prescribed dose for 
reason of abnormal labs, AE, or titration down).
o
Average MTX dosage (in mg) per dose overall
Methotrexate administration and pegloticase infusion details will be listed. The use of
prophylaxis treatments will be provided in listings only.
14.2 Adverse Events
Treatment-emergent AEs (TEAEs) will be summarized separately for the MTX Run-in Period 
using the MTX Analysis Set and for the Pegloticase + MTX Treatment Period using the Safety 
Analysis Set. TEAEs during the MTX 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 through 30 days after the 
last dose of MTX for subjects who do not receive pegloticase. TEAEs during the Pegloticase + 
MTX Treatment 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 MTX (whichever is later).
Partial dates will be imputed. For details on imputation rules, refer to Appendix A: Presentation 
of Data and Programming Specifications. Imputed dates are only used for classification of 
TEAEs. If it cannot be determined whether the AE is treatment emergent due to a partial onset 
date, then it will be counted as such.   
Events with missing relationship to study drug in the MTX Run-in period will be considered 
related to MTX. Events with missing relationship to study drug in the Pegloticase + MTX
periods
MTX
Missing severities will 
be considered severe.
Verbatim terms in the eCRFs will be mapped to PTs and SOCs using the MedDRA version 23.1. 
Adverse event severity will be graded according to Rheumatology Common Toxicity Criteria
(CTC) v2.0 [Woodworth et al, 2007].
An overall summary of TEAEs will be provided for the MTX Run-in Period and Pegloticase + 
MTX Treatment Period, including the number and percentage of subjects with each AE type as 
well as the number of events for each of the following:
TEAEs
Serious TEAEs
TEAEs Related to MTX
TEAEs Related to pegloticase (applicable to Pegloticase + MTX Treatment period only)
Serious TEAEs Related to MTX
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Serious TEAEs Related to pegloticase (applicable to Pegloticase + MTX Treatment 
period only)
TEAEs with a Rheumatology CTC grade of 3 or higher 
TEAEs leading to permanent withdrawal of MTX
TEAEs leading to permanent withdrawal of pegloticase (applicable to Pegloticase + 
MTX Treatment period only)
TEAEs Related to MTX leading to permanent withdrawal of MTX 
TEAEs Related to pegloticase leading to permanent withdrawal of pegloticase (applicable 
to Pegloticase + MTX Treatment period only)
TEAEs leading to death
An overall summary of post-treatment AEs, AEs that occur more than 30 days after the last dose 
of pegloticase and/or MTX, will include the number and percentage of subjects with each AE 
type as well as the number of events for each of the following:
TEAEs
Serious TEAEs
TEAEs with a Rheumatology CTC grade of 3 or higher 
TEAEs leading to death.
The following summaries will be presented:
Subject incidence of TEAEs and total number of unique TEAEs along with the event 
incidence rate by MedDRA SOC and PT, for the MTX Run-in Period, Pegloticase + 
MTX Treatment Period, and post-treatment period.
Subject incidence of TEAEs by MedDRA SOC, PT, and maximum Rheumatology CTC
grade, for the MTX Run-in Period and Pegloticase + MTX Treatment Period. At each 
level of subject summarization, a subject is classified according to the maximum grade if 
the subject reported 1 or more events. 
Subject incidence of TEAEs by MedDRA SOC, PT, and closest relationship to MTX
(Related/Not Related), for the MTX Run-in Period and Pegloticase + MTX Treatment 
Period. At each level of subject summarization, a subject is classified according to the 
closest relationship if the subject reported 1 or more events. Adverse events with a 
missing relationship will be considered related for this summary.
Subject incidence of TEAEs by MedDRA SOC, PT, and closest relationship to 
pegloticase (Related/Not Related), for the Pegloticase + MTX Treatment Period. At each 
level of subject summarization, a subject is classified according to the closest relationship 
if the subject reported 1 or more events. Adverse events with a missing relationship will 
be considered related for this summary.
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Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA SOC and PT, for the MTX Run-in Period and Pegloticase + MTX Treatment 
Period.
Subject incidence of TEAEs leading to MTX discontinuation and total number of unique 
TEAEs leading to MTX discontinuation by MedDRA SOC and PT, for the MTX Run-in 
Period and Pegloticase + MTX Treatment Period
Subject incidence of TEAEs leading to pegloticase discontinuation and total number of 
unique TEAEs leading to pegloticase discontinuation by MedDRA SOC and PT, for the 
Pegloticase + MTX Treatment Period
Each AE summary will be displayed by cohort and overall. Summaries that are displayed by 
SOC and preferred terms (PT) will be ordered alphabetically by SOC and by PT within SOC.  
Event incidence rates adjusted by patient year exposure to study drug will be calculated as the 
(number of events divided by the total patient-years of exposure to the study drug)*100.  The 
patient-years of exposure for the MTX Run-in Period for each subject who continues into the 
Pegloticase + MTX Treatment Period will be derived as (first dose date of pegloticase in the 
Pegloticase + MTX Treatment Period first dose date of MTX )/365.25. The patient-years of 
exposure for the MTX Run-in Period for each subject who does not continue in the Pegloticase + 
MTX Treatment Period will be derived as (last dose date of MTX in the MTX Run-in Period 
first dose date of MTX + 1)/365.25. The patient-years of exposure for the Pegloticase + MTX 
Treatment Period for each subject will be derived as (last dose date of MTX or pegloticase 
(whichever is later) first dose date of pegloticase + 1)/365.25.
All AEs will be listed. SAEs, AEs leading to death, AEs leading to permanent withdrawal of 
MTX, and AEs leading to permanent withdrawal of pegloticase will also be listed.
14.3 Adverse Events of Special Interest
Adverse events of special interest will include infusion reactions (IRs), anaphylaxis, gout flares, 
and MACE including non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and 
congestive heart failure.
IRs and Anaphylaxis
IRs and anaphylaxis reactions are identified by the investigator on the eCRF. The signs and 
symptoms associated with each event are entered on the eCRF and will be coded to the MedDRA 
dictionary. IRs and anaphylaxis events, and the associated signs and symptoms, will be 
summarized in the pegloticase + MTX period by SOC, PT, severity, and the time relative to the 
most recent pegloticase infusion. Time relative to the most recent pegloticase infusion will be 
> 24 hours after infusion, and missing (time of event is missing).
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If 3 or more events of anaphylaxis occur, events will also be reviewed by an external 
adjudication committee. Events as reviewed by the external adjudication committee will be 
summarized separately. 
The following search algorithm will be used to identify possible IR and anaphylaxis cases:
Infusion Reaction
All IRs reported by investigators based on the protocol definition and reported on the 
eCRF.
All other AEs that occur after start of infusion and up to 24 hours following the end of the 
infusion or on the same day of infusion if the start time is missing.
Anaphylaxis
Any anaphylaxis reported by investigators based on the NIAID/FAAN criteria and 
reported on the eCRF.
Any anaphylactic reactions identified by the algorithmic MedDRA SMQ Anaphylactic 
reactions.  
The number and percentage of subjects with IRs including anaphylaxis (investigator reported)
will be summarized overall and by severity of event by the following categories for both 
:
 
 
Cardiovascular Events
Cardiovascular events will include Major Adverse Cardiovascular Events (MACE), including 
non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and congestive heart 
failure. The following search algorithm will be used to identify possible MACE:
For cardiovascular death any fatal case plus:
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o
Standardized MedDRA Queries (SMQ): Myocardial infarction (broad), 
Haemorrhagic central nervous system vascular conditions (narrow), Ischaemic 
Central Nervous System (CNS) Vascular conditions (narrow), Central nervous 
system vascular disorders, not specified as haemorrhagic or ischaemic (narrow),
Embolic and thrombotic events (arterial, venous, vessel type unspecified and 
mixed arterial and venous) (narrow), Cardiac failure (broad), Shock-associated 
circulatory or cardiac conditions (excl torsades de pointes) (broad), Torsade de 
pointes/QT prolongation (broad), Arrhythmia related investigations, signs and 
symptoms (broad), Cardiomyopathy (broad), Supraventricular tachyarrhythmias 
(narrow), Ventricular tachyarrhythmias (narrow), Conduction defects (narrow)
o
All PTs under SOC of Cardiac disorders
o
HLGT Aneurysm
For non-fatal myocardial infarction: SMQ Myocardial infarction (broad) 
For non-fatal stroke: SMQ: Ischaemic Central Nervous System (CNS) Vascular 
conditions (narrow), Haemorrhagic central nervous system vascular conditions (narrow), 
Central nervous system vascular disorders, not specified as haemorrhagic or ischaemic 
(narrow)
Congestive heart failure: SMQ Cardiac failure (broad)
Cardiovascular events will be tabulated only if 5 or more subjects have experienced a
cardiovascular event. Cardiovascular events will be summarized by MedDRA SOC and PT in the 
MTX Analysis Set for the MTX Run-in Period and in the Safety Analysis Set for the pegloticase 
+ MTX period.
Gout Flares
The number and percentage of subjects who experienced a gout flare (recorded in the AE eCRF), 
and number of gout flares per subject will be summarized for the MTX Run-in Period using the 
MTX Analysis Set. Percentages will be calculated using the number of subjects in the MTX 
Analysis Set. The number and percentage of subjects who experienced a gout flare and number 
of gout flares per subject during the Pegloticase + MTX periods (recorded in the AE eCRF) will 
be provided for the Safety Analysis Set. These events will be further summarized as occurring 
from the period from Day 1 to Week 12, after Week 12 Week 24, after Week 24 Week 36, 
and after Week 36 Week 48. Percentages will be based on the number of subjects who had 
follow-up at least as far as the start of the period-specific time period. For the full Pegloticase + 
MTX period, percentages will be calculated using the number of subjects in the Safety Analysis 
Set. Events are summarized for each period according to the onset date of the flare, and only 
summarized in the period of onset. In addition, events during the Pegloticase + MTX period will 
be further summarized by month of occurrence, e.g., Month 1, Month 2, up to Month 12, where 
one month is defined as 30 days.
All AEs of special interest will also be listed.
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14.4 Clinical Laboratory Evaluation
A central laboratory will be used for protocol-specified clinical laboratory parameters. 
Laboratory parameters (chemistry, hematology, and urinalysis) will be summarized in 
conventional units using descriptive statistics at baseline and at each post-baseline time point. 
Changes from baseline will also be summarized for all continuous parameters. Summaries will 
be presented for change from methotrexate baseline (last assessment prior to the first dose of 
MTX in the MTX Run-in Period) and change from pegloticase baseline (last assessment prior to 
the first dose of pegloticase). The following laboratory parameters will be summarized:
Hematology: hemoglobin, hematocrit, erythrocytes, leukocytes, neutrophils/leukocytes, 
lymphocytes/leukocytes, monocytes/leukocytes, eosinophils/leukocytes, 
basophils/leukocytes, platelets.
Chemistry: albumin, aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, total bilirubin, creatinine, glucose, sodium, potassium, calcium, chloride, 
total protein, blood urea nitrogen, hs-CRP.
Urinalysis: albumin:creatinine ratio.
If a continuous laboratory value is reported as either below or above the limits of quantification, 
Shift tables for laboratory parameters by Common Terminology Criteria for Adverse Events
(CTCAE) grade will be presented by visit for those laboratory parameters with CTCAE v5.0
grade defined. 
A summary of subjects with elevated liver function tests (aspartate aminotransferase, alanine 
law criteria will also be provided by visit and overall. 
All laboratory tests will be listed, and results will be categorized as low, normal, or high based 
on their normal ranges. Separate listings of out-of-range results will also be presented. 
14.5 Vital Signs
Vital signs (including heart rate, respiratory rate, systolic blood pressure, diastolic blood 
pressure, and temperature), weight and BMI will be summarized using descriptive statistics at 
baseline and at each applicable post-baseline time point. Changes from baseline will also be 
summarized. During the Pegloticase + MTX Treatment period, vitals will be measured pre-
infusion and post-infusion. Weight will only be measured at Screening, pre-infusion on Day 1, 
pre-infusion at Week 24, at the non-infusion end of pegloticase infusions visit (if applicable) and 
at Week 24 or 48/End of Trial/Early Termination Visits. 
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14.6 Physical Examination
Physical examination results will be listed for each subject.
14.7 Electrocardiogram
An electrocardiogram (ECG) will be performed at Screening for all subjects and at the discretion
of the investigator thereafter. The results will be recorded as normal or abnormal on the eCRF 
and all abnormal results will be evaluated as clinically significant (CS) or not clinically 
significant (NCS) by the investigator. A summary of ECG results at Screening and a summary of 
any post-Screening results will be presented. All ECG results will be listed.
15. CHANGES TO PROTOCOL-SPECIFIED ANALYSES
There are no changes to the protocol-specified analyses.
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16. REFERENCES
Cole JC, Khanna D, Clements PJ, et al. Single-factor scoring validation for the Health
Assessment Questionnaire-Disability Index (HAQ-DI) in patients with systemic sclerosis and
comparison with early rheumatoid arthritis patients. Qual Life Res. 2006;15(8):1383-94.
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for Industry ICH E9 Statistical principles 
for clinical trials. September 1998 [cited 2021 Apr 05]. Available from:
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
073137.pdf
 
.
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.
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17. APPENDICES
APPENDIX A: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS
Scoring for the 
For each of the  sections of the 
 
 
 
 
 
The aids and devices are assigned to the individual sections as follows:
 
 
 
 
 
 
 
 
 
 
 
Missing or incomplete dates
Medications
For prior and concomitant medications with incomplete dates, the following rules will be used to 
impute start and/or stop dates for the purposes of determining if a medication is prior, concomitant 
in the MTX Run-in Period, or concomitant in the Pegloticase + MTX Period. Imputed dates will 
not be presented in the data listings.
For partial start dates:
If the month and year are provided and day is missing, and the month and year match the 
month and the year of the first pegloticase dose date AND match the month and the year 
of the first MTX dose (i.e. the MTX and pegloticase started in the same month), the day of 
the first dose date of MTX will be imputed. Otherwise, if the month and year match the 
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month and year of the first pegloticase dose date, then the first dose date of pegloticase will 
be imputed. Otherwise, if the month and year match the month and year of the first MTX 
dose date, then the first dose date of MTX will be imputed. Otherwise, the first of the month 
will be used. 
If the year is provided and the month and day are missing and the year matches the year of 
the first pegloticase dose date and the year matches the year of the first MTX dose date, 
the month and day of the first MTX date will be imputed. Otherwise, if the year matches 
the year of the first dose of pegloticase, the first dose date of pegloticase will be imputed. 
Otherwise, if the year matches the year of the first MTX date, then the first dose date of 
MTX will be imputed. Otherwise, January will be used. 
If the start date is completely missing, the start date will not be imputed. If the stop date is 
after first dose date of pegloticase, the medication will be considered to be both prior, 
concomitant in the MTX Run-in Period, and concomitant in the Pegloticase + MTX Period. 
If the stop date is after the first dose date of MTX, but prior to the first dose date of 
pegloticase, the medication will be considered to be prior and concomitant in the MTX 
Run-in Period. If the stop date is prior to the first dose date of MTX, the medication will 
be considered to be prior only. 
If the stop date is complete and the imputed start date is after the actual stop date, then the 
start date will be imputed as the stop date.
For partial stop dates:
If the month and year of stop are provided, but the day is missing, then the last day of the 
month will be used.
If the year of stop is provided, but the month and day are missing, then December 31st of 
that year will be used. 
If the stop date is completely missing, then the date of last study visit will be used. 
Adverse Events
For adverse events with incomplete dates, the following rules will be used to impute start and/or 
stop dates for the sole purpose of determining if an AE is treatment-emergent in the MTX Run-in 
Period or Pegloticase + MTX Period. Imputed dates will not appear in the data listings.
For partial start dates:
If the month and year of adverse event onset are provided but day is missing
o
If the month and year match the month and year of the first dose of MTX in the 
MTX Run-in Period AND match the month and year of the first infusion of 
pegloticase in the Pegloticase + MTX Period, the first dose date of MTX in the 
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Run-in Period will be imputed and the event will be considered treatment emergent 
in the MTX Run-in Period and Pegloticase + MTX Period. 
o
Otherwise, if the month and year match the month and the year of the first dose 
date of pegloticase, the day of the first infusion date of pegloticase will be imputed 
and the AE will be considered treatment-emergent in the Pegloticase + MTX
Period. 
o
Otherwise, if the month and year match the month and the year of the first dose 
date of MTX, the day of the first dose date of MTX will be imputed and the AE 
will be considered treatment-emergent in the MTX Run-in Period. 
o
Otherwise, the first of the month will be used and the treatment-emergent status 
will be assessed relative to the first infusion date of pegloticase and the first dose 
date of MTX. 
If the year of adverse event onset is provided, but the month and day are missing
o
If the year matches the year of the first dose of MTX in the MTX Run-in Period 
AND matches the year of the first infusion of pegloticase in the Pegloticase + 
MTX Period, the first dose date of MTX in the Run-in Period will be imputed and 
the event will be considered treatment emergent in the MTX Run-in Period and 
Pegloticase + MTX Period.
o
Otherwise, If the year matches the year of the first infusion date of pegloticase, the 
month and the day of the first infusion date of pegloticase will be imputed, and the 
AE will be considered treatment-emergent in the Pegloticase + MTX Period. 
o
Otherwise, if the year matches the year of the first dose date of MTX, the month 
and day of the first dose of MTX will be imputed and the AE will be considered 
treatment-emergent in the MTX Run-in Period. 
o
Otherwise, January 1st will be used and the treatment-emergent status will be 
assessed relative to the dosing start date of pegloticase and the first dose date of 
MTX.
If the start date is completely missing, the AE will be considered treatment-emergent in the 
Pegloticase + MTX Period and the MTX Run-in Period, unless the stop date is complete 
or provides enough partial information to rule out a treatment-emergent status in the 
Treatment Period. This should be a rare occurrence.
If the stop date is complete and the imputed start date is after the actual stop date, then the start 
date will be imputed as the stop date.
Gout History
If date of first gout attack or date of first gout diagnosis are incomplete, impute as follows for 
calculating time since first gout attack and time since first gout diagnosis:
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If day is missing, impute as first day of month.
If day and month are missing, impute as January 1 of the year.
If year is missing, do not impute and time since date will be missing.
Standard Calculations
Variables requiring calculation will be derived using the following formulas:
Days
A duration expressed in days between 1 date (date1) and another later date (date2) is 
calculated using the formulas noted below:
duration in days = date2 date1 + 1
Age
Age will be calculated as (informed consent date - date of birth + 1) / 365.25 and 
truncated to complete years. If the date of birth is only partially available, the first of the 
month will be imputed for any missing days and January will be imputed for any missing 
months.
Height
Height entries made in inches (in) are converted to centimeters (cm) using the 
following formula:
height (cm) = height (in) × 2.54.
Weight
Weight entries made in pounds (lb) are converted to kilograms (kg) using the 
following formula:
weight (kg) = weight (lb)/2.2046.
Temperature
Temperature entries in degrees Fahrenheit are converted to degrees 
centigrade using the following formula:
temp (degrees centigrade) = 5/9 × [temp (degrees Fahrenheit) 32].
Body Mass Index (BMI)
BMI is calculated using height (cm) and weight (kg) using the 
following formula:
BMI (kg/m2) = weight (kg)/[[height (cm)/100]2].
Change from baseline Change from baseline will be calculated as:
Change = post-baseline value baseline value.
Percent change from baseline Percent change from baseline will be calculated as:
Percent change from baseline = (post-baseline value baseline value)/baseline value 
× 100.
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