A Multicenter, Open-Label, Efficacy and Safety Study of Pegloticase in Patients With Uncontrolled Gout Who Have Undergone Kidney Transplantation
Phase: PHASE4
Conditions: Uncontrolled Gout, Kidney Transplant
Sponsor: Amgen

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Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 2 of 103 
PROTOCOL 
1 
TITLE PAGE 
Study Title:  A Multicenter, Open-Label, Efficacy and Safety Study of 
Pegloticase in in Patients With Uncontrolled Gout Who Have 
Undergone Kidney Transplantation  
Protocol Number:  HZNP-KRY-406 
Version:  3.0, Amendment 2 
Investigational 
Products:  
Pegloticase (recombinant modified mammalian urate oxidase 
[uricase])  
Indication:  Chronic gout in adult patients refractory to conventional therapy 
Sponsor:  Horizon Therapeutics Ireland DAC 
1 Burlington Road 
Connaught House, 1st Floor 
Dublin Ireland D04 C5Y6 
Development Phase:  4  
Sponsor’s Responsible 
Medical Officer:  
 
 
 
150 S. Saunders Road 
Lake Forest, IL 60045 
Sponsor Signatory:  
 
 
Horizon Therapeutics USA, Inc. 
150 S. Saunders Road  
Lake Forest, IL 60045 
Approval Date:  22 June 2020 
 
  
CONTACT IN THE EVENT OF AN EMERGENCY 
Any death, life-threatening event, or other serious adverse event experienced by a subject 
during the course of the study, whether or not judged drug-related, must be reported within 
24 hours of knowledge of the event by entering the information into the electronic case 
report form (eCRF).  If unable to access the eCRF, the event must be reported by submitting 
the completed Serious Adverse Event Form via email or fax to the contact numbers provided 
below. 
Fax: 
 
Email: 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 4 of 103 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number:  
HZNP-KRY-406    
Version: 
3.0, Amendment 2 
Protocol Title:  
A Multicenter, Open-Label, Efficacy and Safety Study of Pegloticase in 
Patients With Uncontrolled Gout Who Have Undergone Kidney 
Transplantation 
Version Date: 
22 June 2020 
I agree to conduct the study according to the protocol named above.  I fully understand that any 
changes instituted by the Principal Investigator without previous discussion with the Sponsor 
constitute a violation of the protocol, unless necessary to eliminate an immediate hazard to the 
safety or well-being of a subject. 
I acknowledge that I have read and understand the protocol named above and agree to carry out 
all of its terms in accordance with applicable regulations and laws. 
I assure that the study drug supplied by the Sponsor will be used only as described in the 
protocol named above. 
Signature: 
 
 
 
 
 
 
 Name  
Study Center 
Address 
City State Country 
 
Date 
 
 
 
 
 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 5 of 103 
SUMMARY TABLE OF CHANGES 
 
Protocol Version 1.0, Original (10 JUN 2019) to 
Protocol Version 2.0, Amendment 1 (21 JAN 2020) 
Protocol Version 2.0, Amendment 1 (21 JAN 2020), Administrative Change 1 (31 MAR 2020) 
Protocol Version 3.0, Amendment 2 (22 JUN 2020) 
 
The table below highlights the changes to the objectives, statistical analysis and study 
design only. Administrative and typographical updates have also been made.  Track 
changes version of the Protocol Version 3.0, Amendment 2 can be provided on 
request. 
 
Text Version 2.0, 
Amendment 1, 
Administrative Change 1  
31 MAR 2020 
Amended Text 
Version 3.0, Amendment 2 
22 JUN 2020 
Reason for Change 
Replacement Policy/Subject: 
Section 9.3.4.1 
 
No subject prematurely 
discontinued from the study for any 
reason will be replaced. 
 
Replacement Policy/Subject: Section 
9.3.4.1 
 
In general, subjects that prematurely 
discontinue from the study for any 
reason will not be replaced. An 
exception may be made for subjects who 
are unevaluable due to the impact of the 
COVID-19 pandemic and associated 
restrictions on movement and work. 
Subjects unable to receive treatment or 
be evaluated due to restrictions during 
the COVID-19 pandemic may be 
replaced, at the discretion of the 
sponsor. This may result in more 
subjects than originally planned being 
enrolled into the study to allow for the 
originally planned number to be 
evaluable for the primary efficacy 
analysis. 
 
Updated due to the COVID-
19 pandemic. 
9.3.4.3 Screen Failures 
Subjects who do not meet all of the 
eligibility criteria or withdraw 
consent between Screening and Day 
1 will be considered screen failures. 
Screen failures may be allowed to 
rescreen for the study if both the 
Investigator and Sponsor are in 
9.3.4.3 Screen Failures 
Subjects who do not meet all of the 
eligibility criteria or withdraw consent 
between Screening and Day 1 will be 
considered screen failures. Screen 
failures may be allowed to rescreen for 
the study if both the Investigator and 
Sponsor are in agreement regarding 
To clarify that screen failure 
subjects who consent to the 
optional blood draw for 
biomarker analysis will be 
requested to return to the clinic 
24 weeks after screening for a 
second blood sample as well as 
assessment of adverse events, 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 6 of 103 
agreement regarding rescreening 
and if the Investigator determines 
that they can satisfy all of the 
eligibility criteria. 
 
rescreening and if the Investigator 
determines that they can satisfy all of 
the eligibility criteria. 
Subjects who fail screening but 
consented to the optional blood draw 
for biomarker analysis will be 
requested to return to the site 24 weeks 
+/- 4 weeks for a second blood sample.  
Adverse events, concomitant 
medications, blood samples for 
hematology and clinical chemistry and 
vital signs will vital signs will also be 
collected as an unscheduled visit at that 
time. 
con meds, safety labs and vital 
signs. 
 
Section 9.6.5.1: Primary and 
Secondary Endpoint Analysis:  
Sentence not previously included. 
Section 9.6.5.1: Primary and 
Secondary Endpoint Analysis:  
Special consideration may be given to 
subjects who discontinue the study or 
miss visits due to reasons related to the 
COVID-19 pandemic. 
Added language due to 
COVID-19 pandemic. 
Section 9.5.4.8: Blood and Urine 
Sample for Potential Analysis of 
Allantoin 
Blood and urine samples will be 
collected prior to pegloticase 
infusion on Day 1 and at the Week 
2, 4, 6, 8, 10, 14, 18, and 22 Visits, 
the End-of-Pegloticase-Infusions 
Visit (if applicable), the Week 
24/End-of-Study/Early Termination 
Visit, and the 3-month Post-
Treatment Follow-up Visit. In 
addition, blood and urine samples 
will be collected after the end of 
pegloticase infusions prior to 
discharge from the site on Day 1, 
Week 2, 6, 14 and 22 Visits. 
Section 9.5.4.8: Blood and Urine 
Sample for Potential Analysis of 
Allantoin  
Blood and urine samples will be 
collected prior to pegloticase infusion 
on Day 1 and at the Week 2, 4, 6, 8, 10, 
14, 18, and 22 Visits, the End-of-
Pegloticase-Infusions Visit (if 
applicable), the Week 24/End-of-
Study/Early Termination Visit, and the 
3-month Post-Treatment Follow-up 
Visit. In addition, blood and urine 
samples will be collected after the end 
of pegloticase infusions prior to 
discharge from the site on Day 1, Week 
2, 6, 14 and 22 Visits. Both allantoin 
and creatinine will be analyzed in urine 
samples collected at these visits to 
calculate allantoin:creatinine ratio.   
 
Added analysis of urine 
creatinine at same time points 
as urine allantoin for 
measurement of 
allantoin:creatinine ratio.  
Section 9.5.4.9: Blood Samples 
for Potential Analysis of 
Biomarkers 
Optional blood samples for 
peripheral blood mononuclear cells 
(PBMC) and serum will be 
collected from each consenting 
Section 9.5.4.9: Blood Samples for 
Potential Analysis of Biomarkers 
Optional blood samples for peripheral 
blood mononuclear cells (PBMC) and 
serum will be collected from each 
consenting subject at Screening, the 
Week 8 and 14 Visits, the End-of-
To clarify that screen failure 
subjects who consent to the 
optional blood draw for 
biomarker analysis will be 
requested to return to the clinic 
24 weeks after screening for a 
second blood sample as well as 
assessment of adverse events, 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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subject at Screening, the Week 8 
and 14 Visits, the End-of-
Pegloticase-Infusions Visit (if 
applicable), and the Week 24/End-
of-Study/Early Termination Visit. 
Subjects who fail Screening will 
also be requested to provide at least 
1 additional blood sample 
approximately 20-24 after the 
initial sample collection. 
Pegloticase-Infusions Visit (if 
applicable), and the Week 24/End-of-
Study/Early Termination Visit. Subjects 
who fail Screening will also be 
requested to provide at least 1 
additional blood sample 24 weeks +/- 4 
weeks after the initial sample collection. 
An unscheduled visit will be arranged 
at that time to also collect adverse 
events, concomitant medications, blood 
samples for hematology and clinical 
chemistry and vital signs.  
con meds, safety labs and vital 
signs. 
 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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2 
SYNOPSIS 
Protocol Title: A Multicenter, Open-label, Efficacy and Safety Study of Pegloticase in Patients With 
Uncontrolled Gout Who Have Undergone Kidney Transplantation 
Protocol Number: HZNP-KRY-406 
Phase: 4 
Protocol Version: 3.0, Amendment 2 
 
Test Drugs: Pegloticase 
Indication: Chronic gout refractory to conventional 
therapy in adult patients 
Number subjects and Number and Country of Study Sites: Twenty subjects at approximately 15 study 
centers in the United States 
Objectives: 
The overall objective of the study is to assess the efficacy and safety of pegloticase in kidney transplant subjects 
with uncontrolled gout refractory to conventional urate lowering therapy. 
Primary Objective: 
To evaluate the effect of pegloticase on the response rate of sustained serum uric acid (sUA) reduction to sUA 
<6 mg/dL during Month 6 of treatment  
Secondary Objectives: 
To evaluate the effect of pegloticase on the response rate of sustained serum uric acid reduction to sUA <5 
mg/dL during Month 6 of treatment; 
To evaluate the effect of pegloticase on pain assessed by the Health Assessment Questionnaire (HAQ) pain 
score; and 
To evaluate the effect of pegloticase on disability assessed by the Health Assessment Questionnaire - 
Disability Index (HAQ-DI) score. 
Exploratory Objectives: 
 
 
 
 
 
 
 
 
To evaluate the pharmacokinetics (PK) of pegloticase and the profile of anti- monomethoxy-poly(ethylene 
glycol) (PEG) and anti-uricase IgG antibodies; and  
To evaluate the safety and efficacy 3 months after the end of treatment with pegloticase 
Safety Objectives: 
To assess the overall adverse event (AE)/serious AE (SAE) profile including AEs of special interest (AESI) 
(infusion reactions [IRs], anaphylaxis, gout flares and cardiovascular [CV] events), laboratory tests, vital signs 
and physical exam, and incidence of biopsy-confirmed renal rejection. 
Study Design: 
This is a Phase 4, multi-site, open-label, efficacy and safety study of pegloticase in adult subjects with 
uncontrolled gout who have undergone kidney transplantation. Twenty subjects will be enrolled. 
The study design will include: 1) a Screening Period, lasting up to 35 days; 2) a 24-week treatment period 
which includes an End-of-Study (Week 24)/Early Termination Visit; 3) a safety follow-up phone/email Visit 
30 days after the last infusion; and 4) a 3-month post-treatment follow up visit. 
During the Screening Period, eligibility will be confirmed. 
Samples for measurement of sUA levels will be collected at the Screening Visit, prior to each infusion, 15-60 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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minutes after the end of each infusion and at the End-of-Study/Early Termination Visit. Additional samples 
for sUA levels will be collected at non-infusion Visits at Weeks 21 and 23. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria during Screening will be 
enrolled at the Day 1 Visit to receive pegloticase 8 mg administered IV every 2 weeks from Day 1 through 
Week 22, inclusive. During this 24-week treatment phase, subjects who meet the stopping rule (pre-dose sUA 
level >6 mg/dL at 2 consecutive study visits beginning with the Week 2 Visit, see Stopping Rule section 
below) or discontinue treatment for any other reason will complete the End-of-Pegloticase-Infusions Visit 
procedures within 2 weeks and be encouraged to continue to participate in all visits through the end of the 
study. Subjects will return for regularly scheduled visits and will complete all study visit procedures with the 
exception of the pegloticase infusion and IR prophylaxis. After the Week 24 Visit (or End-of-Pegloticase-
Infusions Visit [if applicable]), subjects should resume regular care for gout per the judgment of the treating 
physician, including resumption of urate-lowering therapy (ULT) upon pegloticase discontinuation, if 
appropriate. Subjects will have a 3-Month Follow-up visit to assess clinical status, including sUA levels. 
On days of scheduled infusions, pegloticase will be administered after all pre-dose visit assessments have 
been completed. The date and start and stop time of infusion will be recorded. The date of the first dose of 
pegloticase is defined as Day 1. All subsequent doses and study visits will be scheduled based on the Day 1 
visit date. 
It is required that before a subject begins the treatment period, he or she has been taking protocol defined 
standard gout flare prophylaxis (colchicine at initial dose of 0.3 to 0.6 mg/day if tolerated and low-dose 
prednisone ≤ 10 mg/day; for subjects already taking chronic corticosteroids, only colchicine 0.3 to 0.6 
mg/day should be added. In subjects with eGFR ≤ 30 mL/min/1.73m2, the dose of colchicine should not be 
more than 0.3 mg/day. In subjects taking cyclosporine, only low dose prednisone (and not colchicine) should 
be used for ≥ 1 week before the first infusion. Gout flare prophylaxis should continue for the duration of the 
24-week treatment period. Subjects should be monitored closely for symptoms of colchicine excess during 
the study. Reductions in dose, dose frequency or discontinuation of colchicine are permitted if not tolerated. 
For Infusion Reaction (IR) prophylaxis, fexofenadine (60 or 180 mg orally) will be taken the day before each 
infusion; fexofenadine (60 or 180 mg orally) and acetaminophen (1000 mg orally) will be taken in the 
morning before each infusion. In addition, methylprednisolone (125 mg IV from Day 1 to Week 10 and 80 
mg IV from Week 12 until the end of treatment) is recommended to be administered over an infusion duration 
between 10 and 30 minutes, immediately prior to each pegloticase infusion. Alternate IV corticosteroid 
regimen may be substituted for methylprednisolone at the discretion of the Investigator. The dose of 
fexofenadine should be 60 mg orally in subjects with decreased renal function and 180 mg orally in subjects 
with normal renal function (eGFR >90 mL/min/1.73m2). 
Serum samples for PK analysis of pegloticase will be collected approximately 15 minutes to 2 hours after the 
end of infusion on Day 1, prior to the infusion and approximately 15 minutes to 2 hours after the end of 
infusion at Weeks 2, 6, 14 and 22. An additional PK sample will be collected at the Week 21 non-infusion 
visit, 
End-of-Pegloticase-Infusions Visit (if applicable) and End-of-Study/Early Termination Visit. 
Serum samples for evaluation of anti-PEG and anti-uricase immunoglobulin G (IgG) antibodies will be 
collected prior to the infusion on Day 1 and prior to the infusions at the Weeks 2, 6, 14 and 22. An additional 
sample will be collected at the End-of-Pegloticase-Infusions Visit (if applicable), End-of-Study/Early 
Termination Visit and the 
3-month follow up visit. In the event of an AE suspected to be an infusion reaction, a sample will be collected 
at that time or at the subsequent visit for future evaluation of antibodies. 
Safety assessments, including monitoring and recording of all AEs, whether or not drug-related, measurement 
of vital signs, physical examinations, monitoring of hematology and blood chemistry and acute renal 
rejection, will be performed. 
An independent adjudication committee will review reported events of infusion reactions, cardiovascular 
events and anaphylaxis. 
An overview of the study design is presented in the schematic below. 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 11 of 103 
Inclusion Criteria:  
Eligible subjects must meet/provide all of the following criteria: 
1. Willing and able to give informed consent; 
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of 
the study; 
3. Adult men or women ≥ 18 years of age; 
4. Is a recipient of a de novo kidney from a living or deceased donor and is >1 year post-
transplant prior to screening; 
5. Is on a stable standard of care immunosuppression therapy for at least 3 months prior to screening; 
6. Kidney allograft is functional at entry, based on an estimated GFR (eGFR) ≥ 15 mL/min/1.73m2; 
7. Women of childbearing potential have a negative screening serum pregnancy test and will be 
required to use a medically approved form of birth control during their participation in the study; 
8. Uncontrolled gout, defined as: 
9. Hyperuricemia during screening as documented by sUA ≥ 7 mg/dL during Screening and prior to 
entry into the Treatment Period (Note: the sUA may be repeated up to 3 times during the Screening 
Period to confirm eligibility), and 
10. Inability to maintain sUA <6 mg/dL on other urate-lowering therapy or intolerable side 
effects or contraindicated with conventional urate-lowering therapy, and 
11. At least 1 of the following: 
i. Evidence of tophaceous deposits 
ii. Recurrent gout flares defined as 2 or more flares in the 12 months prior to Screening 
iii. Presence of chronic gouty arthritis; and 
12. Able to tolerate low-dose prednisone (<10 mg/day) as part of the required standard gout flare 
prophylaxis regimen for ≥ 1 week before the first infusion. 
Exclusion Criteria: 
Subjects will be ineligible for study participation if they meet any of the following criteria: 
1. Any other organ transplant beside kidney; 
2. Any severe infection, unless treated and completely resolved at least 2 weeks prior to Day 1; 
3. Chronic or active hepatitis B (HBV) infection; 
4. Known history of hepatitis C virus RNA positivity unless treated and viral load is negative; 
5. Known history of Human Immunodeficiency Virus (HIV) positivity; 
6. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit); 
7. Decompensated congestive heart failure or hospitalization for congestive heart failure within 3 
months of the Screening Visit, uncontrolled arrhythmia, treatment for acute coronary syndrome 
(myocardial infarction or unstable angina), or uncontrolled blood pressure (>160/100 mmHg) at 
the end of the Screening Period (Day 1 prior to infusion); 
8. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate female partner, or 
not using an effective form of birth control, as determined by the Investigator; 
9. Prior treatment with pegloticase, another recombinant uricase (rasburicase), or concomitant 
therapy with a polyethylene glycol-conjugated drug; 
10. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant 
protein or porcine product; 
11. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to Day 
1, or plans to take an investigational drug during the study; 
12. Currently receiving systemic or radiologic treatment for ongoing cancer; 
13. History of malignancy within 5 years other than non-melanoma skin cancer, in situ carcinoma of 
cervix, early stage renal cell cancer or early stage prostate cancer that has been completely resected 
>2 years prior to screening; 
14. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at Screening that is not 
subsequently controlled by the end of the Screening Period; 
15. Diagnosis of osteomyelitis; 
16. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 12 of 103 
and Kelley- Seegmiller syndrome; 
17. Unsuitable candidate for the study, based on the opinion of the Investigator (e.g., cognitive 
impairment), such that participation might create undue risk to the subject or interfere with the 
subject’s ability to comply with the protocol requirements or complete the study; 
18. Currently receiving allopurinol, febuxostat or other urate lowering medications and unable to 
discontinue medication 7 days prior to Day 1; or 
19. Currently receiving probenecid and unable to discontinue medication within 3 days, prior to Day 1. 
Dose Regimen/Route of Administration: 
Pegloticase: 
Pegloticase 8 mg will be administered via IV infusion over ≥ 120 minutes every 2 weeks for a total of 12 
infusions from Day 1 through the Week 22 Visit. The date and start and stop time of each infusion will be 
recorded. 
All subjects will receive prophylactic treatment to reduce the risk of acute gout flares beginning ≥ 1 week 
before the first dose of pegloticase and continuing for the duration of the 24-week treatment period. 
Subjects will not be fasting on the day of infusion and will be encouraged to have a snack or normal meal before 
or after the infusion. Standardized IR prophylaxis consisting of pre-treatment with antihistamines, 
acetaminophen and corticosteroids will accompany each infusion: fexofenadine (60 or 180 mg orally) will be 
taken the day before each infusion; fexofenadine (60 or 180 mg orally) and acetaminophen (1000 mg orally) will 
be taken the morning of each infusion. In addition, methylprednisolone (125 mg IV from Day 1 to Week 10 and 
80 mg IV from Week 12 until the end of treatment) is recommended to be administered over an infusion 
duration between 10 and 30 minutes, immediately prior to each pegloticase infusion. Alternate IV corticosteroid 
regimen may be substituted for methylprednisolone at the discretion of the Investigator. The dose of 
fexofenadine should be 60 mg orally in subjects with decreased renal function and 180 mg orally in subjects 
with normal renal function (eGFR >90 mL/min/1.73m2).  
Dosage Form and Strength Formulation: 
Pegloticase is commercially available in the United States as KRYSTEXXA® and will be supplied as clear, 
colorless, sterile solution in phosphate-buffered saline (PBS), 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 a 1 mL volume. Pegloticase will be administered as an admixture of 8 mg in 250 mL of 0.9% Sodium 
Chloride Injection, United States Pharmacopeia (USP) for IV infusion by gravity feed or infusion pump. 
Pegloticase will not be administered as an IV push or bolus. 
Duration of Treatment and Follow-up: 
Screening: Up to 35 days prior to the Day 1 visit 
Treatment Period: Pegloticase for 24 weeks (infusion visits every 2 weeks from Day 1 until the Week 22 
Visit). 
End-of-Pegloticase-Infusion Visit (if applicable): If the subject discontinues pegloticase treatment prior 
to the Week 22 infusion, such as due to the sUA stopping rules, the subject will complete this visit within 
approximately 2 weeks of the last infusion. Subjects will continue in the study. 
End-of-Study/Early Termination Visit: Subjects who discontinue treatment during the 24-week treatment 
period study will be encouraged to continue study participation through the Week 24/End-of-Study Visit. 
Subjects who discontinue treatment prior to the Week 24 Visit and are not willing to continue in the study 
will complete the Early Termination Visit. 
Safety Follow-up Visit: All subjects will receive a safety follow-up phone call/email approximately 30 days 
after the last dose of pegloticase to assess if any AEs/SAEs have occurred and will return to the clinic for a 
follow up visit 3 months after the last pegloticase infusion. 
Criteria for Evaluation: 
Efficacy will be assessed by sUA levels, tophus resolution, tophus size, urate deposition volume and bone 
erosion due to gout (determined by DECT), BP, and physician global assessment of gout. 
Quality of life will be assessed using the Health Assessment Questionnaire - Disability Index (HAQ-DI), 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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Health Assessment Questionnaire pain scale (HAQ pain scale) 
 
 
The PK of pegloticase and evaluation of anti-PEG and anti-uricase IgG antibodies will be assessed at specified 
time points. 
Safety assessments will include monitoring and recording of all AEs, whether or not drug-related, 
measurement of vital signs, physical examinations, and monitoring of hematology and blood chemistry and 
acute renal rejection. 
Hand Held  Uric Acid Measurement Device: 
Devices may be provided to measure subject uric acid levels in real time. 
Stopping Rules: 
Individual Subject Stopping Rule based on sUA levels: 
During the study, all subjects with pre-infusion sUA levels >6 mg/dL at 2 consecutive study visits beginning 
with the Week 2 Visit will be discontinued from pegloticase treatment. 
Statistical Analyses: 
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. 
Secondary Endpoints: 
The secondary endpoints are: 
 
The proportion of 5 mg/dL responders during Month 6 (Weeks 20, 21, 22, 23 and 24), defined as 
subjects achieving and maintaining sUA <5 mg/dL for at least 80% of the time during Month 6; 
 
The change from baseline in mean HAQ pain score to Week 24; and 
 
The change from baseline in mean HAQ-DI score to 
Week 24. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 14 of 103 
  
Pharmacokinetic and Anti-drug Antibody Endpoints: 
 
Serum concentrations of pegloticase; and 
 
Profile of anti-PEG and anti-uricase IgG antibodies.  
Safety Endpoints: 
The safety endpoints include the following: 
 
Overall AE/SAE profile; 
o  Incidences of AESI: IRs, anaphylaxis, gout flares, cardiovascular events; 
 
Laboratory tests; 
 
Vital signs and physical examination; and  
 
Incidence of renal rejection (biopsy proven).  
Statistical Analysis of Efficacy Parameters 
The efficacy analysis will be performed using the modified intention-to-treat (mITT) population, defined as 
all enrolled subjects who received at least 1 dose of pegloticase. The proportion of Month 6 responders will 
be summarized, along with a 95% confidence interval (CI) for the proportion. The proportion of 5 mg/dL 
responders during Month 6 will be analyzed similarly. 
A subject will be declared a non-responder if the subject had sUA level >6 mg/dL at 2 consecutive study visits 
beginning with the Week 2 Visit through Week 24 (for the primary endpoint) and through Week 14 (for 
exploratory endpoints). In addition, a subject who withdraws from study treatment for any reason after the first 
dose of pegloticase and prior to Month 6 (for the primary endpoint) or Month 3 (for exploratory endpoints) 
will be considered a non-responder if sUA values are not collected at the planned time points. 
The proportion of subjects with resolution of ≥ 1 tophus (100% decrease in the area of at least 1 tophus) at Week 
24 will be summarized along with the corresponding 95% CI. HAQ scores (Disability Index [DI], pain, and 
health), sUA, urate volume, tophi size, bone erosion, SBP, DBP, MAP, physician global assessment, eGFR, and 
UACR will be summarized at each visit with descriptive statistics. Changes from baseline will be summarized 
along with 95% CIs. 
Special consideration may be given to subjects who discontinue the study or miss visits due to reasons related to 
the COVID-19 pandemic. 
Sample Size Estimate: 
A sample size of 20 subjects is planned for this study. The primary efficacy endpoint, the proportion of subjects 
achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 6, will be demonstrated to 
be statistically greater than 43.5% (proportion of responders during Month 6 in Phase 3 studies), if at least 14/20 
(70%) responders are observed. In that case, the lower bound of a 95% confidence interval for the proportion of 
responders will be about 46%. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 20 of 103 
 
 
 
 
Footnotes: 
1. 
The Screening Visit can occur up to 35 days prior to the Day 1 Visit. 
2. 
Subjects will be enrolled at the Day 1 Visit to receive pegloticase 8 mg administered IV every 2 weeks from Day 1 through Week 22, inclusive. During 
this 24-week treatment phase, subjects who meet the sUA based stopping rule or discontinue treatment for any other reason will complete the End-of-
Pegloticase-Infusions Visit procedures within 2 weeks and be encouraged to continue to participate in all visits through the end of the study. Subjects 
will return for regularly scheduled visits and will complete all study visit procedures with the exception of the pegloticase infusion and IR prophylaxis. 
After the Week 24 Visit (or End-of-Pegloticase-Infusions Visit [if applicable]), subjects should resume regular care for gout per the judgment of the 
treating physician, including resumption of urate-lowering therapy (ULT) upon pegloticase discontinuation, if appropriate. Subjects will have a 3-
month Follow-up visit to assess clinical status, including sUA levels. 
3. 
Subjects who end treatment due to the stopping rules or other reasons should complete the End-of-Pegloticase-Infusions Visit within 2 weeks of the last 
infusion. Subjects should remain on study. See Section 9.3.3.1.1 for details on visits and procedures. 
4. 
All subjects will have a follow up visit 3 months following the End-of-Pegloticase Infusions Visit or Week 24/End-of-Study/Early Termination Visit. If the 
subject ends treatment early but remains in the study and the 3-month Post Treatment Follow-up Visit occurs prior to Week 24, the 3-month Post Treatment 
Follow-up Visit will be adjusted accordingly based on the timing of the last treatment. 
5. 
The Investigator or designee will collect a complete gout history and other relevant medical/surgical history. 
6. 
Medication history (i.e., prior medications) will include gout medications, starting at the time of diagnosis and up to (but not including) the Day 1 Visit; 
substance use history; and all other medications up to (but not including) the Day 1 Visit. Prior concomitant medications (not including gout medications) 
will be collected for 1 year prior to Screening. 
7. 
A complete physical examination will be performed at the Screening Visit and will include assessments of head, eyes, ears, nose, and throat (HEENT), 
heart, lungs, abdomen, skin, extremities, neurological status and musculoskeletal system, and for presence of tophi, as well as gout history and symptom 
severity. A targeted physical examination (for joint and skin evaluation and assessment of AEs) will be conducted based on potential risk for or occurrence 
of AEs at Day 1, and prior to administration of infusion at Weeks 4, 8, 12, 16, and 20, the End-of-Pegloticase-Infusions Visit (if applicable), Week 24/End-
of-Study/Early Termination Visit and 3-month Post-Treatment Follow Up Visit; at a minimum this should include heart, lungs, and abdomen. Clinically 
significant findings from the targeted physical examinations will be recorded as AEs. 
8. 
BP, respiratory rate, temperature, and heart rate will be measured at every visit, BEFORE study drug infusion and any scheduled blood draws. Heart rate 
and BP measurements should be taken after the subject has been in a sitting position and in a rested and calm state with proper positioning including back 
support, feet flat on the floor, for at least 5 minutes (See Section 9.5.4.4 for detailed BP measurement procedures). 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 the same arm is to be used consistently at 
each study visit. The Korotkoff phase V will be used to determine DBP. The cuff deflation rate should be 2 mmHg per second. 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 22 of 103 
 
16. For all subjects, serum samples for pegloticase PK analysis will be collected approximately 15 minutes to 2 hours after the end of infusion on Day 1; 
prior to infusion and approximately 15 minutes to 2 hours after the end of the infusion at Weeks 2, 6, 14, and 22.  An additional PK sample will be 
collected at Week 21, the End-of-Pegloticase-Infusions Visit (if applicable) and the Week 24/End-of-Study/Early Termination Visit. 
17. Serum samples for measurement of sUA levels will be collected at the Screening Visit, within 48 hours prior to each pegloticase infusion and after the 
end of each pegloticase infusion prior to discharge from the site. Additional serum samples for sUA levels will be collected at non-infusion Visits at 
Weeks 21 and 23 and the End-of-Pegloticase-Infusions Visit (if applicable), the Week 24/End-of-Study/Early Termination Visit, and the 3-month 
Follow-up Visit. For subjects whose previous visit’s pre-infusion sUA value is > 6 mg/dL, two separate samples/tubes of blood should be collected 
within 48 hours prior to the pegloticase infusion (except on Day 1 when only 1 pre-infusion sample is required for the central laboratory); one 
sample/tube will be assessed by the site’s local laboratory for pre-infusion sUA results for on-study subject management. If a local laboratory sample is 
drawn (within 48 hours prior to the pegloticase infusion), a sample for the central laboratory will be drawn prior to the pegloticase infusion on the day 
of the visit. The second sample/tube will be sent to the central laboratory for analysis and recording in the database. Hand held uric acid measurement 
devices  may be provided to measure subject uric acid levels in real time. If hand held devices are provided, blood uric acid levels prior to each 
pegloticase infusion and after the end of each pegloticase infusion prior to discharge from the site at the selected visits will recorded in database, but 
NOT to be used to manage pegloticase treatment. See the Laboratory Manual for instructions for alternate scenarios. 
18. Serum samples for evaluation of anti-PEG antibodies and anti-uricase IgG antibodies will be collected prior to the infusion on Day 1 and at Weeks 2, 
6, 14, and 22. An additional sample will be collected at each of the End-of-Pegloticase-Infusions Visit (if applicable), the Week 24/End-of-Study/Early 
Termination Visit, and the 3-month Study Follow Up Visit. In the event of an AE suspected to be an infusion reaction, a serum sample will be 
collected in a serum separating tube at that time or at the subsequent visit for future evaluation of pegloticase antibodies. 
19. For women of childbearing potential, a serum pregnancy test will be performed at the Screening Visit and at the Week 24/End-of-Study/Early 
Termination Visit. A urine pregnancy test will be performed at all other indicated visits. 
20. Blood samples will be collected from consenting subjects for serum and for peripheral blood mononuclear cell (PBMC) isolation for potential 
analysis of inflammatory biomarkers, markers related transplant outcome, gout or gout co-morbidities in response to pegloticase or other potential 
treatment for gout. Subjects who consent to the optional blood draw for analysis of biomarkers but screen fail will be requested to return 24 weeks 
+/- 4 weeks for an additional blood sample.  Adverse events, concomitant medications and vital signs will also be collected as an unscheduled visit 
at that time. 
21. The Investigator will review the clinical status and individual subject treatment goals at Screening, the End-of-Pegloticase-Infusions Visit (if 
applicable) and the Week 24/End-of-Study/Early Termination Visit. 
22. Blood and urine samples will be collected prior to pegloticase infusion on Day 1 and at the Week 2, 4, 6, 8, 10, 14, 18, and 22 Visits, the End of 
Pegloticase Infusions Visit (if applicable), the Week 24/End of Study/Early Termination Visit, and the 3 month Post Treatment Follow-up Visit. In 
addition, blood and urine samples will be collected after the end of pegloticase infusions prior to discharge from the site at on Day 1, Week 2, 6, 14 
and 22 Visits. The urine collected is aliquoted into separate tubes, one of which will be used by the central lab for analysis of creatinine in order to 
calculate urine allantoin/creatinine ratio.

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


Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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LIST OF TABLES 
Table 6.1 
Table of Non-Sponsor Study Responsibilities ........................................................... 34 
 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Study Design ........................................................................................ 45 
 
 

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KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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5 
ETHICS 
5.1 
Institutional Review Board/Independent Ethics Committee 
The Principal Investigator (PI) (Investigator), the Sponsor and/or designee authorized by the Sponsor 
will submit this protocol, any protocol modifications, the informed consent form (ICF), and all 
applicable study documentation to be used in this study to the appropriate Institutional Review Board 
(IRB) for review and approval/favorable opinion. A letter confirming the IRB approval/ favorable 
opinion of the protocol, the subject ICF, and applicable study documentation, a list of the IRB 
members involved in the vote, as well as a statement that the IRB is organized and operates according 
to Good Clinical Practice (GCP) and the applicable laws and regulations, must be forwarded to the 
Sponsor or its designee prior to the enrollment of subjects into the study. A copy of the approved ICF 
will also be forwarded to the Sponsor or its designee. Appropriate reports on the progress of the study 
will be made to the IRB and the Sponsor or its designee by the Investigator in accordance with 
applicable governmental regulations and in agreement with the policy established by the Sponsor. 
5.2 
Ethical Conduct of the Study 
The Investigators will ensure that this study is conducted in a manner that fully conforms with the 
principles of the Declaration of Helsinki or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The study must fully 
adhere to the principles outlined by International Council for Harmonisation (ICH) Tripartite 
Guideline for GCP or with local law if it affords greater protection to the subject. The Investigator 
will additionally ensure adherence to the basic principles of GCP, as outlined in the current version of 
21 Code of Federal Regulations (CFR), subchapter D, part 312, “Responsibilities of Sponsors and 
Investigators,” part 50, “Protection of Human Subjects,” and part 56, “Institutional Review Boards.” 
5.3 
Subject Information and Consent 
It is the responsibility of the Investigator or a person designated by the Investigator (if acceptable by 
local regulations) to obtain a signed ICF from each subject prior to participating in this study after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. 
The Investigator or designee must also explain that the subjects are completely free to refuse to enter 
the study or to withdraw from it at any time, for any reason. 
The ICF and any other written information provided to subjects will be revised whenever important 
new information becomes available that may be relevant to the subject’s consent, or there is an 
amendment to the protocol that necessitates a change to the content of the subject information and/or 
the written ICF. The Investigator will inform the subject of changes in a timely manner and will ask 
the subject to confirm his/her participation in the study by signing the revised ICF. Any revised 
written ICF and written information must receive the IRB`s approval/favorable opinion in advance of 
use. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 33 of 103 
All signed ICFs are to remain in the Investigator’s site file or, if locally required, in the subjects’ 
notes/files of the medical institution. 
The electronic case report forms (eCRFs) for this study contain a section for documenting all subject 
ICFs, and this must be completed appropriately. If new safety information results in significant 
changes in the risk/benefit assessment, the ICF should be reviewed and updated, if necessary. All 
subjects (including those already being treated) should be informed of the new information, given a 
copy of the revised ICF, and give their consent to continue in the study. 
5.4 
Compensation for Health Damage of Subjects/Insurance 
The Sponsor maintains clinical trial insurance coverage for this study in accordance with the laws and 
regulations of the country in which the study is performed. 
5.5 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the Sponsor. Only the subject number will be recorded in the 
eCRF, and if the subject name appears on any other document, it must be obliterated before a copy of 
the document is supplied to the Sponsor. Study findings stored on a computer will be stored in 
accordance with local data protection laws. As part of the informed consent process, the subjects will 
be informed in writing that representatives of the Sponsor, IRB, or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. The 
Investigator will maintain a list to enable subjects to be identified. 
The Sponsor will ensure that the use and disclosure of protected health information obtained during a 
research study complies with the federal and/or regional legislation related to the privacy and 
protection of personal information (e.g., Health Insurance Portability and Accountability Act 
[HIPAA]). 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 35 of 103 
 
7 
INTRODUCTION 
7.1 
Background 
7.1.1 Gout 
Gout affects approximately 4% of the United States population, is the most common form of 
inflammatory arthritis in men, and is associated with decreased quality of life (Saag and Choi, 2006; 
Singh and Strand, 2008; Zhu et al., 2011; Sattui et al., 2014). The frequency of gout is increasing 
worldwide, with prevalence rates estimated to be as high as 7% in older men (Mikuls et al., 2005; 
Saag and Choi, 2006; Roddy and Doherty, 2010). While the exact prevalence is unknown, as many as 
200,000 persons in the United States experience chronic symptoms of gout, which is sometimes 
referred to as chronic refractory gout, despite trials of oral urate-lowering therapy. This condition 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. 
Gout and hyperuricemia (defined as a serum uric acid level >6.0 mg/dL [Kidney Disease: Improving 
Global Outcomes {KDIGO} Guidelines, 2009]) are major problems in the population of kidney 
transplant recipients. The prevalence rate of 13.1% for gout in the kidney transplant recipient 
population is approximately 12-fold higher than the prevalence rate for gout in the general non 
transplanted US population (p <0.0001) (Brigham et al., 2018).  Potential contributors to greater 
disease severity in gout patients with kidney transplants are reduced urate excretion due to renal 
impairment and reduced utilization of key urate lowering therapies leading to poorer gout control. It is 
also possible that increased gout severity leads to greater risk of renal failure and hence, the need for 
transplantation, consistent with evidence of hyperuricemia and gout as risk factors for chronic kidney 
disease and end-stage renal disease (Radeck et al., 2018). Managing gout in kidney transplant 
recipients is challenging as it is complicated by serious underlying diseases and by drug regimens 
needed to treat these conditions and to prevent graft rejection (Stamp et al., 2005). Some 
immunosuppressive drugs increase uric acid and many conventional urate lowering therapies are 
potentially contraindicated in kidney transplant recipients. 
7.1.2 Pegloticase 
 
 
 
 
 

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KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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Two replicate pivotal Phase 3 studies for pegloticase were undertaken to establish the efficacy and 
safety of the product. The primary endpoint was defined as plasma uric acid (pUA) (highly correlated 
to serum uric acid) reduction to below 6 mg/dL for 80% of the time in Months 3 and 6 combined. The 
pooled response rate for pegloticase 8 mg every two weeks was 42%, versus a placebo response rate 
of 0%. There was also a greater reduction in complete resolution of ≥ 1 tophus in the every 2 weeks 
dosing group, and favorable effect of pegloticase treatment in the reduction of the number of tender 
and swollen joints. In subsequent open-label extension studies, pegloticase led to continued control of 
pUA, reduction in gout flares, and continued resolution of tophi, suggesting continuing benefit with 
extended pegloticase treatment beyond the initial 6 months of therapy, particularly in subjects who 
met responder criteria in the placebo-controlled trials. 
In the Phase 3 pivotal studies, deaths, AEs, SAEs, as well as 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 vs. placebo 
during Months 4-6. Despite use of prophylactic medications against hypersensitivity including 
administration of corticosteroids, antihistamine, and acetaminophen in advance of each pegloticase 
infusion, IRs were seen in 22/85 (26%) of subjects receiving the 8 mg 2 week regimen. There was no 
specified definition of anaphylaxis in the Phase 3 protocols, and there were no investigator-reported 
events of anaphylaxis in the Phase 3 studies with pegloticase. 
However, in a post-hoc review applying the National Institute of Allergy and Infectious Diseases/ 
Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria (Sampson et al., 2006), it was 
determined that across the Phase 2 and Phase 3 program, anaphylaxis occurred in 6.5% of subjects 
treated with pegloticase dosed every 2 weeks. Anaphylaxis generally occurred within 2 hours after 
treatment. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, 
with or without rash or urticaria. All of these events had relatively rapid resolution with the cessation 
of infusion. 
 
In a post-hoc analysis, the apparent role of immunogenicity in both loss of urate lowering effect and 
incidence of IRs was appreciated. Only 2% of subjects with anti-pegloticase antibody titers exceeding 
1:2430 maintained a urate-lowering response to pegloticase compared with 63% of subjects who were 
treated for at least 2 months without developing high-titer antibodies (p <0.001) (Sundy et al., 2011). 
The incidence of IRs was higher among subjects who developed high-titer antibodies compared with 
those who had titers that did not exceed 1:2430 (60% vs. 19%; p <0.001) (Sundy et al., 2011). In 
addition, most IRs occurred when sUA levels were greater than 6 mg/dL. Retrospective analyses 
showed that the loss of urate-lowering efficacy, as reflected by sUA of greater than 6 mg/dL, 
preceded a patient’s first IR, whenever it occurred, in 20 (91%) of 22 subjects treated with pegloticase 
every 2 weeks. 
Therefore, discontinuation of pegloticase therapy in subjects who lose urate-lowering response offers 
a valuable approach for mitigating the risk of IR. A post-hoc analysis of the biweekly pegloticase 
dosing group in the randomized controlled trials (RCTs) illustrated the impact of several possible 
stopping rules based on sUA levels. A stopping rule based on 2 consecutive pre-infusion sUA 

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Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 41 of 103 
 
 
 
7.2 
Rationale for this Study 
During the pre-marketing Phase 3 studies for pegloticase, subjects with organ transplant were 
excluded from participation; however, subjects with renal impairment were included, and showed 
comparable safety and efficacy as the general study population. Kidney transplant recipients with 
uncontrolled gout have the potential to benefit from the ability of pegloticase to rapidly deplete urate 
deposits, even when urate excretion is impaired. In addition, immunosuppressive agents to prevent 
rejections have the potential to thwart the formation of ADA against pegloticase, thereby preserving 
its effectiveness and decreasing the risk of infusion reactions. 
This study will test safety and effectiveness of pegloticase 8 mg administered intravenously every 2 
weeks in kidney transplant subjects with chronic gout refractory to conventional urate lowering 
therapy (ULT). Prospective use of sUA stopping rules, with pegloticase treatment cessation (but study 
continuation) when a subject has a pre-infusion sUA level >6 mg/dL on two consecutive study visits, 
will also help confirm the value of this approach to reduce IR risk. 
7.3 
Rationale for Dose Selection 
 
 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 42 of 103 
 
8 
STUDY OBJECTIVES 
The overall objective of the study is to assess the efficacy and safety of pegloticase in kidney 
transplant subjects with uncontrolled gout refractory to conventional urate lowering therapy. 
 
Primary Objective: 
To evaluate the effect of pegloticase on the response rate of sustained serum uric acid (sUA) 
reduction to sUA <6 mg/dL during Month 6 of treatment. 
 
Secondary Objectives: 
 To evaluate the effect of pegloticase on the response rate of sustained serum uric acid reduction 
to sUA <5 mg/dL during Month 6 of treatment; 
 To evaluate the effect of pegloticase on pain assessed by the Health Assessment Questionnaire 
(HAQ) pain score; and 
 To evaluate the effect of pegloticase on disability assessed by the Health Assessment 
Questionnaire - Disability Index (HAQ-DI) score. 
 
Exploratory Objectives: 
 
 
 
 
 
 
 
 
 
 To evaluate the pharmacokinetics (PK) of pegloticase and the profile of anti-methoxy- 
poly(ethylene glycol) (PEG) and anti-uricase IgG antibodies; and 
 To evaluate the safety and efficacy 3 months after the end of treatment with pegloticase. 
 
Safety and Tolerability Objectives: 
To assess the overall adverse event (AE)/serious AE (SAE) profile including AEs of special interest (AESI) 
(infusion reactions [IRs], anaphylaxis, gout flares and cardiovascular [CV] events), laboratory tests, vital 
signs and physical exam, and incidence of biopsy confirmed renal rejection. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 43 of 103 
 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 4, multi-site, open-label, efficacy and safety study of pegloticase in adult subjects with 
uncontrolled gout who have undergone kidney transplantation. Twenty subjects will be enrolled. 
The study design will include: 1) a Screening Period, lasting up to 35 days; 2) a 24-week treatment 
period which includes an End-of-Study (Week 24)/Early Termination Visit; 3) a safety follow-up 
phone/email Visit 30 days after the last infusion; and 4) a 3-month post-treatment follow up visit. 
During the Screening Period, eligibility will be confirmed. 
Samples for measurement of sUA levels will be collected at the Screening Visit, prior to each 
infusion, 15-60 minutes after the end of each infusion and at the Week 24/End-of-Study/Early 
Termination Visit. Additional samples for sUA levels will be collected at non-infusion Visits at 
Weeks 21 and 23. 
Subjects who meet all of the inclusion criteria and none of exclusion criteria during Screening will be 
enrolled at the Day 1 Visit to receive pegloticase 8 mg administered IV every 2 weeks from Day 1 
through Week 22, inclusive. During this 24-week treatment phase, subjects who meet the stopping 
rule (based on elevated sUA levels, see Stopping Rule in Section 9.5.7.2) or discontinue treatment for 
any other reason will complete the End-of-Pegloticase-Infusions Visit procedures within 2 weeks and 
be encouraged to continue to participate in all visits through the end of the study. Subjects will return 
for regularly scheduled visits and will complete all study visit procedures with the exception of the 
pegloticase infusion and IR prophylaxis. After the Week 24/End-of-Study/Early Termination Visit (or 
End-of-Pegloticase-Infusions Visit [if applicable]), subjects should resume regular care for gout per 
the judgment of the treating physician, including resumption of ULT upon pegloticase 
discontinuation, if appropriate. 
Subjects will have a 3-month Follow-up visit to assess clinical status, including sUA levels. 
On days of scheduled infusions, pegloticase will be administered after all pre-dose study visit 
assessments have been completed. The date and start and stop times of infusion will be recorded. The 
date of the first dose of pegloticase is defined as Day 1. All subsequent doses and study visits will be 
scheduled based on the Day 1 Visit date. 
It is required that before a subject begins the treatment period, he or she has been taking protocol 
defined standard gout flare prophylaxis (i.e., colchicine initial dose 0.3 to 0.6 mg/day if tolerated and 
low-dose prednisone ≤ 10 mg/day); for subjects already taking chronic corticosteroids, colchicine 0.3 
to 0.6 mg/day should be added. In subjects with eGFR ≤ 30 mL/min/1.73m2, the dose of colchicine 
should not be more than 0.3 mg/day. In subjects taking cyclosporine, only low dose prednisone (and 
not colchicine) should be used for ≥ 1 week before the first infusion. Gout flare prophylaxis should 
continue for the duration of the 24-week treatment period. Subjects should be monitored closely for 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 44 of 103 
symptoms of colchicine excess during the study. Reductions in dose, dose frequency or 
discontinuation of colchicine are permitted if not tolerated. 
For IR prophylaxis, fexofenadine (60 or 180 mg orally) will be taken the day before each infusion; 
fexofenadine (60 or 180 mg orally) and acetaminophen (1000 mg orally) will be taken the morning of 
each infusion. In addition, methylprednisolone (125 mg IV from Day 1 to Week 10 and 80 mg IV 
from Week 12 until the end of treatment) is recommended to be administered over an infusion 
duration between 10 and 30 minutes, immediately prior to each pegloticase infusion. Alternate IV 
corticosteroid regimen may be substituted for methylprednisolone at the discretion of the Investigator. 
The dose of fexofenadine should be 60 mg orally unless in subjects with decreased renal function and 
180 mg orally in subjects with normal renal function (eGFR>90 mL /min/1.73m2). 
Serum samples for PK analysis of pegloticase will be collected approximately 15 minutes to 2 hours 
after the end of infusion on Day 1, prior to the infusion and approximately 15 minutes to 2 hours after 
the end of infusion at Weeks 2, 6, 14 and 22. An additional PK sample will be collected at the Week 
21 Visit, End-of-Pegloticase-Infusions Visit (if applicable) and Week 24/End of Study/Early 
Termination Visit. 
Serum samples for evaluation of anti-PEG and anti-uricase IgG antibodies will be collected prior to 
the infusion on Day 1 and prior to the infusions at the Weeks 2, 6, 14 and 22. An additional sample 
will be collected at each of the End-of-Pegloticase-Infusions Visit (if applicable), 
Week 24/End-of-Study /Early Termination Visit and the 3-month follow up visit. In the event of an 
AE suspected to be an IR, a sample will be collected at that time or at the subsequent visit for future 
evaluation of ADAs. 
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 acute renal rejection, will be performed. 
An independent external adjudication committee will review reported events of IRs, major CV events 
and anaphylaxis. 
An overview of the study design is presented in the schematic below, and details of study activities 
are provided in Section 2.1. 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 45 of 103 
 
Figure 9.1 
Schematic of Study Design 
 
 
9.2 
Discussion of Study Design 
This is a Phase 4, multi-site, open-label, single arm study to assess efficacy and safety of pegloticase 
in adult subjects with uncontrolled gout who have undergone kidney transplantation. 
During the pre-marketing Phase 3 studies for pegloticase, subjects with organ transplant were 
excluded from participation; however, subjects with renal impairment were included, and showed 
comparable safety and efficacy as the general study population. Kidney transplant recipients with 
uncontrolled gout have the potential to benefit from the ability of pegloticase to rapidly deplete urate 
deposits, even when urate excretion is impaired. In addition, immunosuppressive agents to prevent 
rejections have the potential to thwart the formation of ADA against pegloticase, thereby preserving 
its effectiveness and decreasing the risk of infusion reactions. 
 
This study will test safety and effectiveness of pegloticase (administered 8 mg via IV infusion every 2 
weeks, consistent with the current pegloticase prescribing information) in kidney transplant subjects 
with chronic gout refractory to conventional urate lowering therapy. 
Prospective use of sUA stopping rules, with pegloticase treatment cessation (but study continuation) 
when a subject has an pre-infusion an sUA level >6 mg/dL on two consecutive study visits, will also 
help confirm the value of this approach to reduce IR risk. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 46 of 103 
9.3 
Selection of Study Population 
9.3.1 Inclusion Criteria 
Eligible subjects must meet/provide all of the following criteria: 
1. Willing and able to give informed consent; 
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the study; 
3. Adult men or women ≥18 years of age; 
4. Is a recipient of a de novo kidney from a living or deceased donor and is >1 year post- 
transplant prior to screening; 
5. Is on a stable standard of care immunosuppression therapy for at least 3 months prior to 
screening; 
6. Kidney allograft is functional at entry, based on an estimated GFR (eGFR) 
≥ 15 mL/min/1.73m2; 
7. Women of childbearing potential have a negative screening serum pregnancy test and will be 
required to use a medically approved form of birth control during their participation in the 
study; 
8. Uncontrolled gout, defined as: 
A. Hyperuricemia during screening as documented by sUA ≥ 7 mg/dL during Screening and 
prior to entry into the Treatment Period (Note: the sUA may be repeated up to 3 times 
during the Screening Period to confirm eligibility); and 
B. Inability to maintain sUA <6 mg/dL on other urate-lowering therapy or intolerable side 
effects or contraindicated with conventional urate-lowering therapy; and 
C. At least 1 of the following: 
i. 
Evidence of tophaceous deposits; 
ii. 
Recurrent gout flares defined as 2 or more flares in the past 12 months prior to 
Screening; 
iii. 
Presence of chronic gouty arthritis; and 
9. Able to tolerate low-dose prednisone (<10 mg/day) as part of the required standard gout flare 
prophylaxis regimen for ≥ 1 week before the first infusion. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 47 of 103 
 
9.3.2 Exclusion Criteria 
Subjects will be ineligible for study participation if they meet any of the following criteria: 
1. Any other organ transplant beside kidney; 
2. Any severe infection, unless treated and completely resolved at least 2 weeks prior to 
Day 1; 
3. Chronic or active hepatitis B (HBV) infection; 
4. Known history of hepatitis C virus RNA positivity unless treated and viral load is 
negative; 
5. Known history of Human Immunodeficiency Virus (HIV) positivity; 
6. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit); 
7. Decompensated congestive heart failure or hospitalization for congestive heart failure 
within 3 months of the Screening Visit, uncontrolled arrhythmia, treatment for acute 
coronary syndrome (myocardial infarction or unstable angina), or uncontrolled blood 
pressure (>160/100 mmHg) at the end of the Screening Period (Day 1 prior to infusion); 
8. 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; 
9. Prior treatment with pegloticase, another recombinant uricase (rasburicase), or 
concomitant therapy with a polyethylene glycol-conjugated drug; 
10. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant 
protein or porcine product; 
11. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, 
prior to Day 1 or plans to take an investigational drug during the study; 
12. Currently receiving systemic or radiologic treatment for ongoing cancer; 
13. History of malignancy within 5 years other than non-melanoma skin cancer, in situ 
carcinoma of cervix, early stage renal cell cancer or early stage prostate cancer that has 
been completed resected >2 years prior to Screening; 
14. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at Screening that 
is not subsequently controlled by the end of the Screening Period; 
15. Diagnosis of osteomyelitis; 
16. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as 
Lesch-Nyhan and Kelley-Seegmiller syndrome; 
17. Unsuitable candidate for the study, based on the opinion of the Investigator (e.g., 
cognitive impairment), such that participation might create undue risk to the subject or 
interfere with the subject’s ability to comply with the protocol requirements or complete 
the study; 
18. Currently receiving allopurinol, febuxostat or other urate lowering medications and 
unable to discontinue medication 7 days prior to Day 1; or 

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Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 55 of 103 
and symptoms of the AE and drugs given for treatment are to be recorded in the medical record and in 
the eCRF. 
After the first incidence of an IR that does not meet the criteria of anaphylaxis (see Section 
9.5.4.1.1.5) or does not meet serious criteria, the Investigator may elect to initiate the next infusion at 
a slower rate. All changes to infusion rate or dilution, and drugs given for prophylaxis or treatment, 
are to be recorded in the medical record and in the eCRF. 
9.4.7 Method of Assigning Subjects to Pegloticase 
Medidata Randomization and Trial Supply Management (RTSM) will be used to assign subjects 
specific pegloticase kit numbers. 
Specific procedures for accessing and assigning study drug through Medidata are contained in the 
study procedures manual. 
9.4.8 Blinding 
Because all subjects will receive pegloticase, this study drug will be administered without blinding 
and all subjects, Investigators and site personnel will know that all subjects are receiving pegloticase. 
9.4.9 Prior and Concomitant Therapy 
Medication history (i.e., prior medications) will include all prior gout medications, starting at the time 
of diagnosis and up to the Screening Visit, and all other medications taken from 1 year prior to the 
Screening Visit. 
Concomitant medications are defined as drug or biological products other than the study drugs (or 
prior gout medications) taken by a subject from Screening through the Post-Treatment Follow-up 
Visits. This includes other prescription medications (including preventive vaccines), over the counter 
medications, herbal medications, vitamins, and food supplements. 
Information about prior and concomitant medications, including those used for any duration to treat 
an AE, will be collected on source documents and the appropriate eCRFs at each visit. The generic 
name of the medication, indication, dose, unit, frequency, route of administration, and start and stop 
dates will be recorded. 
Subjects will be directed to discontinue current ULT prior to initiation of pegloticase therapy as per 
the current package insert. Other medications used at the time of study initiation may be continued at 
the discretion of the Investigator. 
9.4.10 Restricted Medications 
Subjects should not receive the following medications from the time of Screening through the end of 
pegloticase treatment: 
 Oral ULTs including allopurinol, febuxostat, probenecid, lesinurad, or other ULT for gout; 
Re-introduction of oral ULTs should not start until after the End of Pegloticase Visit (or End 
of Study) laboratory tests are collected. 

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Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 59 of 103 
overall response is Complete Response). If any single tophus shows progression, or if a new tophus 
appears during the study, the overall response for that subject will be Progressive Disease, regardless 
of the response of any other tophi.  
9.5.2 Quality of Life Assessment 
 
The HAQ (Appendix 17.2) including the HAQ-DI, pain and health scales, will be administered at 
Screening and prior to the pegloticase infusion at the Day 1 Visit, the Week 6 and 14 Visit, the End-
of-Pegloticase-Infusions Visit (if applicable), the Week 24/End-of-Study/Early Termination Visit, and 
the 3-month Post-Treatment Follow-up Visit (Section 2.1). 
The HAQ-DI is a self-report functional status instrument that can be filled out by a subject in less than 
5 minutes and requires 1 minute to score. The index measures disability over the past week by asking 
a total of 20 questions covering 8 domains of function: dressing and grooming, arising, eating, 
walking, hygiene, reach, grip, and usual activities. There are at least 2 questions in each domain and 
the 8 domains represent a comprehensive set of functional activities. The HAQ-DI is calculated by 
scoring the answer to each question in the HAQ from 0 to 3, with 0 representing the ability to do 
without any difficulty, and 3 representing inability to do. Any activity that requires assistance from 
another individual or requires the use of an assistive device raises a 0 or 1 score to a 2. The highest 
score for each of the 8 domains is summed (range from 0 to 24) and divided by 8 to yield, on a scale 
with 25 possible values, a Functional Disability Index with a range from 0 to 3. The disability index is 
based on the number of domains answered and is computed only if the subject completes answers to 
at least 6 domains (Bruce and Fries, 2003). 
The HAQ pain scale consists of a doubly-anchored, horizontal visual analog scale (VAS), that is 
scored from 0 (no pain) to 100 (severe pain). Subjects are asked to rate the severity of the pain they 
have had because of illness in the past week by placing a vertical mark on the VAS. 
 
 
 
9.5.3 Pharmacokinetic and Anti-drug Antibody Measurements 
Serum samples for PK analysis of pegloticase will be collected after the end of infusion on Day 1 
(prior to discharge); prior to the pegloticase infusion and after the end of the infusion (prior to 
discharge) at Weeks 2, 6, 14, and 22. Additional PK samples will be collected at the Week 21 Visit, 
the End-of-Pegloticase-Infusions Visit (if applicable), and the Week 24/End-of-Study/Early 
Termination Visit. 
Serum samples for evaluation of anti-PEG and anti-uricase IgG antibodies will be collected prior to 
the pegloticase infusion on Day 1 and at the Week 2, 6, 14, 22 Visits, the End-of-Pegloticase-
Infusions Visit (if applicable), the Week 24/End-of-Study/Early Termination Visit, and the 3-month 
Post-Treatment Follow-up Visit. 
Each sample collection date and time will be recorded in source documents and the eCRF. 

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Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 90 of 103 
 
 
 
 
9.6.6 Pharmacokinetic and Anti-drug Antibody Analysis 
Concentrations for pegloticase will be summarized using descriptive statistics for the PK population. 
Incidence of anti-drug antibodies and titer levels will be summarized. 
9.6.7 Safety Analysis 
Treatment-emergent AEs are defined as events with an onset date on or after the start of the first 
pegloticase infusion through 30 days after the last dose of pegloticase. AEs that occur more than 30 
days after the last dose of pegloticase through the 3-month follow-up visit will also be summarized. 
The number and percentage of subjects experiencing AEs will be summarized by system organ class 
and preferred term. Summaries by maximum severity and relationship to study drug will also be 
provided. SAEs and AEs leading to discontinuation of study drug will be presented by system organ 
class and preferred term. The proportion of subjects with each AESI will also be summarized. 
Laboratory test results will be summarized by study visit and change from baseline. Shift tables for 
laboratory parameters by Common Terminology Criteria for Adverse Events grade will be presented. 
Laboratory test results will also be classified relative to the normal reference range (normal, low, or 
high). 
Vital signs, including BP, respiratory rate, temperature, and heart rate, will be summarized by study 
visit and change from baseline. 
Prior and concomitant medications will be summarized and/or included in the data listings. 
9.6.8 Interim Analyses 
No formal interim analysis is planned for this study. Efficacy and safety data may be summarized 
after 10-15 subjects have been followed through Week 24. Additional summary of the data may be 
performed periodically throughout the study, and safety data will be summarized regularly for safety 
monitoring. Final analysis will occur when all subjects have completed the study. 
9.6.9 Sample Size and Power Considerations 
A sample size of 20 subjects is planned for this study. The primary efficacy endpoint, the proportion 
of subjects achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 6, 
will be demonstrated to be statistically greater than 43.5% (proportion of responders during Month 6 
in the Phase 3 studies), if at least 14/20 (70%) responders are observed. In that case, the lower bound 
of a 95% confidence interval for the proportion of responders will be about 46%. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 91 of 103 
9.7 
Changes in the Conduct of the Study 
If any modifications in the experimental design, dosages, parameters, subject selection, or any other 
sections of the protocol are indicated or required, the Investigator will consult with the Sponsor before 
any such changes are instituted. Modifications will be accomplished through formal amendments to 
this protocol by the Sponsor and approval from the appropriate IRB. 
All protocol deviations and the reasons for such deviations must be documented in the eCRF. In the 
event of a major protocol deviation, the Investigator and Sponsor’s Medical Monitor will determine 
whether the subject should continue to participate in the study. 
The Sponsor has a legal responsibility to report fully to regulatory authorities all results of 
administration of investigational drugs to humans. No investigational procedures other than those 
described in this protocol will be undertaken on the enrolled subjects without the agreement of the 
IRB and Sponsor. 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
The Investigator must maintain adequate and accurate records to document fully the conduct of the 
study and to ensure that study data can be subsequently verified. These documents should be 
classified in 2 separate categories: (1) Investigator study file and (2) subject clinical source documents 
that corroborate data collected in the eCRFs. Subject clinical source documents would include, as 
applicable, original hospital/clinic subject records; physicians’ and nurses’ notes; appointment book; 
original laboratory, ECG, electroencephalogram, radiology, pathology, and special assessment 
reports; dispensing records; signed ICFs; consultant letters; and subject screening and enrollment 
logs. 
In order to comply with regulatory requirements, it is the policy of the Sponsor that, at a minimum, 
the following be documented in source documents at the study center: 
 Medical history/physical condition and diagnosis of the subject before involvement in the 
study sufficient to verify that the subject meets protocol entry criteria; 
 Study number, assigned subject number, and verification that written informed consent was 
obtained (each recorded in dated and signed progress notes); 
 Progress notes for each subject visit (each dated and signed); 
 Records of each study visit including each study assessment and the identity of the 
staff member performing the assessment; 
 Study drug dispensing and return; 
 Review by the Investigator or qualified personnel on the 1572 of laboratory test results; 
 AEs (start and stop date, description, action taken, and resolution); 
 Investigator or sub-investigator’s signed assessment of AEs; 
 Concomitant medications (start and stop dates, reason for use); and 
 Condition of subject upon completion of, or premature withdrawal from, the study. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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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 study completion. 
The Investigator will ensure that the eCRFs are accurate, complete, legible, and timely, and will 
review and provide an electronic signature for the eCRF according to the standard operating 
procedure of the Data Management System. Final eCRFs will be provided to the Investigator and 
Sponsor by Data Management. 
12 STUDY MONITORING 
The Investigator will ensure that the study is conducted in accordance with all regulations governing 
the protection of human subjects. The Investigator will adhere to the basic principles of GCP as 
outlined in Title 21 of the CFR, Part 312, Subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, Part 50, “Protection of Human Subjects”; 21 CFR, Part 56, “Institutional Review Boards”; 
21 CFR, Part 54 “Financial Disclosure by Clinical Investigators”; and the ICH guideline entitled 
“Good Clinical Practice: Consolidated Guidance.” Additionally, this study will be conducted in 
compliance with the Declaration of Helsinki and with all local laws and regulations. 
The Investigator will ensure that all work and services described in, or associated with, this protocol 
are conducted in accordance with the investigational plan, applicable regulations, and the highest 
standards of medical and clinical research practice. The Investigator will provide copies of the study 
protocol and Investigator’s Brochure to all Sub-Investigators, pharmacists, and other staff responsible 
for study conduct. 
All aspects of the study will be monitored by qualified individuals designated by the Sponsor. The 
Sponsor will ensure that the study is monitored adequately in accordance with GCP guidelines. 
Prior to initiation of the study, the Sponsor’s representatives will review with study center personnel 
information regarding the investigational drug, protocol requirements, monitoring requirements, and 
reporting of SAEs. 
At intervals during the study, as well as after the completion of subject enrollment, the study center 
will be monitored by the Sponsor or designee for compliance. During these visits, the monitor will 
discuss study progress, verify adherence to the protocol and the completeness, consistency, and 
accuracy of the data being entered on the eCRF (source data verification); oversee the resolution of 
outstanding data discrepancies, and check on various aspects of study conduct (e.g., drug 
accountability, sample storage). The Investigator agrees to allow monitors access to the clinical 
supplies, dispensing and storage areas, and clinical records of the study subjects, and, if requested, 
agrees to assist the monitors. The Investigator must cooperate with the monitors to ensure that any 
problems detected in the course of these monitoring visits are resolved. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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A secondary audit may be conducted by Quality Assurance designated by the Sponsor. The 
Investigator will be informed if this is to take place and advised as to the nature of the audit. 
Representatives of the United States FDA and/or representatives of other regulatory authorities may 
also conduct an inspection of the study at the investigative site. If informed of such an inspection, the 
Investigator should notify the Sponsor immediately. 
Every effort will be made to maintain the anonymity and confidentiality of subjects participating in 
this clinical study. However, because of the investigational nature of this treatment, the Investigator 
agrees to allow representatives of the Sponsor, its designated agents, and authorized employees of the 
appropriate regulatory agencies to inspect the facilities used in this study and to have direct access to 
inspect, for purposes of verification, the hospital or clinical records of all subjects enrolled in this 
study. A statement to this effect should be included in the ICF. 
13 DATA MANAGEMENT 
Data will be entered into a clinical database, as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Data will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures. Data queries requiring 
clarification will be communicated to the investigational site for resolution. Only authorized 
personnel will make corrections to the clinical database, and all corrections will be documented in an 
audit trail. 
The coding of an AE, medical history and concomitant medication terms will be performed by the 
Sponsor or designated vendor and reviewed and approved by the Sponsor. Concomitant medications 
will be coded using the World Health Organization Drug Dictionary (WHODrug) and AE/medical 
history/surgery/non-drug therapy terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
14 RETENTION OF RECORDS 
No study documents at the study site should be destroyed without prior written agreement between 
the Sponsor and the Investigator. All subjects’ medical records, the Investigator’s copy of the eCRF, 
other supporting data, records of drug dispensing and accountability, signed ICFs, IRB 
correspondence, and correspondence with the Sponsor must be kept by the Investigator for at least 2 
years and/or as required by the local law following the date of the last approval of a marketing 
application in an ICH region (including the United States) and until there are no pending or 
contemplated marketing applications in any other ICH region. If an application is not filed or not 
approved for the indication under study, all study-related files must be retained for at least 2 years and 
for a period in compliance with all federal, state, and local regulations. The Sponsor must be notified 
prior to the disposal of any study-related files.  If the Investigator leaves the practice or institution 
during the required retention period, it is important that arrangements be made for continued record 
retention. In that event, the records generally will be retained at the institution at which the study was 
conducted. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 94 of 103 
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 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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16 REFERENCES 
Becker MA. Hyperuricemia and gout in kidney transplant recipients. In: Brennan DC, Dalbeth N, 
Lam AQ, Eds, UpToDate. 2019. 
Bleyer AJ, Wright D, Alcorn H. Pharmacokinetics and pharmacodynamics of pegloticase in patients 
with end-stage renal failure receiving hemodialysis. Clin Nephrol. 2015 May;83(5):286- 92. 
Botson K, Peterson J. Pretreatment and co-administration with methotrexate improved durability of 
pegloticase response: a prospective observational, proof-of-concept, case series. Poster Presentation at 
American College of Rheumatology Meeting 2018. Abstract #1286. 
Brigham MD, Tudor T, Miyasato G, Jeffrey Kent J, LaMoreaux B, Johnson R. Prevalence of gout in 
the surviving U.S. solid organ transplantation population. J Am Soc Nephrol 2018 29 (Kidney Week 
Edition):152. Abstract TH-PO158. 
Brook RA, Forsythe A, Smeeding JE, Lawrence Edwards N. Chronic gout: epidemiology, disease 
progression, treatment and disease burden. Curr Med Res Opin. 2010 Dec;26(12):2813‐  21. 
Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: dimensions and practical 
applications. Health Qual Life Outcomes. 2003 Jun 9;1:20. 
Gaffo AL, Schumacher RH, Saag KG, et al. Developing a provisional definition of flare in patients 
with established gout. Arthritis Rheum. 2012 May;64 (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 Mar;16(2):R63. 
Keenan RT, Baraf HSB, LaMoreaux B. Use of pre-infusion serum uric acid levels as a biomarker for 
infusion reaction risks in patients on pegloticase. Rheumatol Ther. 2019 Jun;6(2):299-304. 
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical 
practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9(Suppl 3): S1–
S157. 
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 Jan;128(1):34-40. 
KRYSTEXXA Product Labeling, 2016. Available at: 
https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=9c0d9fbb-998c-4a62-9354- 
7330d64b144e&type=pdf&name=9c0d9fbb-998c-4a62-9354-7330d64b144e 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
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Malamet R, Howson T, Yeo A, et al. Real world risk of infusion reactions with pegloticase treatment: 
findings from post-approval US safety data. 14th Annual Congress of the European League Against 
Rheumatism : abstr. SAT0355, 12 Jun 2013. Available at: https://b-com.mci- 
group.com/Abstract/Statistics/AbstractStatisticsViewPage.aspx?AbstractID=148548. Accessed Nov 
27 2018. 
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 
Feb;64(2):267‐ 72. 
Radeck L, Mendonca C, Lang I, Kent J, LaMoreaux B, Johnson RJ. Gout severity in kidney 
transplant recipients. J Am Soc Nephrol 2018 29 (Kidney Week Edition): 152. Abstract TH-PO159 
Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. 2010;12(6):223. 
Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 
2006;8 Suppl 1:S2. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report: Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006 
Feb;117(2):391-7. 
Sattui SE, Singh JA, Gaffo AL. Comorbidities in patients with crystal diseases and hyperuricemia. 
Rheum Dis Clin North Am. 2014 May;40(2):251‐ 78. 
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 Sep;67(9):1310‐ 6. 
Stamp L, Searle M, O'Donnell J, Chapman P. Gout in solid organ transplantation: a challenging 
clinical problem. Drugs. 2005;65(18):2593-611. 
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 Aug 17;306(7):711‐ 20. 
Wertheimer A, Morlock R, Becker MA. A revised estimate of the burden of illness of gout. Curr Ther 
Res Clin Exp. 2013 Dec;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 
Jun;34(6):1401-14. 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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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 
Oct;63(10):3136‐ 41.

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
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17.2 Health Assessment Questionnaire (Disability Index, Pain and Health Scales) 
 
 

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Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 101 of 103 
17.3 Physician Global Assessment 
 
 
 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
Page 102 of 103 
17.4 Subject Self-Reported Gout Flare Assessment 
 

Horizon Therapeutics Ireland DAC 
 
KRYSTEXXA IND: 010122 
Date: 22 JUN 2020 
 
Protocol: HZNP-KRY-406 
 
 
Version 3.0 
 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC  
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