Conditions: Cardiovascular Disease
Keywords: Cardiovascular Outcomes Heart Attack Stroke Drug Therapy Physiology Hyperuricemia Uric Acid
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6198
Healthy volunteers: no

Brief summary:
The purpose of this study is to see whether subjects with gout who receive febuxostat or allopurinol for up to 9 years have a higher rate of serious heart and blood vessel complications (major cardiovascular events).

Detailed description:
The drug tested in this study was called Febuxostat (TMX-67). Febuxostat compared with allopurinol was evaluated for the cardiovascular (CV) safety in people with gout and significant CV comorbidities.

The study enrolled 6198 patients. Participants with a diagnosis of gout were enrolled in a 1:1 ratio to receive either:

* Febuxostat
* Allopurinol

Participants received febuxostat 40 mg or 80 mg for the study depending on their serum uric acid levels were either \<6.0 mg/dL or ≥6.0 mg/dL during specified visits. Allopurinol 200 mg to 400 mg (for moderate renal impairment),or 300 mg to 600 mg (for normal and mild renal impairment), increased in 100 mg increments each month until serum uric acid was \<6.0 mg/dL was received.

This multi-center trial was conducted in Canada, Mexico and United States. The overall time to participate in this study was approximately 7 years (84 months). Participants made multiple visits to the clinic and were also contacted through the telephone.

Arms:
arm 1: Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months. arm 2: Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was \<6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance \[eCLcr\] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was \<6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but \<60 mL/min).

Interventions: intervention 1: Febuxostat intervention 2: Allopurinol
Intervention descriptions: intervention 1: Febuxostat tablets intervention 2: Allopurinol tablets

Protocol document:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular 
Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
NCT Number: NCT01101035
Protocol Approve Date:  27 August 2013
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


PROTOCOL AMENDMENT
A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the 
Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and 
Cardiovascular Comorbidities
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway 
Deerfield, IL 60015, United States
Study Number:
TMX-67_301
IND Number:
58,229
EudraCT Number:
N/A
Compound:
Febuxostat
Date:
27 August 2013
Amendment Number:
6
Amendment History:
Date
Amendment Number
Amendment Type
Region
24 August 2009
Initial Protocol
Not applicable
North America
20 January 2010
1
Substantial
North America
24 February 2010
2
Substantial
North America
24 January 2011
3
Substantial
North America
19 May 2011
4
Not Substantial
Canada
26 September 2011
5
Substantial
Global
27 August 2013
6
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is meant for review and compliance by the recipient, his or her staff, and 
applicable institutional review committee to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
Issue
Serious adverse event 
reporting
Medical monitor 
(medical advice on 
protocol, compound 
and medical 
management of 
subjects)
Responsible medical 
officer (carries overall 
responsibility for 
conduct of study)
PPD


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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonization Harmonized Tripartite Guideline for Good 
Clinical Practice E6.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.
SIGNATURES
Date
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD


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1.3
Protocol Amendment TMX-67_301 Summary of Changes
This document describes changes in reference to Protocol TMX-67_301 Amendment 6, dated 
27 August 2013.
Change in Protocol
Rationale
Increased maximum study duration estimate to 9 
years.
Slower than expected enrollment duration has extended the 
overall length of the study.
Exclude non-serious potential cardiovascular events 
from endpoint adjudication.
Non-serious adverse events are not likely to be adjudicated to a 
major adverse cardiac events (MACE) endpoint and the Food 
and Drug Administration (FDA) agreed to remove the 
requirement for adjudication of non-serious events.
Update visit name to End of Study/Discontinuation 
of Treatment/Early Termination.
Correction to remove reference to a final Month 60; clarifies 
the purpose and procedures conducted at this visit type.
Revisions and clarifications in Sections 7.4 and 7.5 
for subjects discontinuing study drug treatment with 
continued participation via follow-up contacts, and 
subjects early terminating from both study drug and 
study visits.
Update to section titles and section content revisions more 
accurately reflects the protocol for subjects with these statuses. 
Revisions also clarify instances where subjects are no longer 
followed via follow-up contacts, expectations for attempted 
contacts with subjects who are lost to follow-up, and instances 
where subjects are early terminated due to adverse events 
(AEs). 


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Package Insert [14], and other 
product information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonization Harmonized Tripartite Guideline for Good 
Clinical Practice E6.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Name of Facility
Location of Facility (City)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment TMX-67_301 Summary of Changes.........................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator...............................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Mechanism of Action.........................................................................................20
4.1.2
Nonclinical Data Summary ................................................................................21
4.2
RATIONALE FOR THE PROPOSED STUDY.......................................................21
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Objectives................................................................................................................23
5.2
Endpoints.................................................................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.2
Justification for Study Design, Dose, and Endpoints ................................................29
6.3
Premature Termination or Suspension of Study or Investigational Site.....................30
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................30
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........30
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................30
7.0
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................31
7.1
Inclusion Criteria .....................................................................................................31
7.2
Exclusion Criteria ....................................................................................................32
7.3
Required Medications and Treatments .....................................................................33
7.3.1
Medications and Treatments Not Provided Directly by Sponsor.........................34
7.3.2
Excluded Medications and Treatments...............................................................34
7.4
Procedures for Discontinuation from Study Drug Treatment with Continued 
Participation in the Study via Follow-up Contacts....................................................36


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7.5
Procedures for Early Termination of a Subject from the Study (Both Drug and 
Visits)......................................................................................................................37
8.0
STUDY MEDICATION AND TREATMENTS............................................................39
8.1
Study Medication and Treatments............................................................................39
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................39
8.1.2
Storage...............................................................................................................40
8.1.3
Dose and Regimen .............................................................................................41
8.1.4
Overdose............................................................................................................45
8.2
Randomization Code Creation and Storage..............................................................45
8.3
Investigational Drug Blind Maintenance ..................................................................46
8.4
Investigational Drug Assignment and Dispensing Procedures ..................................46
8.5
Unblinding Procedure..............................................................................................46
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................46
9.0
STUDY PLAN ..............................................................................................................48
9.1
Study Procedures.....................................................................................................48
9.1.1
Informed Consent Procedure..............................................................................48
9.1.2
Demographics, Medical History, and Medication History Procedure..................48
9.1.3
Physical Examination Procedure ........................................................................48
9.1.4
Weight and Height Procedure.............................................................................49
9.1.5
Vital Sign Procedure..........................................................................................49
9.1.6
Documentation of Concomitant Medications......................................................49
9.1.7
Documentation of Concurrent Medical Conditions.............................................49
9.1.8
Procedures for Clinical Laboratory Samples.......................................................49
9.1.9
Pregnancy ..........................................................................................................50
9.1.10 ECG Procedure..................................................................................................51
9.1.11 Documentation of Screen Failure .......................................................................51
9.1.12 Documentation of Washout Failure....................................................................52
9.1.13 Documentation of Study Entrance/Randomization .............................................52
9.1.14 Gout Flare Prophylaxis ......................................................................................52
9.1.15 Treatment of Gout Flares ...................................................................................53
9.1.16 Gout Flare Assessment.......................................................................................53
9.1.17 Physical Assessment of Tophi............................................................................54
9.1.18 Rash Assessment................................................................................................54
9.1.19 Management, Withdrawal and Follow-Up of Subjects With Liver Enzyme 
Elevations ..........................................................................................................54
9.2
Monitoring Subject Compliance...............................................................................55


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9.3
Schedule of Observations and Procedures................................................................56
9.3.1
Screening...........................................................................................................56
9.3.2
Study Randomization.........................................................................................57
9.3.3
Treatment Phase.................................................................................................58
9.3.3.1 Week 2 (± 3 Days) .......................................................................................58
9.3.3.2 Week 4 (± 3 Days) .......................................................................................58
9.3.3.3 Week 6 (3 Days) ........................................................................................59
9.3.3.4 Week 8 (± 3 Days) .......................................................................................59
9.3.3.5 Week 10 (±3 Days) ......................................................................................60
9.3.3.6 Month 3 (± 3 Days) ......................................................................................60
9.3.3.7 Month 6 (±3 Days).......................................................................................61
9.3.3.8 Months 9, 15 (Elderly and/or Moderately Renally Impaired Subjects) 
(±7 Days) .....................................................................................................61
9.3.3.9 Month 12 and Every 6 Months Until End of Study/Discontinuation of 
Treatment/Early Termination (±7 Days).......................................................61
9.3.3.10
End of Study/Discontinuation of Treatment/Early Termination...............62
9.3.3.11
Unscheduled Visit (if applicable)............................................................63
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................64
10.1
Definitions...............................................................................................................64
10.1.1 Pretreatment Events ...........................................................................................64
10.1.2 AEs....................................................................................................................64
10.1.3 Additional Points to Consider for Pretreatment Events and AEs.........................64
10.1.4 SAEs..................................................................................................................66
10.1.5 Severity of Pretreatment Events and AEs ...........................................................68
10.1.6 Causality of AEs ................................................................................................68
10.1.7 Relationship to Study Procedures.......................................................................68
10.2
Procedures...............................................................................................................68
10.2.1 Collection and Reporting of AEs........................................................................68
10.2.1.1
Pretreatment Event and AE Collection Period.........................................68
10.2.1.2
Pretreatment Event and AE Reporting ....................................................69
10.2.2 Collection and Reporting of SAEs......................................................................69
10.2.3 Follow-up of SAEs ............................................................................................70
10.2.4 Safety Reporting to Investigators, IRBs or ECs, and Regulatory Authorities ......70
10.2.5 Evaluation of CV Safety ....................................................................................71
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................72
11.1
Independent DMC ...................................................................................................72


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11.2
CV Endpoints Committee ........................................................................................72
12.0
DATA HANDLING AND RECORDKEEPING............................................................73
12.1
eCRFs......................................................................................................................73
12.2
Record Retention .....................................................................................................73
13.0
STATISTICAL METHODS..........................................................................................75
13.1
Statistical and Analytical Plans ................................................................................75
13.1.1 Analysis Sets......................................................................................................75
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................75
13.1.3 Safety Analyses..................................................................................................75
13.1.3.1
CV Safety Analysis ................................................................................75
13.1.3.2
Other Safety Analysis.............................................................................76
13.1.4 Efficacy Analysis...............................................................................................76
13.2
Interim Analysis and Criteria for Early Termination ................................................76
13.3
Determination of Sample Size..................................................................................77
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................78
14.1
Study-Site Monitoring Visits ...................................................................................78
14.2
Protocol Deviations..................................................................................................78
14.3
Quality Assurance and Regulatory Agency Audits...................................................78
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................79
15.1
Regulatory Authority and IRB and/or EC Approval.................................................79
15.2
Subject Information, Informed Consent, and Subject Authorization .........................79
15.3
Subject Confidentiality ............................................................................................80
15.4
Publication, Disclosure and Clinical Trial Registration Policy..................................81
15.4.1 Publication and Disclosure.................................................................................81
15.4.2 Clinical Trial Registration..................................................................................82
15.4.3 Clinical Trial Results Disclosure ........................................................................82
15.5
Insurance and Compensation for Injury....................................................................82
16.0
REFERENCES..............................................................................................................83
LIST OF IN-TEXT TABLES
Table 8.a
Study Medication - Sponsor Supplied ................................................................45
Table 9.a
Clinical Laboratory Tests...................................................................................50
Table 10.a
Takeda Medically Significant AE List................................................................67


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LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................28
Figure 6.b
Schematic of Study Design for the First 3 months ..............................................29
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................85
Appendix B
Responsibilities of the Investigator.....................................................................87
Appendix C
Elements of the Subject Informed Consent.........................................................89
Appendix D
Investigator Consent to Use of Personal Information..........................................91
Appendix E
Worksheet for All Potential Cardiovascular (CV) Events (sample).....................92
Appendix F
Rash Adverse Event Worksheet (sample)...........................................................94
Appendix G
Gout Flare Assessment Worksheet (sample).......................................................95
Appendix H
Detailed Description of Amendments to Text.....................................................98


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
One Takeda Parkway 
Deerfield, IL 60015, United States
Compound:
Febuxostat
Title of Protocol: A Multicenter, Randomized, 
Active-Control, Phase 3B Study to Evaluate the 
Cardiovascular Safety of Febuxostat and Allopurinol in 
Subjects with Gout and Cardiovascular Comorbidities
IND No.:
58,229
EudraCT No.:
N/A
Study Number: TMX-67_301
Phase: 3B
Study Design:
This is a phase 3B multicenter, randomized, double-blind, active-controlled study designed to evaluate the 
cardiovascular (CV) safety of febuxostat compared with allopurinol in subjects with gout and significant CV 
comorbidities. Approximately 7500 subjects will be randomly assigned to study medication treatment.
The overall duration of the study is dependent on the number of predefined major cardiovascular events (MACE). The 
length of study is expected to be approximately 9 years. The length of study participation for each subject will vary 
due to the event driven study design. This study is designed to have a maximum of 624 MACE.
Subjects will be screened at Day -7 for entry. Subjects with cardiovascular comorbidities, gout and (1) a serum urate 
level (sUA) ≥7 mg/dL or (2) with a sUA ≥6 mg/dL AND at least 1 flare in the 12 months prior to screening and/or the 
presence of tophi) and who meet the other selection criteria will be enrolled.
On Study Day 1, eligible subjects will be randomized in a 1:1 ratio to receive either febuxostat once daily (QD) or 
allopurinol QD. Randomization will be stratified based on baseline renal function: subjects with normal renal function 
or mild renal impairment (estimated creatinine clearance [eCLcr] ≥60 mL/min) versus subjects with moderate renal 
impairment (eCLcr ≥30 but <60 mL/min).
Subjects randomized to febuxostat will initially receive the 40 mg dose QD. Subjects will remain on 40 mg for the 
remainder of the study if their sUA is <6.0 mg/dL at the Week 2 Visit (3 days). If their sUA is ≥6.0 mg/dL at the 
Week 2 Visit (3 days) they will receive febuxostat 80 mg QD at Week 4 visit (3 days), and will remain on this dose 
for the remainder of the study. No dose adjustment will be made in the febuxostat based on renal function.
Subjects randomized to allopurinol who have normal renal function or mild renal impairment (eCLcr ≥60 mL/min) 
will initially receive allopurinol 300 mg QD with the dose increased in 100 mg increments monthly until either a sUA 
<6.0 mg/dL or an allopurinol dose of 600 mg QD is achieved. Subjects randomized to allopurinol who have moderate 
renal impairment (eCLcr ≥30 but <60 mL/min) will initially receive allopurinol 200 mg QD with the dose increased in 
100 mg increments monthly until either a sUA <6.0 mg/dL or an allopurinol dose of 400 mg QD is achieved.
To maintain the double-blind nature of the study, febuxostat and allopurinol tablets will be over-encapsulated and 
matching placebo capsules will be manufactured which are identical in appearance. Subjects will orally self administer 
2 capsules each morning in the appropriate combination for their assigned dose and treatment. For details regarding 
the appropriate dose combination, please see Section 8.1.3.
Serum urate levels will be unblinded to the investigator and Takeda through the Week 10 Visit of the study to facilitate 
dose increases based on sUA response. After the Week 10 Visit, sUA measurements will be blinded to Takeda and the 
investigator. The interactive voice-activated response system/interactive web-activated response system 
(IVRS/IWRS) will manage the treatment assignment at randomization and throughout the study medication treatment 
period.


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Subjects currently on urate-lowering therapy (ULT) will discontinue treatment at the Day -7 Screening Visit, and will 
begin colchicine 0.6 mg QD for gout flare prophylaxis. Subjects not on ULT will begin colchicine 0.6 mg QD on the 
Day 1/Randomization Visit. All subjects will receive gout flare prophylaxis for the first six months of the study 
medication treatment period. Alternatively, if colchicine is not tolerated and the subject’s eCLcr is ≥50 mL/min, they 
will be administered naproxen 250 mg twice daily (BID) with lansoprazole 15 mg QD. If a subject has been 
maintained on an appropriate dose (as determined by the investigator) of another proton pump inhibitor (PPI) other 
than lansoprazole, he/she may continue treatment with it during this study. In instances when subjects should not 
receive colchicine or naproxen, other nonsteroidal anti-inflammatory drugs (NSAIDs) or prednisone may be provided 
at the investigator’s discretion in accordance with the stated guidelines listed under the Excluded Medications and 
Treatments section of the protocol. In the event that colchicine, naproxen or other NSAIDs, proton pump inhibitors or 
prednisone are not tolerated or are contraindicated, the Investigator may choose not to use prophylaxis but to manage 
the subject’s gout flares as they occur. Alternatively, if colchicine 0.6 mg daily is not tolerated by the subject, 0.6 mg 
every other day may be used.
Following the Day 1 Visit, subjects will return for study visits during the first 3 months of the study based on the 
subject’s sUA response. Once a subject sUA <6.0 mg/dL there will be no further visits until Month 3.
All subjects will return at Week 2 for measurement of sUA and all subjects will return for a Week 4 and Month 3 visit. 
If the Week 2 sUA level is <6.0 mg/dL, the subject will be dispensed study medication at Week 4, and the next visit 
will occur at Month 3. If the Week 2 sUA level is ≥6.0 mg/dL, the subject will be dispensed study medication at Week 
4, and the next visit will occur at Week 6.
For the subset of subjects who have a Week 6 visit, if the Week 6 sUA level is <6.0 mg/dL, the subject will be 
dispensed study medication at Week 8, and the next visit will occur at Month 3. If the Week 6 sUA level is 
≥6.0 mg/dL, the subject will be dispensed study medication at Week 8 and the next visit will occur at Week 10.
For the subset of subjects who have a Week 10 visit, the subject will be dispensed study medication at the Month 3 
visit. After the Month 3 visit, no further dose adjustments will be made. All subjects will have a Month 3 and Month 6 
visits.
Following the Month 6 visit, all subjects will have visits every 6 months for the duration of the study. In addition, 
subjects with moderate renal impairment (eCLcr ≥30 but <60 mL/min) and/or subjects who are elderly (≥65 years of 
age) will have visits at Month 9 and Month 15 to monitor the liver function tests (LFTs). Subjects who are withdrawn 
from study medication treatment but have not withdrawn consent will be contacted every 2 months for the duration of 
the study or until the subject experiences a CV event that is positively adjudicated as a MACE. A Data Monitoring 
Committee (DMC) unblinded to treatment assignment will periodically review results obtained in the study, including 
results at 3 planned interim analyses. They will monitor the progress and the ongoing safety of subjects enrolled into 
the study. An Independent CV Endpoints Committee will prospectively review all suspected serious CV events using 
blinded data. All investigational sites will be required to collect relevant clinical information required for adjudication 
of all deaths and potential CV SAEs.
Primary Objective:
The objective of this study is to compare the risk of predefined MACE during treatment with febuxostat and 
allopurinol in subjects with gout and CV comorbidities.
Subject Population:
Male subjects ≥50 years of age and female subjects ≥55 years of age and at least 2-years post-menopausal with gout 
and a prior history of major CV or cerebrovascular disease.
Number of Subjects:
Estimated total of 7500 subjects:
3750 subjects randomized to febuxostat
3750 subjects randomized to allopurinol
Number of Sites:
Approximately 465 sites (United States, Canada, and 
Mexico)


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Dose Level(s):
Febuxostat 40 mg or 80 mg QD
Allopurinol 200 mg to 600 mg QD in 100 mg increments
Route of Administration:
Oral
Duration of Treatment:
The overall duration of the study is dependent on the number 
of predefined MACE; however, the maximum length of 
participation is expected to be approximately 9 years. The 
length of study participation for each subject will vary (ie, due 
to the event driven study design).
Period of Evaluation:
Up to 7 day screening period
Maximum of 9 years treatment duration
Main Criteria for Inclusion:
Subject eligibility will be determined on the basis of the criteria listed below:

The subject or the subject’s legally acceptable representative signs a written, informed consent form prior to the 
initiation of any study procedures.

Male subjects ≥50 years and female subjects ≥55 years of age and at least 2-years postmenopausal.

In order to enter the study, subject has a history of CV or cerebrovascular disease including at least ONE of the 
following:
–
Myocardial infarction (MI).
–
Hospitalized unstable angina.
–
Cardiac or cerebral revascularization procedure.
–
Stroke.
–
Hospitalized transient ischemic attack (TIA).
–
Peripheral vascular disease (ankle brachial index ≤0.6, revascularization and/or a well-documented history of 
claudication).
–
History of diabetes mellitus with evidence of micro- or macrovascular disease (retinopathy, neuropathy, 
nephropathy, small vessel vascular diseases).

Subject has a history or presence of gout defined as having one or more of the American Rheumatism Association 
criteria for the diagnosis of gout:
–
A tophus proven to contain urate crystals by chemical or polarized light microscopic means, AND/OR
–
Characteristic urate crystals in the joint fluid, AND/OR
–
History of at least 6 of the following clinical, laboratory, and x-ray phenomena:

More than 1 attack of acute arthritis.

Maximum inflammation developed within 1 day.

Monoarticular arthritis.

Redness observed over joints.

First metatarsophalangeal joint painful or swollen.

Unilateral first metatarsophalangeal joint attack.

Unilateral tarsal joint attack.

Tophus (proven or suspected).

Hyperuricemia.

Asymmetric swelling within a joint on x-ray.

Subcortical cysts without erosions on x-ray.

Joint fluid culture negative for organisms during attack.


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
Subjects must have either:
–
a sUA level ≥7.0 mg/dL at the Screening Visit OR
–
a sUA level ≥6.0 mg/dL at the Screening Visit AND inadequately controlled gout (≥1 flare in the 12 months 
prior to screening and/or the presence of tophi).
Main Criteria for Exclusion:

Subject has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant).

Subject has a history of xanthinuria.

The subject has received urate-lowering therapy (ie, febuxostat, allopurinol, probenecid, etc.) or excluded 
medication less than 7 days prior to Study Day 1/Randomization visit. Subject has a known hypersensitivity to 
febuxostat or allopurinol or any components of their formulation.

Subject has active peptic ulcer disease.

Subject has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the first dose of 
study medication.

Subject had a MI or stroke within 60 days prior to the Screening Visit.

Subject has alanine aminotransferase and/or aspartate aminotransferase values greater than 2 times the upper limit 
of normal during the screening period.

Subject has a significant medical condition and/or conditions that would interfere with the treatment, safety, or 
compliance with the protocol.

Subject’s estimated eCLcr is <30 mL/min, where eCLcr is calculated using the Cockcroft and Gault formula 
based on ideal body weight.
Main Criteria for Evaluation and Analyses:
Primary Endpoint
The time from randomization to the first occurrence of any event in the predefined MACE composite, which includes:

CV death.

Nonfatal MI.

Nonfatal stroke.

Unstable angina with urgent coronary revascularization.
Secondary Endpoints

The time from randomization to the first occurrence of any Antiplatelet Trialists’ Collaborative (APTC) event, 
which includes:
–
CV death.
–
Nonfatal MI.
–
Nonfatal stroke.

The time from randomization to the occurrence of each individual event in the pre-defined MACE composite.


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Sample Size Justification:
A total of 7500 subjects (3750 per treatment group) are planned to be enrolled in this study. The sample size will 
provide at least 90% power to meet a noninferiority margin of 1.3 for the hazard ratio (febuxostat relative to 
allopurinol) for the primary endpoint assuming a true hazard ratio of 1.0 at a 1-sided 2.5% significance level. For the 
determination of noninferiority between the febuxostat treatment group and the allopurinol treatment group, the 
sample size calculation assumed constant proportional hazards and exponential survival curves, annual adjudicated 
MACE composite rate of 2.8%, maximum length of participation of 5 years, accrual time of 2.5 years and annual 
drop-out rate of 10%. This study is designed to have a maximum of 624 MACE. These assumptions were used prior to 
the initiation of the study to calculate the number of subjects to be enrolled in order to obtain the required number of 
MACE.
Statistical Considerations:
The primary endpoint and all other analyses by treatment group will be analyzed according to the randomized 
treatment using the Full Analysis Set (FAS). The FAS will consist of all subjects who were randomized and received 
at least one dose of double-blind study medication. If a subject reports a MACE after treatment discontinuation, then 
the reported event will be counted toward the treatment to which they were randomized.
Safety Analyses
Assuming constant proportional hazards, the hazard ratio for the primary endpoint will be computed based on 
febuxostat and allopurinol estimated hazard rates. The febuxostat treatment group will be compared to the allopurinol 
treatment group to test for non-inferiority in the MACE composite rate using a Cox proportional hazards model with 
treatment and baseline renal function as factors in the model. Non-inferiority of febuxostat to allopurinol will be 
declared at an interim analysis or at the final analysis if the current 1-sided upper CI for the hazard ratio (febuxostat 
versus allopurinol) calculated with critical values obtained using the Lan-DeMets-O’Brien-Fleming alpha spending 
function, which preserves an overall 1-sided false-rejection rate of 2.5%, is less than 1.3.
Analysis of the secondary and other safety endpoints will be conducted similarly using a Cox proportional hazards 
model. No adjustments will be made for multiplicity.
Additional analysis on the primary safety endpoint will be performed using Cox-proportional hazards model 
controlling for the effect of NSAIDs use. The model will include treatment group, baseline renal function, and use of 
NSAIDs as explanatory variables. A similar analysis will control for the effect of low-dose aspirin use.
Interim Analysis and Criteria for Early Termination.
This study is designed to have a maximum of 624 MACE for assessing non-inferiority of febuxostat relative to 
allopurinol with regard to cardiovascular risk assuming a true hazard ratio of 1.0 and 90% power. Interim analyses will 
be conducted when approximately 25%, 50% and 75% of the events have occurred, followed by a final analysis. At 
each analysis, if the upper one-sided confidence limit of the hazard ratio is less than 1.3, the study will be stopped and 
the non-inferiority of febuxostat relative to allopurinol with regard to cardiovascular risk will be declared.
Periodically during the course of the study a blinded assessment of the annual adjudicated composite MACE rate will 
be made. The number of subjects planned to be enrolled in this study was based on an event rate of 2.8%, which was 
based on limited information. Based on the overall blinded composite MACE rate observed, an assessment will be 
made to determine whether or not to adjust the number of subjects planned for enrollment.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified below. 
The identified vendors will perform these activities in full or in partnership with the sponsor.
Activity
US and Canada
Mexico
Site Monitoring
Central laboratory
Data management
Statistical analysis
Interactive voice-activated response 
system
Clinical supply packaging and 
distribution
Clinical supply return
PPD
PPD


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3.2
Principal Investigator
Takeda Development Center Americas, Inc. (TDC) will select a Signatory Coordinating 
Investigator from the investigators who participate in the study. Selection criteria for this 
investigator will include significant knowledge of the study protocol, the study medication, their 
expertise in the therapeutic area and the conduct of clinical research as well as study participation. 
The Signatory Coordinating Investigator will be required to review and sign the clinical study 
report and by doing so agrees that it accurately describes the results of the study.


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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BID
twice daily
BMI
body mass index
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
CLcr
creatinine clearance
COX-2
cyclooxygenase 2
ct.
count
CV
cardiovascular
CVD
cardiovascular disease
DMC
Data Monitoring Committee
DoT
discontinuation of treatment
DVT
deep vein thrombosis
EC
ethics committee
ECG
electrocardiogram
EoS
end of study
ET
early termination
eCRF
electronic case report form
eCLcr
estimated creatinine clearance
FDA
Food and Drug Administration
FAS
full analysis set
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HRT
hormone replacement therapy
IBW
ideal body weight
ICH
International Conference on Harmonisation
INR
international normalized ratio
IRB
Institutional Review Board
IVRS/IWRS
interactive voice-activated response system/interactive web-activated response system
LFTs
liver function tests
MACE
major adverse cardiovascular event(s)
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
NSAID
nonsteroidal anti-inflammatory drug
PE
pulmonary embolism
PTE
pretreatment event


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QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
sUA
serum urate level
TIA
transient ischemic attack
×ULN
times the upper limit of normal
ULT
urate-lowering therapy
XO
xanthine oxidase
3.4
Corporate Identification
TDC (Europe)
Takeda Development Centre (Europe) Ltd.
TDC (Americas)
Takeda Development Center, Inc.
TDC
TDC (Americas)
TPC
Takeda Pharmaceutical Company Limited
Takeda
TDC (Asia), TDC (Americas), TDC (Europe), and TPC, collectively


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4.0
INTRODUCTION
4.1
Background
Gout affects 3 to 5 million individuals in the United States and is increasing in incidence and 
prevalence [1-3]. Gout is a serious health condition characterized by flares of acute arthritis, 
chronic gouty arthropathy, tophi, and uric acid urolithiasis, and is associated with a broad range of 
comorbidities, including cardiovascular (CV) disease, chronic kidney disease, and metabolic 
syndrome [4-6]. The underlying metabolic aberration in gout is hyperuricemia, which is defined as 
an elevation in serum uric acid (sUA) level ≥6.8 mg/dL. Hyperuricemia develops into gout when 
urate crystals are formed from supersaturated body fluids and are deposited in joints, tophi, and 
parenchymal organs eliciting acute inflammatory responses.
Urate-lowering therapy (ULT) is used to treat hyperuricemia in subjects with gout. The goal of 
therapy is to reduce sUA to 6.0 mg/dL or less, below the concentration at which monosodium urate 
saturates extracellular fluid. Using ULT to reduce and maintain sUA levels <6.0 mg/dL ultimately 
improves the clinical symptoms of gout by reducing the frequency of gout flares, decreasing size 
and number of tophi, and improving quality of life. Due to the potential for paradoxical flares 
caused by urate crystal mobilization, anti-inflammatory agents and/or colchicine are given as 
prophylaxis with ULT during the first 6 months of treatment [7].
Gout subjects also have a high incidence of comorbidities that may be associated with 
hyperuricemia, gout, or both. This is supported by a growing body of literature demonstrating that 
sUA level is an independent predictive factor for cardiovascular disease (CVD) when the effects of 
other risk factors have been controlled. Several recent studies report an increased risk of CV death, 
myocardial infarction (MI), and stroke associated with higher sUA levels. For example, the 
Preventive Cardiology Information System Database Cohort Study, which assessed the prognostic 
value of sUA in 3098 persons at risk for CVD, found that sUA was an independent predictor of 
death from all causes; for every 1 mg/dL elevation in sUA level, the risk of death from all cause in 
subjects at high risk of CVD increased by 39% (hazard ratio 1.39, 95% CI 1.28-1.50) without 
adjusting for other risk factors. After adjusting for other risk factors, the sUA level remained a 
predictor of death from all causes (hazard ratio=1.26, 95% CI 1.15-1.38) [8]. In the Framingham 
Heart study, sUA was not an independent predictor of coronary artery disease in men without gout, 
but there was a 60% excess incidence of coronaryartery disease in men with gout never treated 
with diuretics [9]. The National Health and Nutrition Examination Survey study reported a direct 
role for hyperuricemia in CV events and mortality, tying sUA levels to increasing CV mortality. 
These findings persisted even after adjustments were made for age, sex, race, body mass index, 
smoking, hypertension, and diabetes [10].
4.1.1
Mechanism of Action
Febuxostat is a potent, nonpurine, selective inhibitor of xanthine oxidase (XO) that exhibits 
antihyperuricemic activity by reducing the formation of uric acid. Uric acid is the end product of 
purine metabolism and is generated in the cascade of hypoxanthine→xanthine→uric acid. Both 
steps in this transformation are catalyzed by XO. Febuxostat has been shown to potently inhibit 
both the oxidized and reduced forms of XO. Unlike febuxostat, administration of allopurinol does 


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not provide persistent enzyme inhibition and has weaker hypouricemic activity. More importantly, 
because allopurinol and its metabolites are purine analogs, they also inhibit other enzymes 
involved in purine and pyrimidine metabolism. In contrast, febuxostat is a selective inhibitor of 
XO.
4.1.2
Nonclinical Data Summary
Relevant CV related nonclinical data are summarized below.
Febuxostat is a nonpurine, selective inhibitor of XO that inhibits the formation of uric acid from 
hypoxanthine and xanthine. XO inhibition is not known to cause CV adverse effects.
Nonclinical safety pharmacology and secondary pharmacology studies demonstrated no 
mechanisms associating febuxostat with CV effects at therapeutic exposures. CV safety 
pharmacology studies included in vitro electrophysiology investigation on cardiac action potential 
parameters and ion channels (potassium [human ether-à-go-go–related gene], sodium, and 
calcium), and in vivo studies for hemodynamic and electrocardiogram (ECG) effects in both 
anesthetized and conscious telemetry-monitored dogs. In addition, the in vitro effects of 
febuxostat on the hemostatic system, protease generation, and platelet function were explored 
using human blood. Febuxostat did not significantly inhibit nor augment platelet or coagulation 
responses and did not have any interactions in vitro with heparin, warfarin, or aspirin.
Furthermore, in a long-term (52-week) toxicology study in dogs, no CV toxicity was observed 
based on electrocardiographic, organ weight, and histopathological examinations.
Febuxostat was also shown to have no detrimental CV effects in animal CV models. Overall, when 
studied in 6 different animal models specific for CV diseases, febuxostat had no detrimental CV 
effect, but rather appeared to have beneficial CV effects. In summary, no biological mechanism 
was identified to be associated with febuxostat that could cause potential CV adverse effects.
4.2
RATIONALE FOR THE PROPOSED STUDY
The febuxostat Phase 3 randomized controlled studies revealed a small number of cardiovascular 
thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions and non-fatal 
strokes) in subjects treated with febuxostat (0.74 per 100 PY with 95% CI 0.36-1.37) compared to 
allopurinol (0.60 per 100 PY with 95% CI 0.16-1.53). In the phase 3 clinical program for 
febuxostat approximately 60% of subjects had 2 or more cardiovascular risk factors (including 
diabetes, hypertension, hyperlipidemia, obesity, and smoking).
In order to further explore the cardiovascular safety of febuxostat, Takeda has committed to 
conduct a randomized, controlled trial of adequate size and duration to determine whether the use 
of febuxostat is associated with a moderate increase in the risk of serious adverse cardiovascular 
outcomes as compared to allopurinol.
This study will enroll subjects with a high cardiovascular risk profile, characterized by the 
presence of documented history of any of the following: cerebrovascular, coronary, peripheral 
vascular disease, or the diagnosis of diabetes with microvascular or macrovascular complications. 


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This randomized controlled study will attempt to enroll populations of interest including women 
(5%), elderly (20%) and renally impaired (30%).
The primary endpoint of the study will be a pre-defined composite of major adverse cardiovascular 
events (MACE). The MACE composite endpoint will include: cardiovascular death, non-fatal 
myocardial infarction, non-fatal stroke and hospitalized unstable angina with urgent coronary 
revascularization.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
The primary objective of this study is to compare the risk of predefined MACE during treatment 
with febuxostat and allopurinol in subjects with gout and CV comorbidities.
5.2
Endpoints
Primary Endpoint
The time from randomization to the first occurrence of any event in the predefined MACE 
composite, which include:

CV death.

Nonfatal MI.

Nonfatal stroke.

Unstable angina with urgent coronary revascularization.
Secondary Endpoints

The time from randomization to the first occurrence of any Antiplatelet Trialists’ 
Collaborative (APTC) event, which includes:
–
CV death.
–
Nonfatal MI.
–
Nonfatal stroke.

The time from randomization to the occurrence of each individual event in the pre-defined 
MACE composite.
Additional Endpoints

The time from randomization to the first occurrence of any event in the pre-defined MACE 
composite plus any of the following events:
–
Urgent Cerebral revascularization [nonelective].
–
Hospitalized CHF.
–
Arrhythmias not associated with ischemia.
–
Venous and peripheral arterial thromboembolic events; eg, Deep Vein Thrombosis (DVT) 
and Pulmonary Embolism (PE).
–
Transient Ischemic Attack (TIA).

Percentage of subjects whose average sUA levels from the end of the first year of treatment to 
the end of the study are <4.0 mg/dL, ≥4 to <5.0 mg/dL, ≥5 to <6.0 mg/dL, and ≥6.0 mg/dL.


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
The mean number of flares requiring treatment from the end of the first year of treatment to the 
end of the study.

Percentage of subjects with tophi resolution by the end of Years 1, 2, 3 and 4 for subjects with 
a primary palpable tophus at the Day 1 Visit.
Safety assessments will include: clinical laboratory results, adverse events (including rash events), 
and vital signs.


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 3B multicenter, randomized, double-blind, active-controlled study designed to 
evaluate the CV safety of febuxostat compared with allopurinol in subjects with gout and 
significant CV comorbidities. Approximately 7500 subjects will be randomly assigned to study 
medication treatment.
The overall duration of the study is dependent on the number of predefined MACE. The length of 
study is expected to be approximately 9 years. The length of study participation for each subject 
will vary due to the event driven study design. This study is designed to have a maximum of 
624 MACE.
Subjects will be screened at Day -7 for entry. Subjects with cardiovascular comorbidities, gout and 
(1) a sUA ≥7 mg/dL or (2) with a sUA ≥6 mg/dL AND at least one flare in the 12 months prior to 
screening and/or the presence of tophi) and who meet the other selection criteria will be enrolled.
On Study Day 1/Randomization Visit, eligible subjects will be randomized in a 1:1 ratio to receive 
either febuxostat once daily (QD) or allopurinol QD. Randomization will be stratified based on 
baseline renal function: subjects with normal renal function or mild renal impairment (estimated 
creatinine clearance [(eCLcr) ≥60 mL/min] versus subjects with moderate renal impairment 
[eCLcr ≥30 but <60 mL/min]).
Subjects randomized to febuxostat will initially receive the 40 mg dose QD. Subjects will remain 
on 40 mg remainder of the study if their sUA is <6.0 mg/dL at the Week 2 Visit (3 days). If their 
sUA is ≥6.0 mg/dL at the Week 2 Visit (3 days) they will receive febuxostat 80 mg QD at Week 
4 visit (3 days), and will remain on this dose for the remainder of the study. No dose adjustment 
will be made in the febuxostat based on renal function.
Subjects randomized to allopurinol who have normal renal function or mild renal impairment 
(eCLcr ≥60 mL/min) will initially receive allopurinol 300 mg QD with the dose increased in 
100 mg increments monthly until either a sUA <6.0 mg/dL or an allopurinol dose of 600 mg QD is 
achieved. Subjects randomized to allopurinol who have moderate renal impairment (eCLcr 
≥30 but <60 mL/min) will initially receive allopurinol 200 mg QD with the dose increased in 
100 mg increments monthly until either a sUA <6.0 mg/dL or an allopurinol dose of 400 mg QD is 
achieved.
To maintain the double-blind nature of the study, febuxostat and allopurinol tablets will be 
over-encapsulated and matching placebo capsules will be manufactured which are identical in 
appearance. Subjects will orally self administer 2 capsules each morning in the appropriate 
combination for their assigned dose and treatment. For details regarding the appropriate dose 
combination, please see Section 8.1.3.
Serum urate levels will be unblinded to the investigator and Takeda through the Week 10 Visit of 
the study to facilitate dose increases based on sUA response. After the Week 10 Visit, sUA 
measurements will be blinded to Takeda and the investigator. The interactive voice-activated 


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response system/interactive web-activated response system (IVRS/IWRS) will manage the 
treatment assignment at randomization and throughout the study medication treatment period.
Subjects currently on ULT will discontinue treatment at the Day -7 Screening Visit, and will begin 
colchicine 0.6 mg QD for gout flare prophylaxis. Subjects not on ULT will begin colchicine 
0.6 mg QD on the Day 1/Randomization Visit. All subjects will receive gout flare prophylaxis for 
the first six months of the study medication treatment period. Alternatively, if colchicine is not 
tolerated and the subject’s eCLcr is ≥50 mL/min, they will be administered naproxen 250 mg twice 
daily (BID) with lansoprazole 15 mg QD. If a subject has been maintained on an appropriate dose 
(as determined by the investigator) of another proton pump inhibitor (PPI) other than lansoprazole, 
he/she may continue treatment with it during this study. In instances when subjects should not 
receive colchicine or naproxen, other nonsteroidal anti-inflammatory drugs (NSAIDs) or 
prednisone may be provided at the investigator’s discretion in accordance with the stated 
guidelines listed under the Excluded Medications and Treatments section of the protocol. In the 
event that colchicine, naproxen or other NSAIDs, proton pump inhibitors or prednisone are not 
tolerated or are contraindicated, the Investigator may choose not to use prophylaxis but to manage 
the subject’s gout flares as they occur. Alternatively, if colchicine 0.6 mg daily is not tolerated by 
the subject, 0.6 mg every other day may be used. Following the Day 1 Visit, subjects will return for 
study visits during the first 3 months of the study based on the subject’s sUA response. Once a 
subject sUA <6.0 mg/dL there will be no further visits until Month 3 (Figure 6.b).
All subjects will return at Week 2 for measurement of sUA and all subjects will return for a 
Week 4 and Month 3 visit. If the Week 2 sUA level is <6.0 mg/dL, the subject will be dispensed 
study medication at Week 4, and the next visit will occur at Month 3. If the Week 2 sUA level is 
≥6.0 mg/dL, the subject will be dispensed study medication at Week 4, and the next visit will occur 
at Week 6.
For the subset of subjects who have a Week 6 visit, if the Week 6 sUA level is <6.0 mg/dL, the 
subject will be dispensed study medication at Week 8, and the next visit will occur at Month 3. If 
the Week 6 sUA level is ≥6.0 mg/dL, the subject will be dispensed study medication at Week 8 and 
the next visit will occur at Week 10.
For the subset of subjects who have a Week 10 visit, the subject will be dispensed study 
medication at the Month 3 visit. After the Month 3 visit, no further dose adjustments will be made. 
All subjects will have a Month 3 and Month 6 visits.
Following the Month 6 visit, all subjects will have visits every 6 months for the duration of the 
study. In addition, subjects with moderate renal impairment (eCLcr ≥30 but <60 mL/min) and/or 
subjects who are elderly (≥65 years of age) will have visits at Month 9 and Month 15 to monitor 
the liver function tests (LFTs). Subjects who are withdrawn from study medication treatment but 
have not withdrawn consent will be contacted every 2 months for the duration of the study or until 
the subject experiences a CV event that is positively adjudicated as a MACE.
A Data Monitoring Committee (DMC) unblinded to the treatment assignment will periodically 
review results obtained in the enrolled into the study. An independent CV Endpoints Committee 
will be established to prospectively review all suspected CV events using blinded data. All 


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investigational sites will be required to collect relevant clinical information required for 
adjudication of all deaths and potential CV SAEs. A CV worksheet will be provided to the 
investigational sites as a guide to ensure that supporting clinical information for each of these 
events are collected and compiled by the site and forwarded by fax or mail to Takeda 
Pharmacovigilance when available. The worksheet is not intended to be all inclusive and 
investigators should use medical judgment to determine what kind of supporting documentation 
should be collected 
A schematic of the study design is presented in Figure 6.a. A schedule of study procedures is listed 
in Appendix A.


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Figure 6.a
Schematic of Study Design
End of Study/ 
Discontinuation of 
Treatment/Early 
Termination Visit
All subjects will receive 2 capsules daily in the morning.
*Screening period up to 7 days (Washout for subjects on ULT).
** Visit Month 9 and 15 for subjects with moderate renal impairment and/or elderly.


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Figure 6.b
Schematic of Study Design for the First 3 months
6.2
Justification for Study Design, Dose, and Endpoints
In order to further explore the CV safety of febuxostat, Takeda has committed to conduct a 
randomized, controlled trial of adequate size and duration to determine whether the use of 
febuxostat is associated with a moderate increase in the risk of serious adverse CV outcomes as 
compared with allopurinol.
This study will enroll subjects with a high CV risk profile, characterized by the presence of 
documented cerebrovascular, coronary, or peripheral vascular disease, or the diagnosis of diabetes 
with microvascular or macrovascular complications. This randomized controlled study will 
attempt to enroll populations of interest including women (5%), elderly (20%), and renally 
impaired (30%).


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The primary endpoint of the study will be a predefined composite of MACE events, including CV 
death, non-fatal MI, non-fatal stroke, and hospitalized unstable angina with urgent coronary 
revascularization.
The overall duration of this study is dependent on the number of predefined MACE; however, the 
duration is expected to be approximately 9 years. The duration of treatment for each subject will 
vary (due to the event driven study design).
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless the following criteria are satisfied that require 
temporary suspension or early termination of the study.
1. New information regarding the safety or efficacy of the study drug that indicates a change in 
the known risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for subjects participating in the study.
2. Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
3. Predefined study-specific criteria for terminating the study (eg, study meets predefined rule for 
futility or benefit).
4. The Data Monitoring Committee recommends that the study should be suspended or 
terminated.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee, or 
regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.


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7.0
SELECTION AND WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria:
1. The subject or the subject’s legally acceptable representative signs and dates a written, 
informed consent form prior to the initiation of any study procedures.
2.
The subject is male ≥50 years of age or female ≥55 years of age and at least 2-years 
post-menopausal.
3. The subject has a history of major CV or cerebrovascular disease including at least 1 of the 
following:

MI.

Hospitalized unstable angina.

Cardiac or cerebrovascular revascularization procedure.

Stroke.

Hospitalized TIA.

Peripheral vascular disease (ankle brachial index ≤0.6, revascularization and/or 
well-documented history of claudication).

History of diabetes mellitus with evidence of micro- or macrovascular disease 
(retinopathy, neuropathy, nephropathy, small vessel vascular diseases).
4. The subject has a history or presence of gout defined as having one or more of the American 
Rheumatism Association criteria for the diagnosis of gout [11]:

A tophus proven to contain urate crystals by chemical or polarized light microscopic 
means, AND/OR

Characteristic urate crystals in the joint fluid, AND/OR

History of at least 6 of the following clinical, laboratory, and x-ray phenomena:
–
More than 1 attack of acute arthritis.
–
Maximum inflammation developed within 1 day.
–
Monoarticular arthritis.
–
Redness observed over joints.
–
First metatarsophalangeal joint painful or swollen.
–
Unilateral first metatarsophalangeal joint attack.
–
Unilateral tarsal joint attack.
–
Tophus (proven or suspected).


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–
Hyperuricemia.
–
Asymmetric swelling within a joint on x-ray.
–
Subcortical cysts without erosions on x-ray.
–
Joint fluid culture negative for organisms during attack.
5. The subjects must have either:

a sUA level ≥7.0 mg/dL (≥416 µmol/L) at the Screening Visit OR

a sUA level ≥6.0 mg/dL (≥354 µmol/L) at the Screening Visit AND inadequately 
controlled gout (≥1 flare in the 12 months prior to screening and/or the presence of tophi).
6. The subject is capable of understanding and complying with protocol requirements.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ 
transplant).
2. The subject has a history of xanthinuria.
3. The subject has received urate-lowering therapy (ie, febuxostat, allopurinol, probenecid, etc.) 
or excluded medication less than 7 days prior to Study Day 1/Randomization visit.
4. The subject has a known hypersensitivity to febuxostat or allopurinol or any components of 
their formulation.
5. The subject has active peptic ulcer disease.
6. The subject has a history of cancer (other than basal cell carcinoma of the skin) within 5 years 
prior to the first dose of study medication.
7. The subject had MI or stroke within 60 days prior to the Screening Visit.
8. The subject has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
values greater than 2 times the upper limit of normal (×ULN) during the Screening period.
9. The subject has a significant medical condition and/or conditions that would interfere with the 
treatment, safety, or compliance with the protocol.
10. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 5 years prior to the Screening Visit or the subject consumes >14 alcoholic 
beverages per week.
11. The subject has received any investigational medicinal product within the 30 days prior to the 
Screening Visit and throughout the study. In addition, the subject has been previously 
randomized in this study and received at least one dose of double blind study drug treatment.


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12. The subject’s estimated CLcr is <30 mL/min, where CLcr is calculated using the Cockcroft 
and Gault formula based on ideal body weight (IBW), as provided below:
Estimated CLcr = (140 – age [yr]) × (IBW [kg]) (women multiply by 0.85)
72 × (serum creatinine [mg/dL])
Where IBW is 50 kg for men and 45.5 kg for women, plus 2.3 kg for each inch in height greater 
than 5 feet (60 inches).
13. The subject is an immediate family member, study site employee, or is in a dependant 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.
14. The subject is required to take excluded medications listed in Section 7.3.2.
15. The subject has a known history of infection with hepatitis B, hepatitis C, or human 
immunodeficiency virus.
7.3
Required Medications and Treatments
Subjects who meet the enrollment criteria will be randomized to 1 of 2 arms in a 1:1 ratio to 
receive either febuxostat or allopurinol at the Day 1/Randomization Visit via the IVRS/IWRS. 
Randomization will be stratified based on baseline renal function (subjects with normal renal 
function or mild renal impairment versus subjects with moderate renal impairment).
Subjects randomized to febuxostat will initially receive the 40 mg dose QD. Subjects will remain 
on 40 mg for the remainder of the study if their sUA is <6.0 mg/dL at the Week 2 visit. If their sUA 
is ≥6.0 mg/dL at the Week 2 visit, they will receive febuxostat 80 mg QD at the Week 4 visit and 
for the remainder of the study.
Subjects randomized to allopurinol with moderate renal impairment (estimated creatinine 
clearance [eCLcr] ≥30 but <60 mL/min) will initially receive allopurinol 200 mg QD with the dose 
increased in 100 mg increments monthly until either a sUA <6.0 mg/dL or a maximum allopurinol 
dose of 400 mg QD is achieved. The titration of the allopurinol dose for these subjects will be 
completed at or by the Week 8 visit. If a subject achieves a sUA <6.0 mg/dL at a given dose of 
allopurinol, the subject will remain on that dose of allopurinol for the remainder of the study.
Subjects randomized to allopurinol, with normal renal function or mild renal impairment (eCLcr
≥60 mL/min) will initially receive allopurinol 300 mg QD with the dose increased in 100 mg 
increments monthly until either a sUA <6.0 mg/dL or a maximum allopurinol dose of 600 mg QD 
is achieved. The titration of the allopurinol dose for these subjects will be completed at or by the 
Month 3 visit. If a subject achieves a sUA <6.0 mg/dL at a given dose of allopurinol, the subject 
will remain on that dose of allopurinol for the remainder of the study.
To maintain the double-blind nature of the study, febuxostat and allopurinol tablets will be 
over-encapsulated and matching placebo capsules will be manufactured which are identical in 
appearance. Subjects will orally self administer 2 capsules each morning (one capsule from each 
bottle) in the appropriate combination for their assigned dose and treatment. For details regarding 
the appropriate dose combination, please see Section 8.1.3. Serum urate levels will be unblinded to 


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Takeda and investigator through the Week 10 Visit of the study to facilitate dose increases based 
on sUA response. After the Week 10 Visit, sUA measurements will be blinded to Takeda and the 
investigator. The IVRS/IWRS will manage the treatment assignment after randomization and 
throughout the study medication treatment period.
For details regarding dosage form, manufacturing, packaging, and labeling please see 
Section 8.1.1.
The Sponsor will supply each site with bottles containing each of the gout flare prophylaxis 
medications: colchicine, naproxen, and lansoprazole. Prophylaxis medications can be taken on the 
morning of the study visit. The prophylaxis medications will remain unblinded. Drug 
accountability will be performed on all Takeda supplied prophylaxis medications.
7.3.1
Medications and Treatments Not Provided Directly by Sponsor
During the first six months subjects should be provided additional treatments as appropriate for 
gout flares by their study physician. In addition to dispensing the gout flare prophylaxis, the 
investigator may provide the subject with a prescription for an anti-inflammatory/analgesic agent 
of the investigator’s choosing to be used in the event the subject experiences a gout flare during the 
study. The Investigator may use a reduced colchicine regimen (for example, colchicine 0.6 mg on 
alternate days) if required because of concomitant medications (medications with potential 
drug-drug interactions with colchicine, including verapamil, diltiazem, etc. (see Section 7.3.2), 
co-morbid conditions including chronic kidney disease, or patient preference based on prior 
experience with colchicine. Subjects should be provided additional treatments as appropriate for 
gout flares by their study physician. In addition to dispensing the gout flare prophylaxis, the 
investigator may provide the subject with a prescription for an anti-inflammatory/analgesic agent 
of the investigator’s choosing to be used in the event the subject experiences a gout flare during the 
study. 
After the first six months of gout flare prophylaxis, the United States (US) subjects only will be 
able to receive medication to treat gout flares during the study (eg, colchicine, naproxen and 
lansoprazole, Medrol dose pack, prednisone, indomethacin) using a prescription card to ensure 
they have adequate medications available to treat gout flares. The study physician should 
determine which medication is appropriate for each subject for treatment of gout flares.
These medications should be documented in the subject’s source documents and on the 
appropriate electronic case report form (eCRF).
7.3.2
Excluded Medications and Treatments
Subjects may not take any medication (other than study medication) for the purpose of lowering 
sUA levels from at least 7 days prior to the Day 1 Randomization Visit to the End of 
Study/Discontinuation of Treatment/Early Termination Visit. Medications prescribed for another 
indication but which have an incidental urate lowering effect (for example losartan, fenofibrate) 
are not excluded.


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Subjects who have taken any of the excluded medications listed below can be enrolled into the 
study if the excluded medication is discontinued at least 7 days prior to the Day 1 Randomization 
Visit. These medications may not be administered during the treatment phase. All medication use 
should be documented in the subject’s source documents and on the appropriate eCRF.
Subjects who have terminated study drug but remain in the study (eg, bimonthly follow-up 
contacts) may have their gout treated in keeping with the physician’s accepted practice.
Additionally, the following medications are not to be administered within 7 days prior to the Day 1 
Randomization Visit and throughout the study medication treatment phase:

Any urate-lowering drug other than study medication. 

Salicylates (chronic use of aspirin ≤325 mg/day is allowed).

Azathioprine.

Mercaptopurine.

Theophylline.

Intravenous colchicine.

Pyrazinamide.

Sulfamethoxazole/trimethoprim.

Macrolides or ketolides, only when a subject is receiving concomitant colchicine.

Subjects with renal or hepatic impairment should not be given colchicine in conjunction with 
P-gp or strong CYP3A4 inhibitors. In these patients, life-threatening and fatal colchicine 
toxicity has been reported with colchicine taken in therapeutic doses.
The following restrictions also apply during the study:

Long-term (>4 continuous weeks) use of high dose corticosteroids (prednisone >10 mg/day or 
its equivalent) is not allowed. The chronic use of prednisone ≤10 mg/day (or its equivalent) 
and short-term use of higher doses of prednisone is allowed.

Long-term use (>4 continuous weeks) of prescription or over-the-counter NSAIDs and 
cyclooxygenase 2 (COX-2) inhibitors, other than protocol required prophylaxis therapy 
supplied by Takeda, is not allowed.

Short-term use of NSAIDs and COX-2 inhibitors is allowed (short-term use is defined as a 
duration of ≤4 weeks of continuous use).
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.


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7.4
Procedures for Discontinuation from Study Drug Treatment with Continued 
Participation in the Study via Follow-up Contacts
Subjects who discontinue study drug treatment will continue to participate in the study through 
follow-up contacts unless: consent is withdrawn by the subject; the subject experiences a CV event 
that is positively adjudicated as a MACE (the study team will notify the site in writing when it is no 
longer necessary to follow the subject with a positive MACE adjudication); the required number of 
study MACE events have occurred; or until the study is ended. Follow-up contacts will occur 
every 2 months (±10 days).
The primary reason for permanent discontinuation of study drug treatment should be noted using 
the following categories:
1. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.
NOTE: Subjects who experience ALT or AST >3xULN in conjunction with elevated total 
bilirubin >2×ULN and satisfy the following 2 criteria: (1) The liver injury is hepatocellular in 
nature and there is not a prominent cholestatic component, or (2) there is no more likely 
alternative cause than drug induced liver injury, such as acute viral hepatitis A or B, or other 
acute liver disease, should be permanently discontinued from the study drug treatment.
2. Major protocol deviation. The discovery post randomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unnecessary risk to the subject’s health.
3. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from taking study drug treatment. The reason for withdrawal, if provided, should be 
recorded in the eCRF.
NOTE: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded.
4. Pregnancy. The subject is found to be pregnant.
5. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 
6. Study termination. The sponsor, IRB, ethics committee (EC), or regulatory agency terminates 
the study.
7. Other. The specific reasons should be recorded in the “specify” field of the eCRF.
The primary reason that the subject prematurely discontinued study drug should be listed on the 
End of Study Drug page of the eCRF. End of Study Drug eCRF should be completed when the 
subject discontinues study medication or completes the full cycle of study medication; end of 
Study Drug eCRF completion is independent of the decision to continue participation in the study 
via follow-up contacts.


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These subjects should undergo all procedures required as part of the Discontinuation of Treatment 
Visit when the subject stops study drug treatment. In the event that these subjects later withdraw 
consent from participation in the study, an additional final Early Termination visit does not need to 
be performed.
At each follow-up contact, sites will ask the subject if they have taken any new medications (over 
the counter or prescription) since the last contact, or have stopped taking any ongoing medications 
recorded at the last contact. If yes, the generic medication name, start date, and end date and reason 
for use will be recorded on the Medication Information Obtained During Follow-up Contact 
eCRF.
Sites will also ask the subject at each follow-up contact if they have had any serious adverse events 
(SAEs) or any potential cardiovascular adverse events since the last contact. If yes, these will be 
recorded on the AE eCRF, and sites should follow the instructions in the Protocol Section 10.2.2, 
Collection and Reporting of SAEs if applicable. All SAEs should be followed up until resolution 
or permanent outcome of the event.
If the subject has had a potential serious CV event, he/she should bring the event related 
documents (labs, hospital discharge summary, etc) to the clinic. The study team will notify the site 
in writing upon a positive MACE adjudication when it is no longer necessary to follow a subject.
Efforts will be made to prevent any subject being lost to follow-up during the conduct of the study. 
Investigators should refer to Section 9.0 for gout flare assessment and Section 9.1.15 for gout flare 
treatment. Before a subject is considered lost to follow-up, a minimum of two documented 
telephone contact attempts must have been made and one certified letter must have been sent 
within 4 weeks of the most recently missed telephone call to the subject and/or emergency contact 
in an effort to contact the subject.
7.5
Procedures for Early Termination of a Subject from the Study (Both Drug and 
Visits)
A subject may discontinue his or her participation from the study without giving a reason at any 
time during the study. In addition, efforts should be made to perform all procedures required as 
part of the Early Termination Visit, even if the subject withdrew consent.
The primary reason for discontinuation of study participation should be noted using the following 
categories:
1. Adverse Event. A subject taking study medication has experienced a pretreatment event or AE 
that requires early termination because continued participation imposes an unacceptable risk to 
the subject’s health or the subject is unwilling to continue because of the event. Also applies to 
subjects no longer taking study medication who are in follow-up who experience a serious CV 
event that is positively adjudicated as a MACE. NOTE: this reason is not intended to be 
selected for subjects in follow-up experiencing non-MACE AEs as these subjects can, and 
should, continue participation.
2. Lost to follow-up. The subject did not return to the clinic and/or attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. Before a subject is 


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considered lost to follow-up, a minimum of two documented telephone contact attempts and 
one certified letter within 4 weeks of the most recently missed study visit must be sent in an 
effort to contact the subject.
3. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
4. Major protocol deviation. The discovery post randomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unnecessary risk to the subject’s health.
5. Study termination. The sponsor, IRB, EC, or regulatory agency terminates the study.
6. Other. The specific reasons should be recorded in the “specify” field of the eCRF.
The primary reason that the subject prematurely discontinued planned study visits, including the 
planned follow-up contacts, should be listed on the End of Study Visits page of the eCRF. End of 
Study Visits eCRF should be completed when the subject discontinues from the study visits, 
including the follow-up contacts, independent of the decision to discontinue study medication.
Investigators should refer to Section 9.0 for gout flare assessment and Section 9.1.15 for gout flare 
treatment.


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8.0
STUDY MEDICATION AND TREATMENTS
8.1
Study Medication and Treatments
Oral administration of:

Over-encapsulated capsule containing 40 mg tablet of febuxostat (35 count [ct.] bottle).

Over-encapsulated capsule containing 80 mg tablet of febuxostat (35 ct. bottle).

Over-encapsulated capsule containing two 100 mg tablets of allopurinol (35 ct. bottle).

Over-encapsulated capsule containing three 100 mg tablets of allopurinol (35 ct. bottle).

One matching placebo capsule (35 ct. bottle).

Over-encapsulated capsule containing 40 mg tablet of febuxostat (100 ct. bottle).

Over-encapsulated capsule containing 80 mg tablet of febuxostat (100 ct. bottle).

Over-encapsulated capsule containing two 100 mg tablets of allopurinol (100 ct. bottle).

Over-encapsulated capsule containing three 100 mg tablets of allopurinol (100 ct. bottle).

One matching placebo capsule (100 ct. bottle).

Over-encapsulated capsule containing 40 mg tablet of febuxostat (200 ct. bottle).

Over-encapsulated capsule containing 80 mg tablet of febuxostat (200 ct. bottle).

Over-encapsulated capsule containing two 100 mg tablets of allopurinol (200 ct. bottle).

Over-encapsulated capsule containing three 100 mg tablets of allopurinol (200 ct. bottle).

One matching placebo capsule (200 ct. bottle).

Prophylaxis treatment: colchicine 0.6 mg tablet (100 ct. bottle) OR naproxen 250 mg tablet 
(100 ct. bottle) and lansoprazole 15 mg capsule (30 ct. bottle) will be provided for the first 
6 months.
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
Double-Blind Study Medication (febuxostat 40 mg, 80 mg and Allopurinol 200 mg, 300 mg)
Double-blind study medication will consist of over-encapsulated febuxostat 40 mg, febuxostat 
80 mg, allopurinol 200 mg, allopurinol 300 mg and matching placebo capsules which are identical 
in appearance.
The capsules will be packaged into 3 different sizes of high density polyethylene bottles with child 
resistant caps containing 35 capsules, 100 capsules and 200 capsules each. Each bottle will bear a 
clinical label containing the pertinent study information, including the appropriate 
country-specific requirements and regulatory statements.


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The over-encapsulation of febuxostat 40 mg, febuxostat 80 mg, allopurinol 200 mg, or allopurinol 
300 mg tablets and the manufacturing of matching placebo capsules will be performed by 
 and A
 
s. The packaging, labeling and distribution are also performed by 
 
 on behalf of Takeda Development Center Americas, Inc.
Gout Flare Prophylaxis Treatments
The commercial products provided for prophylaxis of gout flares (colchicine 0.6 mg or naproxen 
250 mg and lansoprazole 15 mg) will be provided in the manufacturer’s original packaging 
configurations. In addition, an ancillary label containing pertinent study information, including the 
appropriate country-specific requirements and regulatory statements, will be applied permanently 
to each bottle without covering the original manufacturer’s product label. Package Inserts of the 
prophylaxis medication are available for further reference [12, 15,16].
Colchicine 0.6 mg tablets
Colchicine 0.6 mg tablets (
 or Takeda 
Pharmaceuticals America, Deerfield, IL [formerly URL Pharma, Inc. / Mutual Pharmaceutical 
Company, Inc., Philadelphia, PA]) will be supplied in child resistant bottles containing 100 tablets 
each.
Naproxen 250 mg tablets
Naproxen (
 
will be supplied in child resistant bottles with 100 tablets, 
each tablet containing 250 mg of naproxen.
Lansoprazole 15 mg capsules
Subjects who are assigned to receive naproxen for gout flare prophylaxis will also be dispensed 
lansoprazole 15 mg capsules, to be taken in the morning prior to a meal, as protection against 
possible NSAID-associated peptic ulcers.
Lansoprazole (Takeda Pharmaceuticals America, Deerfield, IL) will be supplied in child-resistant 
bottles containing 30 capsules each.
8.1.2
Storage
All study medications supplied for the study must be kept in an appropriate, limited-access, secure 
location at the site and utilized according to sponsor’s instructions and GCP until administered to 
study subjects or returned to TDC or its designee for destruction.
All double-blind study medication supplied for the study must be stored as follows:
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F-86°F).
Store of commercial medication should be in accordance with the manufacturer storage 
conditions.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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The investigator should ensure that study medication is used only in accordance with the approved 
protocol. Study medication shall be dispensed only to subjects enrolled in the study.
8.1.3
Dose and Regimen
Double-Blind Study Medication (Febuxostat 40 mg, febuxostat 80 mg, allopurinol 200 mg, 
allopurinol 300 mg and matching placebo capsules)
Febuxostat (manufactured by 
) and allopurinol (manufactured by 
 
) tablets will be over-encapsulated to ensure blinding of study medication. 
The matching placebo capsule will ensure the blinding of the study medication. Subjects will 
orally self administer 2 capsules (one capsule from each bottle) each morning to receive one of the 
following:

febuxostat 40 mg (1 capsule containing one 40 mg febuxostat tablet and 1 matching placebo 
capsule),

febuxostat 80 mg (1 capsule containing one 80 mg febuxostat tablet and 1 matching placebo 
capsule),

allopurinol 200 mg (1 capsule containing two 100 mg, allopurinol tablets and 1 matching 
placebo capsule),

allopurinol 300 mg (1 capsule containing three 100 mg allopurinol tablets and 1 matching 
placebo capsule),

allopurinol 400 mg (2 capsules each containing two 100 mg allopurinol tablets),

allopurinol 500 mg (1 capsule containing two 100 mg allopurinol tablets and 1 capsule 
containing three 100 mg allopurinol tablets), OR

allopurinol 600 mg (2 capsules each containing three 100 mg allopurinol tablets).
As specified in Section 6.0, febuxostat and allopurinol dose during the first 3 months of the study 
will be based on sUA level. Febuxostat, allopurinol, and matching placebo capsules will be 
identical in appearance.
Clinical supplies will be packaged, labeled, and distributed by 
 on 
behalf of Takeda.
The study sites will be supplied with the following study medication in a double-blind manner, 
blinded via over-encapsulation: febuxostat 40 mg tablet over-encapsulated (35 ct., 100 ct. and 
200 ct. bottles), febuxostat 80 mg tablet over-encapsulated (35 ct., 100ct. and 200 ct. bottles), two 
allopurinol 100 mg tablets over-encapsulated (35 ct., 100 ct. and 200 ct. bottles) [200 mg dose], 
three allopurinol 100 mg tablets over-encapsulated (35 ct., 100 ct. and 200 ct. bottles) [300 mg 
dose] and matching placebo capsule (35 ct., 100 ct. and 200 ct. bottles). Capsules will be identical 
in appearance.
Each 35 ct,100 ct. and 200 ct. bottle will bear a single-panel computer-generated label containing 
the required information, including the country-specific requirements and regulatory statements 
PPD
PPD
PPD
PPD


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contents, study medication number and spaces to enter subject’s initials, subject number, and date 
dispensed.
During the treatment period, subjects should be advised to withhold the study medication on the 
scheduled visit days. If the subject does not withhold the study medication, the visit should not be 
rescheduled; however, the taking of the study medication must be recorded in the source 
document.
Gout Flare Prophylaxis Treatments
The prophylaxis medications will be provided in the manufacturer’s original packaging 
configuration. In addition, an ancillary label containing pertinent study and subject information 
will be applied to each manufacturer’s bottle without covering the product information.
Colchicine 
Colchicine 
. or Takeda Pharmaceuticals America, Inc. [formerly 
URL Pharma, Inc. / Mutual Pharmaceutical Company, Inc., Philadelphia, PA)] will be supplied in 
child-resistant bottles with 100 tablets each containing 0.6 mg of colchicine. Subjects should not 
receive colchicine if they have a history of hypersensitivity to colchicine. Subjects with renal or 
hepatic impairment should not be given colchicine in conjunction with P-gp or strong CYP3A4 
inhibitors. In these patients, life-threatening and fatal colchicine toxicity has been reported with 
colchicine taken in therapeutic doses. In addition, the following warnings and precautions are 
noted for colchicine use:

Fatal overdoses have been reported with colchicine in adults and children. Keep colchicine out 
of the reach of children.

Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia 
have been reported with colchicine at therapeutic doses.

Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with 
chronic treatment at therapeutic doses. Patients with renal dysfunction and elderly patients, 
even those with normal renal and hepatic function, are at increased risk. Concomitant use of 
atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil, fenofibrate, fenofibric acid, 
benzafibrate or cyclosporine with colchicine may potentiate the development of myopathy. 
Once colchicine is stopped, the symptoms generally resolve within one week to several months 
[12].

Co-administration of colchicine with P-gp and/or CYP3A4 inhibitors have been demonstrated 
to alter the concentration of colchicine resulting in life-threatening interaction and death. The 
potential for drug-drug interactions must be considered prior to and during concomitant 
therapy with colchicine and diltiazem, verapamil, grapefruit juice, aprepitant, fluoconazole, 
itraconazole, ketaconazole, cyclosporine, ranolazine, atazanavir, daruanavir, indinavir, 
lopinavir, nefazodone, nelfinavir, ritonavir, squinavir, tipranavir, amprenavir and 
fosamprenavir. Colchicine dosage adjustment or alternate therapy should be considered [12],
PPD


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
Monitor for toxicity and if present consider temporary interruption or discontinuation of 
colchicine [12].

Avoid eating Seville oranges and drinking grapefruit juice
Subjects currently taking ULTs and who receive colchicine for gout flare prophylaxis will be 
dispensed 1 bottle of 100 tablets of colchicine 0.6 mg at the Day -7 Screening Visit. At 
Day 1/Randomization Visit, subjects will be redispensed the 1 bottle of 100 tablets dispensed at 
the Day -7 Visit. At the Month 3 visit, subjects will be dispensed 1 new bottle of 100 tablets of 
colchicine 0.6 mg. Subjects will orally self-administer a single dose of 0.6 mg colchicine QD 
beginning on the day that it is dispensed and continuing until the next study visit.
Subjects not currently taking ULTs and who receive colchicine for gout flare prophylaxis will be 
dispensed 1 bottle of 100 tablets of colchicine 0.6 mg at Day 1/Randomization Visit and at the 
Month 3 visit. Subjects will orally self-administer a single dose of 0.6 mg colchicine QD 
beginning on the day that it is dispensed and continuing until the next Study Visit.
The Investigator may use a reduced colchicine regimen (for example, colchicine 0.6 mg on 
alternate days) if required because of concomitant medications (medications with potential 
drug-drug interactions with colchicine, including verapamil and diltiazem but excluding those 
with potential strong interactions listed in Section 7.3.2), co-morbid conditions including chronic 
kidney disease, or patient preference based on prior experience with colchicine.
Subjects receiving colchicine for gout flare prophylaxis will return the previously dispensed bottle 
and any unused medication to the site at their next scheduled visit.
Drug Interaction: Macrolides, Ketolides, and Concomitant Colchicine
When a subject is receiving colchicine, the administration of a concomitant macrolide or ketolide 
is prohibited. An alternative antibiotic treatment option is recommended, when possible. However, 
if no alternative is available, a subject who is on colchicine for gout flare prophylaxis or treatment, 
and who requires treatment with a macrolide or ketolide must be temporarily discontinued from 
colchicine and switched to naproxen, when possible, for the duration of the macrolide or ketolide 
treatment and remain off of colchicine for 3 days following the last dose of the macrolide or 
ketolide. Subjects may resume colchicine on the fourth day following the last dose of the 
macrolide or ketolide. Subjects, who are temporarily switched from colchicine to naproxen for 
gout flare prophylaxis during the course of the macrolide or ketolide prescription, and for the 
3 days following the last dose, should be provided with a prescription for naproxen for the duration 
they need to take it. However, if subjects are permanently switched from colchicine to naproxen as 
a result of requiring a concurrent macrolide or ketolide, the sites may contact the IVRS/IWRS to 
have naproxen supplies administered. If naproxen is not tolerated by a subject, the Takeda Medical 
Monitor should be contacted to discuss alternative prophylaxis options. Although it is preferred 
that a subject who requires a macrolide or ketolide be switched to naproxen (or an alternative 
prophylaxis), gout flare prophylaxis may be interrupted entirely, but is not recommended as the 
risk of a gout flare may increase. Subjects who are on naproxen for gout flare prophylaxis may take 
a concomitant macrolide or ketolide without stopping naproxen.


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Naproxen
Naproxen 
.) [16] will be supplied in 
child-resistant bottles with 100 tablets, each tablet containing 250 mg of naproxen. Subjects 
should not receive naproxen if they have a history of hypersensitivity to naproxen or any of its 
components, any other NSAID or aspirin or have active peptic ulcer disease. If colchicine is not 
tolerated by the subject and the subject has an eCLcr <50 mL/min, the investigator should contact 
the Takeda Medical Monitor for alternate prophylaxis treatment options.
Subjects currently taking ULTs and who receive naproxen with lansoprazole for gout flare 
prophylaxis, will be dispensed 2 bottles of naproxen 250 mg tablets at the Day - 7 Screening Visit. 
Subjects will orally self-administer a single dose of naproxen 250 mg BID, in the morning and in 
the evening with food, beginning on the day that it is dispensed and continuing until the next Study 
Visit.
Subjects not currently taking ULTs and who receive naproxen with lansoprazole for gout flare 
prophylaxis will be dispensed 2 bottles (100 counts) of naproxen 250 mg tablets at the 
Day 1/Randomization Visit and at the Month 3 Visit. Subjects will orally self-administer a single 
dose of naproxen 250 mg BID, in the morning and in the evening with food, beginning on the day 
that it is dispensed and continuing until the next Study Visit.
At Month 3, all subjects receiving naproxen for gout flare prophylaxis will return the previously 
dispensed bottle(s) and unused medication to the site and will receive another 2 bottles of 
naproxen 250 mg tablets.
Lansoprazole
Subjects who are assigned to receive naproxen for gout flare prophylaxis will also be dispensed 
lansoprazole 15 mg, to be taken in the morning prior to a meal, as protection against possible 
NSAID-associated peptic ulcers.
Lansoprazole [15] (Takeda Pharmaceuticals America, Deerfield, IL) will be supplied in 30 capsule 
bottles each capsule containing 15 mg of lansoprazole. Subjects should not receive lansoprazole if 
they have a history of hypersensitivity or intolerance to lansoprazole or any of its components.
Subjects currently taking ULTs and who receive lansoprazole will be dispensed 4 bottles of 
lansoprazole at the Day - 7 Screening Visit and Month 3 Visit. Subjects will orally self-administer 
a single dose of lansoprazole 15 mg in the morning, prior to a meal beginning on the day it is 
dispensed and continuing until the next study visit.
Subjects not currently taking ULTs and who receive lansoprazole will be dispensed 4 bottles of 
lansoprazole 15 mg at the Day 1/Randomization Visit and Month 3 Visit. Subjects will orally 
self-administer a single dose of lansoprazole 15 mg in the morning, prior to a meal beginning on 
the day it is dispensed and continuing until the next study visit.
All subjects receiving lansoprazole will return the previously dispensed lansoprazole bottles and 
unused study medication to the site.
PPD


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Table 8.a
Study Medication - Sponsor Supplied
Group
Study Medication
Dose
A
Febuxostat
1 capsule containing 40 mg or 80 mg febuxostat over-encapsulated AND 
1 matching placebo capsule QD
B
Allopurinol
200 mg or 300 mg allopurinol over-encapsulated or matching placebo 
capsule QD in appropriate combination of two capsules for subject’s dose 
of 200 mg, 300 mg, 400 mg, 500 mg or 600 mg
Prophylaxis medication will be provided for the first 6 months
Colchicine
0.6 mg tablet QD
OR
Naproxen
250 mg tablet BID
AND
Lansoprazole
15 mg capsule QD
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose of double-blind study medication (with or without associated adverse 
events) will be documented on an Overdose page of eCRF, in order to capture this important safety 
information consistently in the database. Adverse events associated with an overdose will be 
documented on AE eCRF(s) according to Section 10.0, Pretreatment Events and Adverse Events.
SAEs of overdose should be reported according to the procedure outlined in Section 10.2.2, 
Collection and Reporting of SAEs.
Febuxostat has been studied in healthy subjects in doses up to 300 mg daily for 7 days without 
evidence of dose-limiting toxicities. No overdose of febuxostat has been reported in clinical 
studies. Subjects should be managed by symptomatic and supportive care should there be an 
overdose.
There has been no clinical experience in the management of a subject who has taken massive 
amounts of allopurinol. Both allopurinol and oxypurinol are dialyzable; however, the usefulness of 
hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol is unknown.
8.2
Randomization Code Creation and Storage
The Analytical Sciences department at Takeda or designee will generate the randomization 
schedule. All randomization information will be stored in a secured area, accessible only by 
authorized personnel. Subjects will be randomized in a 1:1 ratio to receive either febuxostat or 
allopurinol. Randomization will be stratified based on baseline renal function (subjects with 
normal renal function or mild renal impairment versus subjects with moderate renal impairment).


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8.3
Investigational Drug Blind Maintenance
The study medication blind will be maintained using the IVRS/IWRS, which will be accessed by 
the study sites for randomization and study medication assignments.
8.4
Investigational Drug Assignment and Dispensing Procedures
An IVRS/IWRS will be used for the study. Subjects will be assigned, in the order in which they are 
enrolled into the study, to receive their treatment according to the schedule allocated.
The investigator or the investigator’s designee will contact the IVRS/IWRS to register the subject 
into the study at Screening. During this contact, the investigator or designee will provide the 
necessary subject-identifying information. At subsequent drug-dispensing visits, the investigator 
or designee will again contact the IVRS/IWRS to request additional investigational drug for a 
subject. The medication number of the investigational drug to be dispensed will be provided by the 
IVRS/IWRS.
8.5
Unblinding Procedure
The investigational drug blind shall not be broken by the investigator unless information 
concerning the study medication is necessary for the medical treatment of the subject. The sponsor 
must be notified before the investigational drug blind is broken unless a medical emergency 
requiring unblinding occurs. In this case the investigator (or designee) at the site should contact the 
sponsor (see contact information listed in Section 1.1) within 24 hours.
For unblinding a subject, the investigational drug blind can be obtained by accessing the IVRS. 
Please refer to IVRS Unblinding Worksheet packet. 
The date, time, and reason the blind was broken must be recorded in the source document and on 
the appropriate eCRF.
If the investigator is unblinded, investigational drug must be stopped immediately. Subjects will 
have the End of Study/Discontinuation of Treatment/Early Termination visit but will continue to 
be followed until the end of the study via follow-up contacts.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned.
Upon receipt of delivery of study medication and prophylaxis medications, the investigator (or 
investigator’s designee) must access the IVRS/IWRS to confirm receipt of study medication and 
prophylaxis medications and verify the contents and condition of the shipment against the packing 
list. Any discrepancies between the packing list and the actual contents must be communicated to 
the assigned study monitor or a Takeda designee to resolve the issue. The packing list should then 
be filed in the investigator’s essential document file. Once this process is completed, the study 
medication and prophylaxis medications should be stored in an appropriate, secure location as 
described in Section 8.0. Resupplies will be handled via IVRS/IWRS. The number of 
capsules/tablets dispensed and returned will be documented in the subject’s source documents, 


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eCRF, and recorded on drug accountability logs retained with the investigator’s essential 
document file.
The investigator must maintain 100% accountability for all sponsor-supplied drugs received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that all bottles used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator must maintain a current inventory (Drug Accountability Log) of all 
sponsor-supplied study medication delivered to the site, inventory at the site, and subject’s use 
records. This log must accurately reflect the drug accountability of the study medication at all 
times. The following information will be recorded at a minimum: protocol number and title, name 
of investigator, site identifier and number, description of sponsor-supplied medication and amount 
dispensed, and the date and amount returned to the site by the subject, including the initials of the 
person dispensing and receiving the study medication. The log should include all required 
information as a separate entry for each subject to whom study medication is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee for destruction. The investigator will retain the 
copy of the original documentation regarding clinical study material accountability, return, and/or 
destruction, and the original will be sent to the sponsor.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the procedures to be completed at Screening and during the study. 
Subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is found in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned via IVRS/IWRS to each 
subject at the time that informed consent is obtained and this subject number will be used 
throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, height, weight, alcohol use, and smoking status of the subject at 
Screening.
A complete medical, CV, and social history, will be obtained at Screening (at the time of informed 
consent). The general medical history will include a review of all major organ systems. The social 
history will include tobacco and alcohol use. The CV history will include CV medications and 
detailed history of prior CV procedures and/or events that stopped. Ongoing conditions are 
considered concurrent medical conditions (see Section 9.1.7).
Subjects will also be asked about their gout disease history, including frequency of acute gout 
attacks and the related symptoms experienced.
Medication history information to be obtained includes any medication stopped at or within 
30 days prior to the Screening Visit, and will be documented in the subject’s source documents and 
on the appropriate eCRF. Prior NSAID and aspirin use will be collected for the year prior to 
informed consent.
9.1.3
Physical Examination Procedure
A complete physical examination (defined as the pretreatment assessment immediately prior to the 
start of study medication) will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) CV system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) genitourinary system (optional) and (12) other. All subsequent physical examinations should 
assess clinically significant changes from the baseline examination. A complete physical 
examination will be performed at Day 1, Month 12, and annually until End of Study/DoT/Early 
Termination.


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9.1.4
Weight and Height Procedure
The subject’s body weight will be collected (in kilograms) at Screening and End of 
Study/DoT/Early Termination. The subject’s height will be collected at Screening. A subject 
should have weight and height measured while wearing indoor clothing and with shoes off.
9.1.5
Vital Sign Procedure
Vital signs will be obtained at every scheduled clinic visit (Appendix A). Vital sign 
measurements include: body temperature (oral), blood pressure (systolic and diastolic blood 
pressure), and pulse/beats per minute (bpm). Measurements will be made prior to dosing where 
applicable. One measurement of blood pressure and pulse will be measured while subjects are in a 
sitting position after they have been seated for at least 5 minutes and in accordance with American 
Heart Association guidelines (arm supported heart level, proper cuff size, etc).
9.1.6
Documentation of Concomitant Medications
At each study visit, subjects will be asked whether they have taken any medication other than the 
study medication (used from Screening through End of Study/DoT/Early Termination), and all 
medication, including vitamin supplements, over-the-counter medications, and oral herbal 
preparations must be recorded in the eCRF, along with Reason for Use. Changes in medication for 
subjects that have discontinued treatment but remain in follow-up should be recorded on the 
Medication Information Obtained During Follow-up Contact eCRF, and not on the Concomitant 
Medications eCRF.
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at Screening (at time of informed consent). This includes clinically significant laboratory, ECG, or 
physical examination abnormalities. The condition (ie, diagnosis) should be described, and the 
date that the condition began should be documented.
9.1.8
Procedures for Clinical Laboratory Samples
Laboratory samples will be taken at the time points stipulated in the Schedule of Study Procedures 
(Appendix A). All samples will be collected in accordance with acceptable laboratory procedures. 
Details of these procedures and required safety monitoring will be given in the laboratory manual.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cell count
White blood cell count with auto 
differential
Hemoglobin
Hematocrit
Platelet count
Mean corpuscular volume
Mean corpuscular
hemoglobin
Mean corpuscular hemoglobin 
concentration
ALT
Albumin
Alkaline phosphatase
AST 
Total bilirubin
Total protein
Creatinine (b)
Blood urea nitrogen
Creatine kinase
-Glutamyl transferase
Potassium
Sodium
Calcium
Magnesium
Glucose
Serum urate (a)
Triglycerides
Cholesterol
Qualitative
Appearance
Color
pH
Specific gravity
Ketones
Protein
Glucose
Nitrite
Urobilinogen
Blood
OTHER:
Coagulation: prothrombin and activated partial thromboplastin time (only for subjects on warfarin) 
International normalized ratio (only for subjects on warfarin)
Lipid panel (fasting) (c)
(a) sUA results will be unblinded to the Sponsor and study site through the Week 10 Visit. 
(b) Estimated Creatinine clearance will be calculated by Central Lab.
(c) Lipid panel only at Day 1.
Serum urate values will be blinded to the Sponsor and study site after the Week 10 Visit. A 
member of the Takeda Pharmacovigilance Department, not involved with the febuxostat program, 
will be contacted by the central laboratory in the event of a serum urate value ≤2 mg/dL or 
>18 mg/dL at any visit. The same non blinded member from Pharmacovigilance will follow up 
with the study site.
Subjects receiving warfarin will have the international normalized ratio (INR) in addition to 
prothrombin time and activated partial thromboplastin time monitored annually.
The central laboratory will perform laboratory tests. The results of laboratory tests will be returned 
(with the exception of sUA after Week 10 during the treatment period) to the investigator, who is 
responsible for reviewing and filing these results together with the source data in the eCRF. The 
investigator will maintain a copy of the laboratory accreditation and the reference ranges for the 
laboratory used.
9.1.9
Pregnancy
Women of childbearing potential will not be included in this study; therefore, this study does not 
require any specific contraception.


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If any subject is found to be pregnant during the study, she should be withdrawn from the study 
medication treatment phase. Any medication treatment and any sponsor-supplied drug should be 
immediately discontinued.
If the pregnancy occurs during administration of active study medication, (eg, after Screening or 
within 30 days of the last dose of study medication) the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.1.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of her right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator.
If the subject agrees to the primary care physician being informed, the investigator should notify 
the subject’s primary care physician that she was participating in a clinical study at the time she 
became pregnant and provide details of treatment the subject received (blinded or unblinded, as 
applicable).
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor.
9.1.10 ECG Procedure
A standard 12-lead electrocardiogram (ECG) will be performed and recorded at the Day 1 and End 
of Study/ DoT/Early Termination, using the site’s ECG equipment. The investigator will interpret 
the ECG using one of the following categories: within normal limits, abnormal but not clinically 
significant, or abnormal and clinically significant. Paper copies of the ECG tracings will be 
included in each subject’s source document and details of the findings will be captured in the 
source and eCRF. For subjects who experience a CV AE that potentially meets the predefined 
MACE criteria, all available ECG tracings must be forwarded to the sponsor, along with all ECGs 
associated with the AE.
9.1.11 Documentation of Screen Failure
Investigators must account for all subjects who sign the informed consent form.
If the subject is found to be ineligible at the Screening Visit, and they have not taken a dose of 
prophylaxis medication, the site personnel should complete the screen failure eCRF. The 
IVRS/IWRS should be contacted as a notification of screen failure, and the primary reason for 
screen failure should be recorded in the eCRF.
The primary reason for screen failure is recorded using the following categories:

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specific inclusion/exclusion 
criteria should be recorded in the eCRF).

Major protocol deviation.

Lost to follow-up.


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
Voluntary withdrawal of the consent (The reason for withdrawal, if provided, should be 
recorded in the eCRF).

Study termination.

Pregnancy.

Other (The specific reason for withdrawal, if provided, should be recorded in the eCRF).
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.12 Documentation of Washout Failure
If the subject signs the informed consent, and takes at least one dose of prophylaxis medication, 
but does not randomize to double-blind study medication, they are considered a washout failure. 
The primary reason for washout failure is recorded using the following categories:

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria (The specific inclusion criteria 
not met or the specific exclusion criteria met should be recorded in the eCRF.)

Major protocol deviation.

Lost to follow-up.

Voluntary withdrawal of the consent (The reason for withdrawal, if provided, should be 
recorded in the eCRF.)

Study termination.

Pregnancy.

Other (The specific reason for withdrawal, if provided, should be recorded in the eCRF.)
9.1.13 Documentation of Study Entrance/Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be ineligible for randomization the investigator should record the primary 
reason for failure on the applicable eCRF.
9.1.14 Gout Flare Prophylaxis
All subjects will remain on gout flare prophylaxis for the first 6 months of the study.
Subjects currently on ULT will discontinue these treatments at the Day -7 Screening Visit, and 
will begin taking colchicine 0.6 mg QD for gout flare prophylaxis.
Subjects not currently taking ULT will begin taking colchicine 0.6 mg QD at the 
Day 1/Randomization Visit.


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Alternatively, if colchicine is not tolerated by the subject and the subject’s eCLcr is ≥50 mL/min 
they will be administered naproxen 250 mg BID with lansoprazole 15 mg QD.
In instances when subjects should not receive colchicine or naproxen, other NSAIDs or prednisone 
may be provided at the investigator’s discretion in accordance with the stated guidelines listed 
under Excluded Medications and Treatments (Section 7.3.2). In the event that colchicine, 
naproxen or other NSAIDs, proton pump inhibitors or prednisone are not tolerated or are 
contraindicated, the Investigator may choose not to use prophylaxis but to manage the subject’s 
gout flares as they occur. Alternatively, if colchicine 0.6 mg daily is not tolerated by the subject, 
0.6 mg every other day may be used.
Prophylaxis medication is only provided until the Month 6 visit, but upon the Investigator’s 
request, continued prescription may be allowed. Please note that study prescription cards intended 
to pay for acute gout flare medication cannot be used to pay for ongoing prophylaxis medication.
9.1.15 Treatment of Gout Flares
Subjects who experience a gout flare and who are taking colchicine for prophylaxis and have taken 
their daily dose, may take an additional colchicine 0.6 mg tablet at the onset of the flare, with 
another tablet one hour later, for a maximum of 3 tablets (1.8 mg) in a 24 hour period. After 
12 hours, the original prophylaxis dose may be resumed [12].
Subjects experiencing a gout flare and who are taking naproxen for prophylaxis, may take 
naproxen 500 mg BID (2 additional doses of naproxen 250 mg) on the day the gout flare starts 
followed by 1 additional 250 mg dose on each subsequent day until the flare subsides. Gout flares 
may also be treated at the discretion of the investigator, as long as this treatment is in compliance 
with the prohibited medications for this study.
At the Day -7 Screening Visit in addition to dispensing the gout flare prophylaxis, the investigator 
should provide the subject with a prescription for an anti-inflammatory/analgesic agent of the 
investigator’s choosing, to be used in the event the subject experiences a gout flare during the 
study and an increase of the prophylaxis medication dose is not efficacious in treating the flare. 
This may be done at the discretion of the investigator and in accordance with their practice 
guidelines.
Subjects are to be instructed to contact the investigator as soon as they begin to have a gout flare. 
An unscheduled visit can be conducted if deemed appropriate by the investigator. All subjects that 
experience flares while on the study will have the option to receive acute gout flare treatment if 
deemed appropriate by the principal investigator. The investigator may also consult with the 
Takeda Medical Monitor for further discussion. A Gout Flare Assessment Worksheet (sample 
shown in Appendix G) will be used to collect the gout flare information.
9.1.16 Gout Flare Assessment
Subjects will be assessed for gout flares beginning at the Day -7 Screening Visit and throughout 
the duration of the study. Subjects are to be instructed to call the investigator as soon as they think 
they may be having a gout flare. The Gout Flare Assessment Worksheet, developed with 


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Drs. Schumacher, Gaffo, Saag and Singh [13] (sample shown in Appendix G) will be completed 
by the site personnel (ie, study coordinator, study nurse, or the investigator).
All gout flares should be followed until complete resolution. Subjects should be instructed to 
contact the site when the flare has resolved (typically 7-10 days after onset). The study site will 
contact the subject 7 days after the initial report if the subject fails to report the end date of the gout 
flare. The attempts to contact the subject to obtain the end date of the gout flare must be 
documented (2 documented telephone contact attempts).
Subjects will be instructed to report the following information: the onset and end date of the flare, 
the kind of prophylaxis medication they are taking at the time of the event, whether or not the 
attack required medication (including type) and dates of treatment, the location of the flare, signs 
and symptoms regarding the flare including: swelling, redness, tenderness and joint warmth the 
worst pain of the gout flare (pain at rest), the assessment of current gout flare compared with all 
previous gout flares in any joints. The investigator will review the information provided and assess 
whether or not they believe the subject experienced a gout flare and/or document an alternative 
etiology.
The Gout Flare Assessment Worksheet will be maintained with the subject’s source documents. 
All confirmed gout flares will be transcribed from the worksheet onto the Gout Flare eCRF page. 
These entries should not to be documented on the Adverse Event eCRF (unless they meet SAE 
criteria). If the investigator feels it is appropriate, an unscheduled visit may be scheduled.
9.1.17 Physical Assessment of Tophi
Subjects will be assessed for the presence of tophi by palpation at the Day 1 visit. The most easily 
identified and palpable tophus will be designated as “primary” and the presence or absence of this 
tophus should be assessed annually and at the End of Study/DoT/Early Termination visit. In 
addition, all tophi will be counted and the number recorded on the Tophi eCRF page at all tophi 
assessment visits.
9.1.18 Rash Assessment
AEs of rash will be collected beginning at the Day -7 Visit until 30 days after study medication is 
discontinued. AEs of rash will be documented on the Rash Adverse Event Worksheet (sample 
shown in Appendix F) that will be maintained with the subject’s source documents. Rash AEs 
recorded on the Rash Adverse Event Worksheet will be transcribed over to the Adverse Event 
eCRF. So long as the event is not deemed a SAE, the completed Rash Adverse Event Worksheet 
will be faxed to Takeda, in accordance with the instructions on the worksheet, within 48 hours of 
the site’s knowledge of the event. If the event is deemed a serious adverse event, follow procedure 
in 10.2.2.
9.1.19 Management, Withdrawal and Follow-Up of Subjects With Liver Enzyme Elevations
If the ALT or AST value rises to >3×ULN, laboratory tests (at minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, and INR) should be repeated within 48 to 72 hours. If the 
ALT or AST value remains elevated >3×ULN when repeated, and this observation cannot be 


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explained by concomitant disease or another alternative etiology, the abnormality must be 
recorded as an AE, if it has not already. In these cases, additional tests are required to rule out other 
etiologies. The investigator must contact the Takeda Medical Monitor for determination of 
additional testing, consideration of immediate discontinuation of study medication, discussion of 
the relevant subject details, and possible alternative etiologies.
In addition, study medication should be temporarily discontinued with appropriate clinical 
follow-up, including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal, if the following circumstances occur at any time during study medication treatment phase:

ALT or AST >8×ULN, or

ALT or AST >5×ULN and persists for more than 2 weeks, or

ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or INR >1.5, or

ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or eosinophilia (>5%).
Subjects who experience ALT or AST >3×ULN in conjunction with elevated total bilirubin 
>2×ULN and who also satisfy one of the following criteria should be permanently discontinued 
from the study medication treatment phase:

The liver injury is hepatocellular in nature and there is not a prominent cholestatic component; 
or

There is no more likely alternative cause than drug induced liver injury, such as acute viral 
hepatitis A or B, or other acute liver disease.
Additional information will be collected in the eCRF for liver enzyme AEs that cannot be 
explained by concomitant disease. This information will include recent history (if any), of alcohol 
use, blood transfusions, occupational/toxic exposure, tattooing, recreational drug use, special diet, 
surgery/general anesthesia, travel, or use of herbal supplements or teas. This information will also 
include signs and symptoms (if any) associated with the AE and results of any additional 
diagnostic tests performed.
9.2
Monitoring Subject Compliance
Subjects will be required to bring study medication containers to each clinic visit, regardless of
whether the study medication container is empty.
If a subject is persistently noncompliant with the sponsor-supplied double blind study drugs
(<80% or >120% of the allocated medication for the period since the last visit) it may be 
appropriate to withdraw the subject from the study medication treatment and continue in the study 
to monitor for potential CV events. All subjects should be reinstructed about the dosing 
requirement during study visits. The authorized study personnel conducting the re-education must 
document the process in the subject source records.


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9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). Study days/weeks and visit 
windows should be calculated after randomization and should be calculated from the day of the 
first dose of double-blind treatment (Day 1).
The overall duration of the study is dependent on the number of the predefined MACE; the study 
will end when the required number of events has accrued. The duration of the study is expected to 
be 9 years. The length of study participation for each subject will vary (due to the event driven 
study design).
Subjects are required to bring all of the Sponsor supplied medication to every visit.
9.3.1
Screening
Subjects will be evaluated for enrollment based on all inclusion/exclusion criteria. Subjects will be 
evaluated for enrollment based on their prior history of a major CV or cerebrovascular event. 
Subjects currently receiving ULT will begin the 7 day washout and should receive prophylaxis 
medication.
If a subject has a gout flare at the Screening Visit, the visit procedures should be delayed and the 
subject should be treated for the gout flare and return to the study site no earlier than 2, but no later 
than 3, weeks after the resolution of the flare. Please contact the Medical Monitor if randomization 
does not occur within four weeks of the Screening visit. Screening may be less than 7 days for 
subjects not washing off of ULTs. Screening period may be up to 28 days depending on whether 
subject has a flare or requires a repeat sUA test.
Procedures to be done at Screening Day -7 to Day -1

Obtain informed consent. 

Review of inclusion/exclusion criteria.

Demographics, medical, gout, social, CV and medication history.

Access IVRS/IWRS to obtain the subject number and dispense prophylaxis medication (for 
subjects discontinuing prior ULT at Day -7).

Concurrent medical conditions.

Vital signs.

Weight and height.

Assess for pre-treatment events.

AEs assessment (for subjects discontinuing prior ULT at Day -7).

Gout flare assessment.

Laboratory assessments.


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
Concomitant medications assessment.

Educate subject on reporting of potential CV events and gout flares.

Dispense prescription for additional gout flare medication.
All subjects who do not meet the sUA inclusion criteria but meet all remaining criteria will be 
allowed to have one repeat sUA test. This additional test should occur no earlier than two weeks 
but no later than three weeks after the initial test.
9.3.2
Study Randomization
Study Randomization will take place on Day 1. If the subject has satisfied all of the inclusion 
criteria and none of the exclusion criteria for randomization, the subject should be randomized 
using the IVRS/IWRS, as described in Section 8.4. Subjects will be asked to take the first dose of 
study medication in the office after randomization, as described in Section 8.4. The procedure for 
documenting Screening failures is provided in Section 9.1.11.
If a subject has a gout flare at the Randomization (Day 1) Visit, the visit procedures should be 
delayed and the subject should be treated for the gout flare and return to the study site no earlier 
than 2 but no later than 3 weeks after the resolution of the flare. If the subject had a flare that started 
after the screening visit, the randomization visit procedures should be delayed until no earlier than 
2 but no later than 3 weeks after the resolution of the flare.
The following procedures will be performed and documented during Study Randomization:

Review of inclusion/exclusion criteria.

Access IVRS/IWRS and dispense assigned study medication with dosing instructions.

Physical examination.

Collect vital signs.

Tophus assessment (includes primary tophus assessment and counting of all other tophi).

Collect laboratory assessments (fasting if at all possible, however if the subject is not fasting 
continue with visit).

12-lead ECG.

Assess for pretreatment events.

AEs assessment.

Gout flare assessment.

Concomitant medication assessment.

Dispense prophylaxis medication, with dosing instructions (for subjects not taking ULTs at 
Screening).

Educate subject on reporting of potential CV events and gout flares.


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
Assess compliance of prophylaxis medication and re-dispense (for subjects discontinuing prior 
ULT at Day -7).

Verify subject’s contact information (including details of emergency contact).

Review the Retention Program (subjects in the US and Canada only). Unless subjects opt-out, 
enroll them in the program.

Review the Gout Flare brochure.
9.3.3
Treatment Phase
All scheduled visits should occur in the morning, if possible. During the treatment period, subjects 
should be advised to withhold double blind study medication on scheduled visit days. If the subject 
does not withhold the study medication, the visit should not be rescheduled; however, the taking of 
the study medication must be recorded in the source document. If a subject has a gout flare during 
the treatment phase, the visit does not need to be re-scheduled.
9.3.3.1
Week 2 (± 3 Days)
All subjects will return at Week 2 for measurement of sUA.
The following procedures will be performed at Week 2:

Vital signs.

AE assessment.

Gout flare assessment

Laboratory assessments.

Concomitant medication assessment.

Educate subject on reporting of potential CV events and gout flares.

Assess compliance of the study medication and re-dispense.

Assess compliance of prophylaxis medication and re-dispense.

Verify subject’s contact information (including details of emergency contact).
9.3.3.2
Week 4 (± 3 Days)
If the Week 2 sUA level is <6.0 mg/dL, the subject will be dispensed study medication at 
Week 4, and the next visit will occur at Month 3.
If the Week 2 sUA level is ≥6.0 mg/dL, the subject will be dispensed study medication at 
Week 4, and the next visit will occur at Week 6.
The following procedures will be performed at Week 4:

Access IVRS/IWRS and dispense assigned study medication with dosing instructions.


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
Vital signs.

AE assessment.

Gout flare assessment.

Concomitant medication assessment.

Educate subject on reporting of potential CV events and gout flares.

Collect unused study medication and assess compliance.

Assess compliance of prophylaxis medication and re-dispense.

Verify subject’s contact information (including details of emergency contact).
9.3.3.3
Week 6 (3 Days)
For the subset of subjects who have a Week 6 visit the following procedures will be performed:

Vital signs.

AE assessment.

Gout flare assessment.

Laboratory assessments.

Concomitant medication assessment.

Educate subject on reporting of potential CV events and gout flares.

Assess compliance of study medication and re-dispense.

Assess compliance of prophylaxis medication and re-dispense.

Verify subject’s contact information (including details of emergency contact).
9.3.3.4
Week 8 (± 3 Days)
For the subset of subjects who have a Week 8 visit:
If the Week 6 sUA level is <6.0 mg/dL, the subject will be dispensed study medication at 
Week 8, and the next visit will occur at Month 3.
If the Week 6 sUA level is ≥6.0 mg/dL, the subject will be dispensed study medication at 
Week 8 and the next visit will occur at Week 10.
The following procedures will be performed at Week 8:

Access IVRS/IWRS and dispense assigned study medication with dosing instructions.

Vital signs.

AE assessment.


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
Gout flare assessment.

Concomitant medication assessment.

Educate subject on reporting of potential CV events and gout flares.

Collect unused study medication and assess compliance.

Assess compliance of prophylaxis medication and re-dispense.

Verify subject’s contact information (including details of emergency contact).
9.3.3.5
Week 10 (±3 Days)
For the subset of subjects who have a Week 10 visit, the subject will be dispensed study 
medication at the Month 3 visit. After the Month 3 visit, no further dose adjustments will be made.
The following procedures will be performed at week 10:

Vital signs.

AE assessment.

Gout flare assessment.

Laboratory assessments.

Concomitant medication assessment.

Educate subject on reporting of potential CV events and gout flares.

Assess compliance of study medication and re-dispense.

Assess compliance of prophylaxis medication and re-dispense.

Verify subject’s contact information (including details of emergency contact).
9.3.3.6
Month 3 (± 3 Days)
The following procedures will be performed at Month 3:

Access IVRS/IWRS and dispense assigned study medication with dosing instructions.

Vital signs.

AE assessment.

Gout flare assessment.

Laboratory assessments.

Concomitant medication assessment.

Dispense new prophylaxis medication.

Collect unused prophylaxis medication and assess compliance.


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
Collect unused study medication and assess compliance.

Educate subject on reporting of potential CV events and gout flares.

Verify subject’s contact information (including details of emergency contact).
9.3.3.7
Month 6 (±3 Days) 

Access IVRS/IWRS and dispense assigned study medication with dosing instruction.

Vital signs.

AE assessment.

Gout flare assessment.

Laboratory assessments.

Concomitant medication assessment.

Collect unused prophylaxis medication and assess compliance.

Collect unused study medication and assess compliance.

Educate subject on reporting of potential CV events and gout flares and possibility of obtaining 
the prescription card to obtain medication to treat gout flares (only in the US).

Verify subject’s contact information (including details of emergency contact).

Review the Retention Program (subjects in the US and Canada only).

Review the Gout Flare Brochure.
9.3.3.8
Months 9, 15 (Elderly and/or Moderately Renally Impaired Subjects) (±7 Days)

Vital signs.

AE assessment.

Gout flare assessment.

Laboratory assessments.

Concomitant medication assessment.

Educate subjects on reporting of potential CV events and gout flares.

Assess compliance of double blind medication.

Verify subject’s contact information (including details of emergency contact).
9.3.3.9
Month 12 and Every 6 Months Until End of Study/Discontinuation of Treatment/Early 
Termination (±7 Days)

Access IVRS/IWRS and dispense assigned study medication with dosing instruction.


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
Physical examination (performed annually).

Vital signs.

Tophus Assessment (performed annually for subjects with tophi present).

AE assessment.

Gout flare assessment.

Laboratory assessments (fasting if at all possible, however if the subject is not fasting continue 
with visit).

Concomitant medication assessment.

Collect unused study medication and assess compliance.

Educate subject on reporting of potential CV events and gout flares and possibility of obtaining 
the prescription card to obtain medication to treat gout flares (only in the US).

Verify subject’s contact information (including details of emergency contact).
9.3.3.10 End of Study/Discontinuation of Treatment/Early Termination
All efforts should be made to prevent any subject being lost to follow-up during the conduct of the 
study.
Subjects who either discontinue study drug treatment, or who fully withdraw consent, should 
complete the following procedures at their Discontinuation of Treatment Visit or Early 
Termination Visit, respectively. For subjects who are active in the study (taking study medication) 
at the time the independent CV Endpoints Committee determines that the targeted number of 
adjudicated MACE have been reached, instructions will be provided by the Sponsor regarding the 
scheduling of the End of Study Visit, which includes the following procedures. 

Access IVRS/IWRS to complete the subject or for Early Termination.

Physical examination.

Vital signs.

Weight.

Tophus assessment.

AE assessment.

Gout flare assessment.

Laboratory assessments (fasting if at all possible, however if the subject is not fasting continue 
with visit).

12-lead ECG.

Concomitant medication assessment.


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
Collect unused study medication and assess compliance.

Collect unused prophylaxis medication (if applicable).
For all subjects receiving any Sponsor supplied medication, the investigator must complete both 
the End of Study Drug eCRF page and the End of Study Visit eCRF page.
9.3.3.11 Unscheduled Visit (if applicable)
Subjects may return to the study center for unscheduled visits, as needed. If a subject presents to 
the study site for an Unscheduled Visit, the date and reason for the Unscheduled Visit must be 
documented on the Unscheduled Visit eCRF page. In addition, if study medication is dispensed or 
if procedures are completed (for example: physical examination, vital signs), the information must 
be documented on the appropriate eCRF and in the subject’s source documents. Sites must call the 
IVRS/IWRS if additional drug is dispensed.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for Pretreatment Events and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should be not considered PTEs or 
AEs).

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a pretreatment event(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be pretreatment events 
or AEs if they are judged to be clinically significant (ie, if some action or intervention is 
required or if the investigator judges the change to be beyond the range of normal physiologic 
fluctuation). A laboratory retest and/or continued monitoring of an abnormal value are not 


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considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a pretreatment event or as an AE.

If the ALT or AST value rises to >3×ULN, laboratory tests (at minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, and INR) should be repeated within 48 to 72 hours. If 
the ALT or AST value remains elevated >3×ULN when repeated, and this observation cannot 
be explained by concomitant disease or another alternative etiology, the abnormality must be 
recorded as an AE, if it has not already.

Pre-existing conditions: Pre-existing conditions (present at the time of signing of informed 
consent) are considered concurrent medical conditions and should NOT be recorded as 
pretreatment events or AEs. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a pretreatment event (worsening or complication occurs before start of study 
medication) or an AE (worsening or complication occurs after start of study medication). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, ”worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg, “worsening of…”)

If a subject has a degenerative concurrent condition (eg, cataracts), worsening of the condition 
should only be captured as a PTE/AE if occurring to a greater extent to that which would be 
expected. Again, investigators should ensure that the AE term recorded captures the change in 
the condition (eg, “worsening of…”).
Worsening of pretreatment or AEs:

If the subject experiences a worsening or complication of a pretreatment event after starting 
administration of the study medication, the worsening or complication should be recorded 
appropriately as an AE. Investigators should ensure that the AE term recorded captures the 
change in the condition (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs/PTEs/SAEs:

If the subject experiences changes in severity of an AE/PTE/SAE, the event should be captured 
once with the maximum severity recorded.


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered pretreatment events or AEs. However, if a preplanned 
procedure is performed early (eg, as an emergency) due to a worsening of the pre-existing 
condition, the worsening of the condition should be captured appropriately as a pretreatment 
event or an AE. Complications resulting from any planned surgery should be reported as 
adverse events.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as pretreatment events or AEs, but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should be 
reported as adverse events.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The principal investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
pretreatment events or AEs, but will instead be documented on an Overdose page of the eCRF. 
Any manifested side effects will be considered PTEs or AEs and will be recorded on the AE 
page of the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires subject HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.


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
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List
Term
1.
Acute respiratory failure/acute respiratory distress syndrome.
2.
Torsade de pointes/ventricular fibrillation/ventricular tachycardia.
3.
Malignant hypertension.
4.
Convulsive seizures.
5.
Agranulocytosis.
6.
Aplastic anaemia.
7.
Toxic epidermal necrolysis/Stevens-Johnson syndrome.
8.
Hepatic necrosis.
9.
Acute liver failure.
10. Anaphylactic shock.
11. Acute renal failure.
12. Pulmonary hypertension.
13. Pulmonary fibrosis.
14. Neuroleptic malignant syndrome/malignant hyperthermia.
15. Spontaneous abortion/stillbirth and fetal death.
16. Confirmed or suspected transmission of infectious agent by a medicinal products.
17. Confirmed or suspected endotoxic shock.
Note:
1.
As a general rule, the event terms mentioned in the list above should be handled as “serious.”
2.
This list is applicable when any of the above terms are reported as the newly occurred event after drug 
administration.
Pretreatment events that fulfill 1 or more of the serious criteria above are also to be considered 
SAEs and should be reported and followed up in the same manner (see Sections 10.2.2 and 10.2.3).


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10.1.5 Severity of Pretreatment Events and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Yes:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
No:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all pretreatment events and 
AEs.
The relationship should be assessed as “Yes” if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as “No”.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 Pretreatment Event and AE Collection Period
Collection of pretreatment events will commence from the time the subject signs the informed 
consent to participate in the study and continue until either the administration of sponsor-supplied 
gout flare prophylaxis on Day -7 for subjects requiring ULT washout, or administration of 
double-blind medication at Day 1 for subjects not requiring ULT washout. For subjects who 
discontinue prior to any prophylaxis or double-blind study drug administration, pretreatment 
events are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that subjects are administered sponsor-supplied 
medication, which is at Day -7 for subjects requiring ULT washout, or administration of 
double-blind medication at Day 1 for subjects not requiring ULT washout. Subjects will be 
instructed at their last study visit to call and report any AEs that occur within 30 days of last dose of
study medication and any potential CV events until the completion of the study. All adverse events 


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will be reported in detail on the appropriate eCRF and followed to a satisfactory conclusion (ie. 
until the adverse event resolves, and returns to baseline, or becomes stabilized).
10.2.1.2 Pretreatment Event and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study.
All non-SAEs that occur will be collected from the time the informed consent form is signed.
Subjects experiencing a serious PTE must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or there is a satisfactory 
explanation for the change. Non-serious PTEs, related or unrelated to the study procedure, need 
not to be followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All pretreatment events and AEs will be documented in the pretreatment 
event/AE page of the eCRF, whether or not the investigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event:

Event term.

Start and stop date.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (the relationship should be assessed as “Yes” if the investigator considers that there is 
reasonable possibility that an event is due to study drug (double-blind or prophylaxis). 
Otherwise, the relationship should be assessed as “No”) (not completed for pretreatment 
events).

Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.

Action concerning study drug (not applicable for pretreatment events).

Outcome of event.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs after informed consent through the AE collection period it should be 
reported according to the following procedure:


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A Takeda SAE form must be completed in English and signed by the investigator immediately or 
within 1 working day of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE form should be transmitted within 1 working day to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 1 working day of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.4 Safety Reporting to Investigators, IRBs or ECs, and Regulatory Authorities
The sponsor will be responsible for reporting all applicable SAEs to regulatory authorities, 
investigators and IRBs or ECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. The sponsor will also prepare an expedited report for other 
safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal products administration or in the overall conduct of the trial.
For all active investigators, the sponsor will prepare an expedited report for all SAEs that are 
unexpected and potentially related to the study medication, and copies will be distributed to all 
concerned regulatory authorities, investigator(s), and IRBs or ECs according to all applicable laws 
and regulations. The investigational site also will forward a copy of all expedited reports to his or 
her IRB or EC.


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10.2.5 Evaluation of CV Safety
Each death and selected serious cardiovascular adverse events, including any medically significant 
updates, will be sent by Takeda to a blinded CV Endpoints committee (see Section 11.2) for 
adjudication. The final selection of the CV events for adjudication is done by the adjudication 
committee chair. Non-serious, potential CV events will not be adjudicated. 
All investigational sites will be required to collect relevant clinical information required for 
adjudication of all deaths and selected CV SAEs. A CV worksheet will be provided to the 
investigational sites as a guide to ensure that supporting clinical information for each of these 
events are collected and compiled by the site and forwarded to Takeda Pharmacovigilance when 
available. The worksheet is not intended to be all inclusive and investigators should use medical 
judgment to determine what additional supporting documentation should be collected.


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11.0
STUDY-SPECIFIC COMMITTEES
11.1
Independent DMC
An independent DMC will be established to monitor the progress and the overall safety of subjects 
enrolled in this study. This committee will periodically review study safety data and make 
recommendations to Takeda as appropriate to ensure the safety of subjects. The committee will 
comprise of external consultants who have expertise in the conduct and review of clinical trials. 
Details of the DMC membership and responsibilities will be described in the DMC charter. The 
recommendations by the DMC based upon their review of the data will be communicated to the 
Sponsor.
11.2
CV Endpoints Committee
An independent CV Endpoints Committee consisting of 3 cardiovascular experts will be 
established to prospectively review and adjudicate all suspected cardiovascular events in a blinded 
fashion to determine if the reported event meets the criteria for MACE.
The procedures and rules of adjudication of these events by the CV Endpoints Committee will be 
described in a separate charter.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, pretreatment events, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject.
The sponsor or its designee will supply investigative sites with eCRFs. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Corrections to eCRFs include an audit trail that 
captures the old information, the new information, the name of the person making the correction, 
the date the correction was made and the reason for change. The principal investigator must review 
the eCRFs for completeness and accuracy and must sign and date the appropriate eCRF page as 
indicated. Furthermore, the investigator must retain full responsibility for the accuracy and 
authenticity of all data entered on the eCRFs.
eCRFs are accessed through the Medidata remote data capture application, which allows for 
on-site data entry and data management. Site users can read from and write to the Sponsor’s 
database where the clinical data are collected. This provides immediate, direct data transfer to the 
database, as well as immediate detection of discrepancies, enabling site coordinators to resolve and 
manage discrepancies in a timely manner. Each person involved with the study at each site will 
have an individual identification code and password that allows for record traceability. Thus, the 
system, and subsequently any investigative reviews, can identify coordinators, investigators, and 
individuals who have entered or modified records.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors for completeness and acceptability. The sponsor or its designee will be 
permitted to review the subject’s medical and hospital records pertinent to the study to ensure 
accuracy of the eCRFs. The completed original eCRFs are the sole property of the sponsor and 
should not be made available in any form to third parties, except for authorized representatives of 
appropriate governmental health or regulatory authorities, without written permission of the 
sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, source worksheets, all original signed and dated informed 
consent forms, subject authorization forms regarding the use of personal health information 
(if separate from the informed consent forms), and detailed records of drug disposition to enable 
evaluations or audits from regulatory authorities, the sponsor or its designees. Each study site will 
have access to the study data in Medidata until they receive a CD of all subject data in PDF format 
after database lock. Furthermore, International Conference on Harmonisation (ICH) 4.9.5 requires 


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the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH 4.9.5 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to the first subject enrolled. 
This document will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives.
A periodic blind data review will be conducted prior to unblinding of subject’s treatment 
assignment. This review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
The primary endpoint and all other analyses by treatment group will be analyzed according to the 
randomized treatment using the Full Analysis Set (FAS). The FAS will consist of all subjects who 
were randomized and received at least one dose of double-blind study medication. If a subject 
reports a composite MACE after treatment discontinuation, then the reported event will be counted 
toward the treatment to which they were randomized.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics (eg, age, race, gender, height, weight, body mass index 
[BMI], sUA) will be summarized using descriptive statistics for each treatment group and overall 
(eg, mean, SD, median, minimum, and maximum values, and the number and percent of subjects 
in specified categories). For categorical variables (eg, race, gender) the number and percent of 
subjects in specified categories will be presented. Unless otherwise specified, descriptive statistics 
on continuous variables (eg, age, height, weight, BMI, sUA) will consist of the number of subjects 
(N), mean, SD, minimum, 25th percentile, median, 75th percentile, and maximum. Gout history and 
CV history will also be summarized.
13.1.3 Safety Analyses
Safety will be assessed by evaluating the incidence of adverse events including pre-defined 
MACE, laboratory tests and vital signs. A blinded CV Endpoints Committee will adjudicate each 
death and selected serious cardiovascular adverse event to determine if the event meets the MACE 
criteria.
13.1.3.1 CV Safety Analysis
Assuming constant proportional hazards, the hazard ratio for the primary endpoint will be 
computed based on febuxostat and allopurinol estimated hazard rates. The febuxostat treatment 
group will be compared to the allopurinol treatment group to test for non-inferiority in the MACE 
composite rate using a Cox proportional hazards model with treatment and baseline renal function 
as factors in the model. Non-inferiority of febuxostat to allopurinol will be declared at an interim 
or at the final analysis if the current upper 1-sided CI for the hazard ratio calculated with critical 


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values obtained using the Lan-DeMets-O’Brien-Fleming alpha spending function, which 
preserves an overall 1-sided false-rejection rate of 2.5%, is less than 1.3.
Analysis of the secondary and other cardiovascular endpoints will be conducted similarly using a 
Cox proportional hazards model. No adjustments will be made for multiplicity.
Additional analysis on the primary safety endpoint will be performed using Cox-proportional 
hazards model controlling for the effect of NSAIDs use. The model will include treatment group, 
baseline renal function, and use of NSAIDs as explanatory variables. A similar analysis will 
control for the effect of low-dose aspirin use.
13.1.3.2 Other Safety Analysis
Treatment-emergent AEs will be summarized using the MedDRA coding dictionary. In general 
AEs will be tabulated at each of the following levels: overall summary (subject with at least 1 AE), 
the MedDRA system organ class (SOC), the MedDRA high level term (HLT), and the MedDRA 
preferred term (PT). Tabulations at each level of a term will present count (n) and percentage of 
subjects reporting any event for that term. Subjects reporting more than one occurrence for the 
term (level) being summarized will be counted only once.
13.1.4 Efficacy Analysis
The percentage of subjects whose average sUA level during the period from the end of the first 
year of treatment to the end of the study will be summarized, using the following categories
<4.0 mg/dL, ≥4 to <5.0 mg/dL, ≥5 to <6.0 mg/dL, and ≥6.0 mg/dL.
The flare rate from the end of the first year of treatment to the end of the study will be summarized 
by the average sUA level during the period from the end of the first year of treatment to the end of 
the study, using the following categories <4.0 mg/dL, ≥4 to <5.0 mg/dL, ≥5 to <6.0 mg/dL, and 
≥6.0 mg/dL. Flare rate will be calculated as the number of flares from the end of the first year of 
treatment to the end of the study divided by the length of time on treatment during the period after 
the first year and through the end of the study.
The percentage of subjects with tophi resolution by the end of Year 1, 2, 3, and 4 will be 
summarized by the average sUA level during the period from the end of the first year of treatment 
to the end of the study, using the following categories <4.0 mg/dL, ≥4 to <5.0 mg/dL, ≥5 to 
<6.0 mg/dL, and ≥6.0 mg/dL. The estimate for tophi resolution rate will be calculated for each 
average post-baseline sUA category using the life-table method. In calculating the percentage of 
subjects with tophi resolution by average post-baseline sUA, yearly intervals will be used in the 
life-table analysis.
13.2
Interim Analysis and Criteria for Early Termination
This study is designed to have a maximum of 624 MACE for assessing non-inferiority of 
febuxostat relative to allopurinol with regard to cardiovascular risk assuming a true hazard ratio of 
1.0 and 90% power. Interim analyses will be conducted when approximately 25%, 50% and 75% 
of the events or equivalently approximately 156, 312, and 468 events have occurred, followed by a 


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final analysis. In this group sequential trial with 4 equally-spaced analyses and a one-sided overall 
significance level of 0.025, the Lan-DeMets alpha spending approach with an O’Brien-Fleming 
stopping boundary will be used. Therefore, at the 3 interim and at the final analyses, one-sided 
confidence intervals for the hazard ratio of febuxostat relative to allopurinol for the primary 
endpoint will be constructed using critical values obtained using the Lan-DeMets 
-O’Brien-Fleming alpha spending function. At each analysis, if the upper one-sided confidence 
limit of the hazard ratio is less than 1.3, the study will be stopped and the non-inferiority of 
febuxostat relative to allopurinol with regard to cardiovascular risk will be declared.
Periodically during the course of the study, a blinded assessment of the annual adjudicated MACE 
rate will be made. The number of subjects planned to be enrolled in this study was based on an 
event rate of 2.8%, which was based on limited information. Based on the overall blinded MACE 
rate observed, an assessment will be made to determine whether or not to adjust the number of 
subjects planned for enrollment.
13.3
Determination of Sample Size
A total of 7500 subjects (3750 per treatment group) are planned to be enrolled into this study. This 
sample size provides at least 90% power to meet a noninferiority margin of 1.3 for the hazard ratio 
(febuxostat relative to allopurinol) for the primary endpoint, assuming a true hazard ratio of 1.0, at 
a 1-sided 2.5% significance level. This study is designed to have a maximum of 624 MACE.
For the determination of noninferiority between the febuxostat treatment group and the allopurinol 
treatment group, the sample size calculation used the following assumptions: 

Constant proportional hazards and exponential survival curves.

Annual adjudicated MACE rate of 2.8%.

Maximum length of participation of 5 years.

Accrual time of 2.5 years.

Annual drop-out rate of 10%.
These assumptions were used prior to the initiation of the study to calculate the number of subjects 
to be enrolled in order to obtain the required number of MACE.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or EC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or EC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria.
14.3
Quality Assurance and Regulatory Agency Audits
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments. If the study site is contacted for an inspection by a regulatory body, 
the sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonized Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B.
15.1
Regulatory Authority and IRB and/or EC Approval
IRBs and ECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or EC. If any member of the IRB or EC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those US sites unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
EC for the protocol’s review and approval. This protocol, the Package Insert [14], a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB or EC for approval. The IRB’s or EC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug). The IRB or EC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date.
Sites must adhere to all requirements stipulated by their respective IRB or EC. This may include 
notification to the IRB or EC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or EC, and submission of the investigator’s final status report to IRB or EC. All 
IRB and EC approvals and relevant documentation for these items must be provided to the sponsor 
or its designee.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations (Appendix B). The informed consent form, subject authorization 
form (if applicable), and subject information sheet (if applicable) describe the planned and 
permitted uses, transfers, and disclosures of the subject’s personal and personal health information 
for purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 


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requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or EC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or EC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or EC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subjects should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator must 
also sign and date the informed consent form and subject authorization (if applicable) at the time of 
consent and prior to subject entering into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised informed consent 
form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.


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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the Food and Drug Administration [FDA]), the sponsor’s designated 
auditors, and the appropriate IRBs and ECs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, ECG 
reports, admission and discharge summaries for hospital admissions occurring during a subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During the study, only the sponsor may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
If the study is being conducted as part of a multicenter clinical study, data from all sites 
participating in the study will be pooled and analyzed by the sponsor or the sponsor’s designee. 
The first publication of the study results shall be made in conjunction with the results from other 
study sites as a multicenter publication. If a multicenter publication is not forthcoming within 
24 months of completion of the study at all sites, the investigator may publish or present the results 
generated at his or her site.
The investigator will provide the sponsor with a copy of any proposed publication or presentation 
for review and comment at least 60 days prior to such presentation or submission for publication. 
The sponsor shall inform the investigator in writing of any changes or deletions in such 
presentation or publication required to protect the sponsor’s confidential and proprietary technical 
information and to address inaccurate data or inappropriate interpretations in the context of any 
pooled multicenter results. At the expiration of such 60-day period, the investigator may proceed 
with the presentation or submission for publication unless the sponsor has notified the institution 
or the investigator in writing that such proposed publication or presentation discloses the sponsor’s 


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confidential and proprietary technical information. Further, upon the request of the sponsor, the 
investigator will delay the publication or presentation for an additional 90 days to permit the 
sponsor to take necessary actions to protect its intellectual property interests.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum register all 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. Takeda contact information, along with 
investigator’s city, state (for US investigators), country, and recruiting status will be registered and 
available for public viewing.
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov or 
other publicly accessible websites, as required by applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject participating in the study must be insured in accordance with the regulations 
applicable to the site where the subject is enrolled. If a local underwriter is required, then the 
sponsor or sponsor’s designee will obtain clinical study insurance against the risk of injury to 
clinical study subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy 
on subject compensation and treatment for injury. If the investigator has questions regarding this 
policy, he or she should contact the sponsor or sponsor’s designee.


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16.0
REFERENCES
1. Becker Ma, Schumacher Hr Jr, Wortmann Rl, Macdonald Pa, Eustace D, Palo Wa, et al. 
febuxostat compared with allopurinol in subjects with hyperuricemia and gout. n engl j med
2005;353(23):2450-61.
2. Becker MA, Schumacher HR, MacDonald PA, Lloyd E, Lademacher C. Clinical efficacy and 
safety of successful long-term urate lowering with febuxostat or allopurinol in subjects with 
gout. J Rheumatol 2009;36(6):1273-82.
3. Kim KY, Ralph Schumacher H, Hunsche E, Wertheimer AI, Kong SX. A literature review of 
the epidemiology and treatment of acute gout. Clin Ther 2003;25(6):1593-617.
4. Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects 
of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with 
hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial 
Arthritis Rheum 2008;59(11):1540-8.
5. Schumacher HR Jr, Becker MA, Lloyd E, MacDonald PA, Lademacher C. Febuxostat in the 
treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology 
(Oxford) 2009;48(2):188-94.
6. White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis 
trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003;92(4):411-8.
7. Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for 
prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 
2004;31:2429-2432.
8. Ioachimescu AG, Brennan DM, Hoar BM, Hazen SL, Hoogwerf BJ. Serum uric acid is an 
independent predictor of all-cause mortality in subjects at high risk of cardiovascular disease: 
A preventive cardiology information system (PreCIS) database cohort study. Arthritis Rheum 
2008;58(2):623-630.
9. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular 
disease and death: the Framingham Heart Study. Ann Intern Med 1999;131(1):7-13.
10. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I 
epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination 
Survey. JAMA 2000;283(18):2404-10.
11. Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF. Preliminary criteria for 
the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20(3):895-900.
12. ColcrysTM (colchicine) tablets Package Insert. URL Pharma, Inc. (current version).
13. Gaffo A, Schumacher HR, Saag K, Taylor W, Allison J et al. Developing American College of 
Rheumatology and European League against Rheumatism Criteria for definition of a flare in 
patients with gout. Arthritis Rheum 2009;Abstract 1508.


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CONFIDENTIAL
14. Uloric® (febuxostat) tablets Package Insert, Takeda Pharmaceuticals America, (current 
version).
15. Prevacid (lansoprazole) tablets Package Insert, Takeda Pharmaceuticals America (current 
version).
16. Naproxen tablets Package Insert, 
 (current version).
17. Allopurinol tablets Package Insert, 
. (current version).
PPD
PPD


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Appendix A
Schedule of Study Procedures
Procedure
Screen
-ing 
Visit
Day 
1
Wk
2
Wk 
4
Wk 
6
(a)
Wk 
8
Wk 
10 
(a)
Mon 3
Mon 
6
Mon 
9
(b)
Mon 12 
and 
Every 
6 Mos 
Until 
End of 
Study/ 
DoT/ET
Mon 
15
(b)
End of 
Study/ 
DoT/ 
Early 
Termin-
ation
Visit window
Day -7 
to 
Day -1
(± 3 
Days)
(±3 
Days)
(±3 
Days)
(±3 
Days)
(±3 
Days)
(-3 
Days)
(±3 
Days)
(±7 
Days)
(±7 
Days
(±7 
Days)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics
X
Access IVRS/IWRS
X
X
X
X
X
X
X
X
Physical examination
X
X(c)
X
Medical, social, and CV 
history
X
Medication history
X
Concurrent medical 
conditions
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight (d)
X
X
Height
X
Tophus assessment (e)
X
X
X
Pretreatment event 
assessment (f)
X
X
AE assessment (g)
X(h)
X
X
X
X
X
X
X
X
X
X
X
X
Gout flare assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessment (i)
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessment 
(fasting) (j)
X
X
X
12-lead ECG
X
X
Dispense study medication
X
X
X
X
X
X
Concomitant medication 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense prophylaxis (k)
X(l)
X(m
)
X
Collect unused prophylaxis
X
X
X (n)
Collect unused study 
medication
X
X
X
X
X
X
Educate subject on CV 
events and gout flare 
reporting (o) and possibility 
of obtaining the prescription 
card to obtain the medication 
to treat gout flare (p)
X
X
X
X
X
X
X
X
X
X
X
X
Dispense prescription for 
additional gout flare 
medication
X
Compliance assessment
X(l)
X
X
X
X
X
X
X
X
X
X
X
Verify subject’s contact 
information.
X
X
X
X
X
X
X
X
X
X
X
Follow-up contact (q)
X
Review Gout Flare Brochure
X
X
Review Retention Program 
(r)
X
Footnotes are on last table page.


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(a) Visit will occur only if the sUA≥6.0 mg/dL.
(b) Visits at Months 9 and 15 will occur only for elderly subjects (≥65 at the time of signing the ICF) and/or moderately renally 
impaired (eCLcr ≥30 but <60 mL/min).
(c) After Month 12, physical examinations will be performed annually until End of Study/DoT/Early Termination. 
(d) Weight will be measured at Screening and End of Study/DoT/Early Termination.
(e) For those subjects with tophi present, assessments will be done at Day 1, Month 12, and annually thereafter until End of 
Study/DoT/Early Termination.
(f) Collection of Pretreatment Events starts at informed consent and ends at first dose of prophylaxis or double-blind study 
medication, whichever comes first. 
(g) Collection of Adverse Events starts at first dose of prophylaxis or double-blind study medication, whichever comes first.
(h) For subjects who are dispensed prophylaxis at Day -7. If not dispensed prophylaxis at Day -7, AE collection begins at Day 1.
(i) Laboratory assessment: hematology (done only at Screening), urinalysis (done only at Screening), fasting lipid panel (done only 
at Day 1), INR, prothrombin and activated partial thromboplastin for subjects receiving warfarin (done at Screening and annually). 
Chemistry Panel 18 (at every visit): ALT, AST Albumin, Alkaline phosphatase, Total bilirubin, Total protein, Creatinine, Blood 
urea nitrogen, Creatine kinase, γ-Glutamyl transferase, Potassium, Sodium, Calcium, Magnesium, Glucose, Serum urate, 
Triglycerides, and Cholesterol.
(j) Fasting labs required at Day 1/Randomization Visit, Month 12, and annually thereafter until End of Study/DoT/Early 
Termination. However, if the subject is not fasting, assessment should still be conducted.
(k) Subjects currently on febuxostat, allopurinol, or other uricosuric agents will discontinue these medications starting at Day -7 
visit and begin the washout period. Subjects are expected to remain on TDC provided open-label prophylaxis medication until the 
end of Month 6.
(l) Subjects discontinuing prior ULT at Day -7.
(m) Subjects not taking ULTs 
(n) Only when DoT or Early Termination Visit done.
(o) Flare assessment information reported by the subject will be collected by the site personnel onto the gout flare worksheet and 
later transcribed to the eCRF.
(p) The prescription card is available in the US only to treat the gout flare past Month 6 Visit for currently randomized subjects.
(q) Subjects discontinuing study medication treatment (but have not withdrawn consent) prior to the end of study will be contacted 
every 2 months (±10 days) to determine if any potential CV events have occurred. Further, sites will ask the subject if they have 
taken any new medications (OTC or prescription) since the last contact, or have stopped taking any ongoing medications recorded 
at the last contact. If yes, the generic medication name, start date, and end date will be recorded on the eCRF.
Sites will also ask the subject at each contact if they have had any SAEs since the last contact. If yes, these will be recorded on the 
AE eCRF, and sites should follow the instructions in the Protocol Section 10.2.2, Collection and Reporting of SAEs. All SAEs 
should be followed up until resolution or permanent outcome of the event.
(r) Retention Program is available in the US and Canada.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572 or Site Registration Form),
which must be completed and signed before the investigator may participate in this study.
In signing a Form FDA 1572 or Site Registration Form the investigator agrees to assume the 
following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
4. Secure prior approval of the study and any changes by an appropriate IRB/EC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
5. Ensure that the IRB/EC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/EC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/EC, and issue a final report within 3 months of study completion.
6. Ensure that requirements for informed consent, as outlined in 21 CFR Party 50, ICH and local 
regulations, are met.
7. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Each informed consent form should contain 
a subject authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
8. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
9. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
10. Maintain current records of the receipt, administration, and disposition of study medication, 
and return all unused study medication to the sponsor.


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11. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 1 working day.


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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The approximate number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/EC, 
and the monitor may inspect the records. By signing a written Informed Consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/EC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 


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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing partners; 
(3) regulatory agencies and other health authorities; and (4) IRBs/ECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer subjects 
the same level of protection as the data protection laws within this country; however, Takeda 
will make every effort to keep your personal information confidential, and your name will not 
be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to Takeda’s 
research databases for purposes of developing a better understanding of the safety and 
effectiveness of the study medication(s), studying other therapies for subjects, developing a 
better understanding of disease, and improving the efficiency of future clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information (including 
personal health information) upon withdrawal from the study to the extent that the restricted 
use or disclosure of such information may impact the scientific integrity of the research; and
e) that the subject’s identity will remain confidential in the event that study results are published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active will not be eligible for enrollment into this study. If a subject is found 
to be pregnant during study, study medication will be discontinued and the investigator will 
offer the subject the choice to receive unblinded treatment information.


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and ECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting study details and results on publicly accessible clinical trial registries, databases, and 
websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Worksheet for All Potential Cardiovascular (CV) Events (sample)
Cardiovascular History
Initial___________ Follow-up ______________
TO: TDC Pharmacovigilance
FAX: (country specific number) 
Protocol Number: ______________________
Investigator Name/Site Number: ______________________ Subject No/Initials: 
Adverse Event (diagnosis): ___________________________________
Brief description of cardiovascular event:
When applicable, please provide the following for all events:
Pertinent laboratory results (with reference lab values), imaging and cardiac testing reports
Hospital admission notes and relevant hospital records related to the event
Surgical, consultant and pathology reports
Hospital discharge summary
If a potential MI event (eg, MI, Chest Pain, Silent MI, ECG Changes, Ischemia, Shortness of Breath)
Cardiac enzymes (CPK-MB and/or troponin with reference values)
ECG (pre-treatment and related documentation)
Description of clinical signs and symptoms
Cardiology consultation notes
If a potential STROKE event (eg, Ischemic Stroke, Cerebral Hemorrhage, TIA)
CT or MRI images and results
Other relevant tests and duration of neurological signs and symptoms
Description of neurologic signs and symptoms
Neurology consultation notes
If a potential ANGINA event (eg, Unstable Angina, Chest Pain)
Cardiac biomarkers with reference ranges
ECG (pretreatment and all other tracings related to the event)
Other relevant tests (stress tests, cardiac catheterization) and duration of symptoms of ischemia
Coronary revascularization procedure records


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Protocol Number: ______________________
Investigator Name/Site Number: ______________________ Subject No/Initials: 
If a potential CORONARY REVASCULARIZATION (eg, Angioplasty or Coronary Bypass Graft 
surgery)
Coronary revascularization procedure records
If a potential CEREBRAL REVASCULARIZATION
Revascularization procedure records
If a potential VENOUS AND PERIPHERAL ARTERIAL VASCULAR THROMBOTIC event (eg, 
Pulmonary Embolism, DVT, Thrombosis, Ischemia)
Evidence of embolism (eg, CT angiography)
Evidence of occlusion (eg, Doppler studies)
If a potential CONGESTIVE HEART FAILURE event (eg, Dyspnea, Shortness of Breath, Pulmonary 
Edema)
Physical examination and auscultatory findings
Radiographic documentation
Echocardiographic documentation
Cardiology Consultation Notes with documentation of parenteral therapy
If a potential ARRYTHMIA event (eg, atrial fibrillation, ventricular tachycardia)
Pre-treatment ECG and all other ECGs related to the event
Clinical history
Other relevant hospital records (please list):
Investigator Signature _______________________________      Date _________________


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Appendix F
Rash Adverse Event Worksheet (sample)
Rash Adverse Event Worksheet
Investigator Name/Number: ______________________Protocol Number: TMX_67-________________
Subject Initials/Number:
Date of Subject Contact:
Date of Onset:
End Date:
Description of Rash (check all that apply):
ERYTHEMATOUS
MACULAR
BULLOUS
PAPULAR
EXFOLLIATIVE
VESICULAR
CONTACT DERMATITIS
OTHER (specify):_________________
Location (check all that applies):
TRUNK
FACE
NECK EXTREMITIES →
Study medications Discontinued → 
Yes 
No
Concurrent Medication: List Medication(s)
Medication
Dose
Units
Freq.
Route
Start/Stop Date
Reason for Use
/
/
Medication Used To Treat → 
Yes 
No
If Yes List Medication(s)
Medication
Dose
Freq.
Route
Start/Stop Date
Was this effective?
/
/
Laboratory Test Done? → 
Yes 
No
If Yes, which one:
CBC
PLATELET
CHEMISTRY
OTHER:
Physician assessment of the likelihood that this episode is related to blinded study medication:
YES
NO
________________________________________
_________
Signature of Person Completing Assessment 
Date
This form must be completed and faxed to TDC within 48 hours of site knowledge of the event:
Attention: Rash Worksheet Coordinator
FAX number: (country specific number)


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Appendix G
Gout Flare Assessment Worksheet (sample)
GOUT FLARE ASSESSMENT WORKSHEET
PLEASE RECORD INFORMATION FOR ONLY ONE SITE OF A GOUT FLARE PER PAGE!
Protocol Number: TMX-67_____________________________________________________________
Investigator Name/Number: _____________________________________________________________
Subject Initials/Number: ________________________________________________________________
Date of Subject Contact:__________________________________
Date of Onset of the Gout Flare:
__________
Name and dose of prophylaxis at the time of event (if applicable):____
Medications taken to relieve symptoms associated with current gout flare:
Medication
Dose
Freq.
Route
Start/Stop Date
Has this been helpful so far?
/
/
yes                      no
/
yes                      no
Site of gout attack (CHECK ONLY ONE, record each additional site on a separate worksheet):
Specify right or left and specific joint involved.
FIRST TOE
ANKLE
OTHER TOES
KNEE
WRIST
INSTEP
ELBOW
OTHER (specify):____________________
HAND
Signs/Symptoms (Check all that apply):
Swelling :        
mild  
moderate 
severe
Redness:          
mild  
moderate 
severe
Joint Warmth :   
mild  
moderate 
severe
Tenderness:     
mild  
moderate 
severe
Other (specify):____________________
Using the scale below, ask the subject to rate the worst pain, of the current gout flare, at rest, with 0=no pain 
at rest and 10=worst possible pain at rest. (Please circle their response):
0
1
2
3
4
5
6
7
8
9
10
no pain at rest
worst possible pain at rest
Current gout flare compared to all previous gout flares in any joint:
definitely similar
probably similar
possibly similar
not similar at all
______________________________________________
___________
Signature of Person Completing Assessment
Date


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Protocol Number: TMX-67____________________________________________________________
Investigator Name/Number:____________________________________________________________
Subject Initials/Number:______________________________________________________________
PHYSICIAN ASSESSMENT
Was additional medication prescribed to treat the gout flare?
Yes:
No
Medication Name:_________________________
Dose ___________Freq.________Route________
Physician assessment of the likelihood that this episode is a true gout attack:
Definitely
Probably
Possibly: Alternative etiology:_____________________________________________________________
Probably Not: Alternative etiology:_________________________________________________________
Date of Full Resolution of Flare: __________________________
Comments:
________________________________________
_____________
Signature of Investigator
Date


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Gout Flare Assessment Worksheet (continued)
Guideline for assessing signs and symptoms:
Tenderness
Mild
- subject states tender
Moderate 
- subject winces
Severe 
- subject withdraws
Swelling
Mild
- just detectable
Moderate
- obvious swelling of the joint
Severe
- swelling beyond the joint
Warmth
Mild
- detectable compared to contralateral joint
Moderate
- obviously warmer
Severe
- Hot
Redness
Mild 
- slightly darker than contralateral joint
Moderate 
- obviously darker
Severe
- bright red


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Appendix H
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 6.
Pages 1, 2, 11, 16, 17, 19, 40, 86, 92, 94
Universal update to protocol to update the name of the Sponsor from Takeda Global Research & 
Development Center, Inc. (TGRD) to Takeda Development Center Americas, Inc. (TDC).
Page 2, Section 1.1 Contacts
Existing Text
Medical monitor (medical 
advice on protocol, 
compound and medical 
management of subjects)
Responsible medical 
officer (carries overall 
responsibility for conduct 
of study)
Revised Text
Medical monitor (medical 
advice on protocol, 
compound and medical 
management of subjects)
Responsible medical 
officer (carries overall 
responsibility for conduct 
of study)
Rationale for Amendment
Update to Contacts to reflect change in Medical Monitor and Responsible Medical Officer, and the 
addition of a backup Medical Monitor.
Page 3, Section 1.2 Approval
Existing Text
Date
Date
PPD
PPD
PPD
PPD


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Revised Text
Date
Date
Rationale for Amendment
Update to reflect change in Medical Director and Clinical Study Manager.
Page 11, Section 2.0 Study Summary, Study Design
Page 25, Section 6.1 Study Design
Page 30, Section 6.2 Justification for Study Design, Dose, and Endpoints
Page 56, Section 9.3 Schedule of Observations and Procedures
Existing Text
The length of the study is expected to be approximately 5 years.
Revised Text
The length of the study is expected to be approximately 9 years.
Rationale for Amendment
Slower than expected enrollment duration has extended the overall length of the study.
Page 12, Section 2.0 Study Summary, Study Design
Page 26, Section 6.1 Study Design
Page 86, Appendix A Schedule of Study Procedures, footnote (b)
Existing Text
In addition, subjects with moderate renal impairment (eCLcr <60 mL/min) and/or subjects…
Revised Text
In addition, subjects with moderate renal impairment (eCLcr ≥30 but <60 mL/min) and/or 
subjects…
Rationale for Amendment
Clarification to creatine clearance criteria that includes the lower acceptable bound as determined 
by study exclusion criteria.
Page 12, Section 2.0 Study Summary, Study Design
Page 72, Section 11.2 CV Endpoints Committee
Existing Text
An Independent Cardiovascular (CV) Endpoints Committee will prospectively review all 
suspected CV events using blinded data. All investigational sites will be required to collect 
relevant clinical information required for adjudication of all deaths and potential CV AEs.
PPD
PPD


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Revised Text
An Independent Cardiovascular (CV) Endpoints Committee will prospectively review all 
suspected serious CV events using blinded data. All investigational sites will be required to collect 
relevant clinical information required for adjudication of all deaths and potential CV SAEs.
Rationale for Amendment
Non-serious adverse events are not likely to be adjudicated to a MACE endpoint and the FDA 
agreed to remove the requirement for adjudication of non-serious events.
Page 12, Section 2.0 Study Summary, Study Design
Page 26, Section 6.1 Study Design
Page 87, Appendix A Schedule of Study Procedures, footnote (q)
Existing Text
Subjects who are withdrawn from study medication treatment but have not withdrawn consent will 
be followed for the duration of the study or until the subject experiences a CV event that is 
positively adjudicated as a MACE via phone calls every 2 months.
Revised Text
Subjects who are withdrawn from study medication treatment but have not withdrawn consent will 
be contacted every 2 months for the duration of the study or until the subject experiences a CV 
event that is positively adjudicated as a MACE.
Rationale for Amendment
Renamed follow-up contact procedure to indicate flexibility in method of contacting subjects.
Page 13, Section 2.0 Study Summary, Duration of Treatment
Existing Text
[T]he maximum length of participation is expected to be approximately 5 years.
Revised Text
[T]he maximum length of participation is expected to be approximately 9 years.
Rationale for Amendment
Slower than expected enrollment duration has extended the overall length of the study.
Page 13, Section 2.0 Study Summary, Period of Evaluation
Existing Text
Maximum of 5 years treatment duration.
Revised Text
Maximum of 9 years treatment duration.


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Rationale for Amendment
Slower than expected enrollment duration has extended the overall length of the study.
Page 15, Section 2.0 Study Summary, Sample Size Justification
Page 77, Section 13.3 Determination of Sample Size
Added Text
These assumptions were used prior to the initiation of the study to calculate the number of 
subjects to be enrolled in order to obtain the required number of MACE.
Rationale for Amendment
To clarify the observed information from the ongoing study may no longer be consistent with the 
assumptions used to calculate sample size.
Page 16, Section 3.1 Study-Related Responsibilities
Added Text
Clinical supply return
Rationale for Amendment
Updated to include additional clinical trial material return facility.
Page 27, Section 6.1 Study Design
Existing Text
All investigational sites will be required to collect relevant clinical information required for 
adjudication of all deaths and potential CV AEs.
Revised Text
All investigational sites will be required to collect relevant clinical information required for 
adjudication of all deaths and potential CV SAEs.
Rationale for Amendment
Non-serious adverse events are not likely to be adjudicated to a MACE endpoint and the FDA 
agreed to remove the requirement for adjudication of non-serious events.
PPD
PPD


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Page 28, Figure 6.a
Page 34, Section 7.3.2 Excluded Medications and Treatments
Page 46, Section 8.5 Unblinding
Page 48, Section 9.1.3 Physical Examination Procedure
Page 49, Section 9.1.4 Weight and Height Procedure
Page 49, Section 9.1.6 Documentation of Concomitant Medications
Page 51, Section 9.1.10 ECG Procedure
Page 54, Section 9.1.17 Physical Assessment of Tophi
Page 85, Appendix A Schedule of Study Procedures, table and footnotes
Existing Text
Final Visit/End of Treatment/Early Termination Visit
Revised Text
End of Study/Discontinuation of Treatment/Early Termination Visit
Rationale for Amendment
Revised visit name to more accurately reflect the purpose and procedures being performed; and to 
delineate the differences between the three visit types.
Page 32, Section 7.1 Inclusion Criteria
Added Text
5. The subjects must have either:

a sUA level ≥7.0 mg/dL (≥416 µmol/L) at the Screening Visit OR

a sUA level ≥6.0 mg/dL (≥354 µmol/L) at the Screening Visit AND inadequately 
controlled gout (≥1 flare in the 12 months prior to screening and/or the presence of tophi).
Rationale for Amendment
Added International System of Units (SI) to aid ex-US sites, who are more familiar with, and tend 
to maintain patient records in SI units, in quickly and accurately determining entry criteria for 
serum uric acid levels.
Page 34, Section 7.3 Required Medications and Treatments
Existing Text
Subjects randomized to allopurinol, with normal renal function or mild renal impairment 
(eCLcr ≥30 but ≥60 mL/min) will initially receive allopurinol 300 mg QD with the dose increased 
in 100 mg increments monthly until either a sUA <6.0 mg/dL or a maximum allopurinol dose of 
600 mg QD is achieved. 
Revised Text
Subjects randomized to allopurinol, with normal renal function or mild renal impairment (eCLcr
≥60 mL/min) will initially receive allopurinol 300 mg QD with the dose increased in 100 mg 


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increments monthly until either a sUA <6.0 mg/dL or a maximum allopurinol dose of 600 mg QD 
is achieved.
Rationale for Amendment
Removed eCLcr ≥30 mL/min as this was not the correct range for normal or mild renal 
impairment.
Page 37, Section 7.4 Procedures for Discontinuation from the Study Drug Treatment with 
Continued Participation in the Study via Follow-up Contacts
Existing Text
(Section 7.4)
Subjects who discontinue study drug treatment will continue to participate in the study through 
Telephone Contacts unless consent is withdrawn by the subject or until the subject experiences a 
CV event that is positively adjudicated as a MACE.
The primary reason for permanent discontinuation of study drug treatment should be noted using 
the following categories:
1. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.
NOTE: Subjects who experience ALT or AST >3xULN in conjunction with elevated total 
bilirubin >2×ULN and satisfy the following 2 criteria: (1) The liver injury is hepatocellular in 
nature and there is not a prominent cholestatic component, or (2) there is no more likely 
alternative cause than drug induced liver injury, such as acute viral hepatitis A or B, or other 
acute liver disease, should be permanently discontinued from the study drug treatment.
2. Major protocol deviation. The discovery post randomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unnecessary risk to the subject’s health.
3. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from taking study drug treatment. The reason for withdrawal, if provided, should be 
recorded in the eCRF.
NOTE: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded.
4. Pregnancy. The subject is found to be pregnant
5. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. Before a subject is 
considered lost to follow-up, a minimum of 2 documented telephone contact attempts and 
1 certified letter within 4 weeks of the most recently missed study visit must be sent in an effort 
to contact the subject.
6. Study termination. The sponsor, IRB, ethics committee (EC), or regulatory agency terminates 
the study.


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7. Other. The specific reasons should be recorded in the “specify” field of the eCRF.
The primary reason that the subject prematurely discontinued study drug should be listed on the 
End of Study Drug page of the eCRF. End of Study Drug eCRF should be completed when the 
subject discontinues study medication or completes the full cycle of study medication; end of 
Study Drug eCRF completion is independent of the decision to continue participation in the study 
via telephone contacts.
Efforts will be made to avoid any subject being lost to follow-up during the conduct of the study. 
Investigators should refer to Section 9.0 for gout flare assessment and Section 9.1.15 for gout flare 
treatment.
(Section 7.5)
Subjects who stop taking study medication will continue in the study as long as consent is not 
withdrawn by the subject until the subject experiences a CV event that is positively adjudicated as 
a MACE, the required number of study MACE events have occurred, or until the study concludes. 
The contacts will occur via phone calls every 2 months.
In addition, efforts should be made to perform all procedures required as part of the Early 
Termination Visit when the subject discontinues study drug treatment, regardless of whether or 
not the subject continues participation in the study.
Further, at each telephone contact, sites will ask the subject if they have taken any new 
medications (OTC or Prescription) since the last contact, or have stopped taking any ongoing 
medications recorded at the last contact. If yes, the generic medication name, start date, and end 
date and reason for use will be recorded on the eCRF.
Sites will also ask the subject at each telephone contact if they have had any SAEs or any potential 
cardiovascular adverse events since the last telephone contact. If yes, these will be recorded on the 
AE eCRF, and sites should follow the instructions in the Protocol Section 10.2.2, Collection and 
Reporting of SAEs if applicable. All SAEs should be followed up until resolution or permanent 
outcome of the event.
Subjects who have withdrawn from study medication treatment but have not withdrawn consent 
will be followed until the subject experiences a CV event that is positively adjudicated as a MACE 
or until the study concludes. Subjects will be contacted by telephone every 2 months (±10 days) to 
determine if any potential CV events have occurred.
If the subject has had a potential CV event, he/she should bring the event related documents (labs, 
hospital discharge summary, etc) to the clinic.
If after two telephone attempts a subject cannot be reached, then the subject’s emergency person 
will be contacted. Before a subject is considered lost to follow-up, a minimum of two documented 
telephone contact attempts must have been made and 1 certified letter must have been sent within 
4 weeks of the most recently missed telephone call to the subject or emergency contact in an effort 
to contact the subject.


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Revised Text
Subjects who discontinue study drug treatment will continue to participate in the study through 
follow-up contacts unless: consent is withdrawn by the subject; the subject experiences a CV 
event that is positively adjudicated as a MACE (the study team will notify the site in writing 
when it is no longer necessary to follow the subject with a positive MACE adjudication); the 
required number of study MACE events have occurred; or until the study is ended. 
Follow-up contacts will occur every 2 months (±10 days).
The primary reason for permanent discontinuation of study drug treatment should be noted using 
the following categories:
1. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.
NOTE: Subjects who experience ALT or AST >3xULN in conjunction with elevated total 
bilirubin >2×ULN and satisfy the following 2 criteria: (1) The liver injury is hepatocellular in 
nature and there is not a prominent cholestatic component, or (2) there is no more likely 
alternative cause than drug induced liver injury, such as acute viral hepatitis A or B, or other 
acute liver disease, should be permanently discontinued from the study drug treatment.
2. Major protocol deviation. The discovery post randomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unnecessary risk to the subject’s health.
3. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from taking study drug treatment. The reason for withdrawal, if provided, should be 
recorded in the eCRF.
NOTE: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded.
4. Pregnancy. The subject is found to be pregnant
5. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 
6. Study termination. The sponsor, IRB, ethics committee (EC), or regulatory agency terminates 
the study.
7. Other. The specific reasons should be recorded in the “specify” field of the eCRF.
The primary reason that the subject prematurely discontinued study drug should be listed on the 
End of Study Drug page of the eCRF. End of Study Drug eCRF should be completed when the 
subject discontinues study medication or completes the full cycle of study medication; end of 
Study Drug eCRF completion is independent of the decision to continue participation in the study 
via follow-up contacts.


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These subjects should undergo all procedures required as part of the Discontinuation of 
Treatment Visit when the subject stops study drug treatment. In the event that these 
subjects later withdraw consent from participation in the study, an additional final Early 
Termination visit does not need to be performed.
At each follow-up contact, sites will ask the subject if they have taken any new medications (over 
the counter or prescription) since the last contact, or have stopped taking any ongoing medications 
recorded at the last contact. If yes, the generic medication name, start date, and end date and reason 
for use will be recorded on the Medication Information Obtained During Follow-up Contact 
eCRF.
Sites will also ask the subject at each follow-up contact if they have had any serious adverse events 
(SAEs) or any potential cardiovascular adverse events since the last contact. If yes, these will be 
recorded on the AE eCRF, and sites should follow the instructions in the Protocol Section 10.2.2, 
Collection and Reporting of SAEs if applicable. All SAEs should be followed up until resolution 
or permanent outcome of the event.
If the subject has had a potential serious CV event, he/she should bring the event related 
documents (labs, hospital discharge summary, etc) to the clinic. The study team will notify the 
site in writing upon a positive MACE adjudication when it is no longer necessary to follow a 
subject.
Efforts will be made to prevent any subject being lost to follow-up during the conduct of the 
study. Investigators should refer to Section 9.0 for gout flare assessment and Section 9.1.15
for gout flare treatment. Before a subject is considered lost to follow-up, a minimum of two 
documented telephone contact attempts must have been made and one certified letter must 
have been sent within 4 weeks of the most recently missed telephone call to the subject 
and/or emergency contact in an effort to contact the subject.
Rationale for Amendment
Combined two sections (7.4 and 7.5) from previous protocol version to clarify and aid in proper 
protocol for DoT subjects; which includes adding all instances where a DoT subject will no longer 
be followed. Clarify the expectations for attempted contacts with subjects who are lost to 
follow-up. Renamed follow-up contact procedure to indicate flexibility in method of contacting 
subjects.
Page 38, Section 7.5 Procedures for Early Termination of a Subject from the Study (Both 
Drug and Visits)
Existing Text
A subject’s study medication may be temporarily suspended or permanently ceased at any time at 
the discretion of the Investigator. 
If consent is withdrawn for continued participation (ie, bimonthly phone calls) after discontinuing 
study medication treatment, the primary reason for discontinuation of study participation should 
be noted using the following categories:


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1. Adverse Event. The subject experiences a CV event that is positively adjudicated as a MACE.
Revised Text
A subject may discontinue his or her participation from the study without giving a reason at 
any time during the study. In addition, efforts should be made to perform all procedures 
required as part of the Early Termination Visit, even if the subject withdrew consent.
The primary reason for discontinuation of study participation should be noted using the following 
categories:
1. Adverse Event. A subject taking study medication has experienced a pretreatment event 
or AE that requires early termination because continued participation imposes an 
unacceptable risk to the subject’s health or the subject is unwilling to continue because 
of the event. Also applies to subjects no longer taking study medication who are in 
follow-up who experience a serious CV event that is positively adjudicated as a MACE. 
NOTE: this reason is not intended to be selected for subjects in follow-up experiencing 
non-MACE AEs as these subjects can, and should, continue participation.
Rationale for Amendment
Updated section title to more accurately reflect the content of the section. Corrected language 
around early termination due to AEs. Renamed follow-up contact procedure to indicate flexibility 
in method of contacting subjects.
Page 40, Section 8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling
Page 44, Section 8.1.3 Dose and Regimen
Existing Text
Colchicine 0.6 mg tablets 
 or URL Pharma, Inc. 
/ Mutual Pharmaceutical Company, Inc., Philadelphia, PA) will be supplied in child resistant 
bottles containing 100 tablets each.
Naproxen (West-ward Pharmaceutical Corp., Eatontown, NJ) will be supplied in child resistant 
bottles with 100 tablets, each tablet containing 250 mg of naproxen.
Revised Text
Colchicine 0.6 mg tablets 
 or Takeda 
Pharmaceuticals America, Deerfield, IL [formerly URL Pharma, Inc. / Mutual Pharmaceutical 
Company, Inc., Philadelphia, PA]) will be supplied in child resistant bottles containing 100 tablets 
each.
Naproxen (
 or 
 
 India) will be supplied in child resistant bottles with 100 tablets, 
each tablet containing 250 mg of naproxen.
Rationale for Amendment
To reflect most recent manufacturing information.
PPD
PPD
PPD
PPD
PPD


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Page 46, Section 8.5 Unblinding Procedure
Page 86, Appendix A Schedule of Study Procedures
Existing Text
Telephone Contact
Revised Text
Follow-up contact
Rationale for Amendment
Renamed follow-up contact procedure to indicate flexibility in method of contacting subjects.
Page 46, Section 8.5 Unblinding Procedure
Added Text
For unblinding a subject, the investigational drug blind can be obtained by accessing the IVRS. 
Please refer to IVRS Unblinding Worksheet packet.
Rationale for Amendment
Added text to offer further guidance for finding instructions on how to unblind a subject in IVRS.
Page 49, Section 9.1.6 Documentation of Concomitant Medications
Added Text
Changes in medication for subjects that have discontinued treatment but remain in 
follow-up should be recorded on the Medication Information Obtained During Follow-up 
Contact eCRF, and not on the Concomitant Medications eCRF.
Rationale for Amendment
Provide further clarification and reminder to users about where to properly record concomitant 
medication information collected during follow-up contact calls. Renamed follow-up contact 
procedure to indicate flexibility in method of contacting subjects.
Page 50, Table 9.a footnotes
Existing Text
(c) Lipid panel fasting at Day 1, Months 12/24/36/48 & Final Visit/ET/EoT only.
Revised Text
(c) Lipid panel only at Day 1.
Rationale
Correction to protocol discrepancy whereas lipid panel testing was noted in Table 9.a as performed 
at Day 1 and then annually thereafter, but Appendix A noted the panel as being done at Day 1 only. 
Because the contracted central laboratory was only performing testing as designated in Appendix 


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A, this lipid panel was not being conducted for any subjects beyond Day 1, and it was determined 
that the appropriate correction was to maintain this schedule.
Page 53, Section 9.1.14 Gout Flare Prophylaxis
Added Text
Prophylaxis medication is only provided until the Month 6 visit, but upon the Investigator’s 
request, continued prescription may be allowed. Please note that study prescription cards 
intended to pay for acute gout flare medication cannot be used to pay for ongoing 
prophylaxis medication.
Rationale for Amendment
Provided further instruction and clarification around proper use of the study prescription card due 
to extensive questions from clinical sites about its use.
Page 56, Section 9.3.1 Screening
Existing Text
Please contact the Sponsor, if randomization does not occur within four weeks of the Screening 
visit. Screening may be less than 7 days for subjects not washing off of ULTs. Screening period 
may be longer than 7 days depending on whether subject has a flare or requires a repeat sUA test.
Revised Text
Please contact the Medical Monitor if randomization does not occur within four weeks of the 
Screening visit. Screening may be less than 7 days for subjects not washing off of ULTs. Screening 
period may be up to 28 days depending on whether subject has a flare or requires a repeat sUA 
test.
Rationale for Amendment
To correct who is the proper person to contact with these communications; also further clarifies the 
parameters within which a repeat screening visit is allowed to be conducted.
Page 58, Section 9.3.2 Study Randomization
Added Text

Review the Retention Program (subjects in the US and Canada only). Unless subjects opt-out, 
enroll them in the program.

Review the Gout Flare brochure.
Rationale for Amendment
Added text around the procedures for review of the retention program to emphasize the importance 
of enrolling subjects in the program, if possible. Added a bulleted study procedure to remind sites 
of the need for review of gout flare brochure to further subject education around flares.


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Page 60, Section 9.3.3 Treatment Phase
Existing Text
9.3.3.6
Month 3 (-3 Days)
Revised Text
9.3.3.6
Month 3 (±3 Days)
Rationale for Amendment
Correct visit range typographical error.
Page 61, Section 9.3.3 Treatment Phase
Existing Text
9.3.3.7
Months 6 (±3 Days), 12, 18, 24, 30, 36, 42 48 and 54 (±7 Days)

Call IVRS/IWRS and dispense assigned study medication with dosing instruction.

Physical examination (Months 12, 24, 36 and 48).

Vital signs.

Tophus Assessment (Months 12, 24, 36 and 48).

AE assessment.

Gout flare assessment.

Laboratory assessment (fasting, if at all possible on Months 12, 24, 36, and 48).

Concomitant medication assessment.

Collect unused prophylaxis medication and assess compliance (Month 6).

Collect unused study medication and assess compliance.

Educate subject on reporting of potential CV events and gout flares and possibility of obtaining 
the prescription card to obtain medication to treat gout flares (only in the US).

Verify subject’s contact information (including details of emergency contact).
Revised Text
9.3.3.7
Month 6 (±3 Days)

Access IVRS/IWRS and dispense assigned study medication with dosing instruction.

Vital signs.

AE assessment.

Gout flare assessment.

Laboratory assessments.


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
Concomitant medication assessment.

Collect unused prophylaxis medication and assess compliance.

Collect unused study medication and assess compliance.

Educate subject on reporting of potential CV events and gout flares and possibility of obtaining 
the prescription card to obtain medication to treat gout flares (only in the US).

Verify subject’s contact information (including details of emergency contact).

Review the Retention Program (subjects in the US and Canada only).

Review the Gout Flare Brochure.
9.3.3.9
Month 12 and Every 6 Months Until End of Study/Discontinuation of 
Treatment/Early Termination (±7 Days)

Access IVRS/IWRS and dispense assigned study medication with dosing instruction.

Physical examination (performed annually).

Vital signs.

Tophus Assessment (performed annually for subjects with tophi present).

AE assessment.

Gout flare assessment.

Laboratory assessments (fasting if at all possible, however if the subject is not fasting continue 
with visit).

Concomitant medication assessment.

Collect unused study medication and assess compliance.

Educate subject on reporting of potential CV events and gout flares and possibility of obtaining 
the prescription card to obtain medication to treat gout flares (only in the US).

Verify subject’s contact information (including details of emergency contact).
Rationale for Amendment
Split existing section up (into Section 9.3.3.7 and 9.3.3.9) to more clearly define the procedures to 
be completed at the Month 6 visit versus visits from Month 12 onwards. Removed reference to 
specific visit months because subject participation will vary due to the endpoint nature of the 
study. Added review of the retention program and gout flare brochure as reminders to conduct 
those procedures at Month 6.


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Page 62, Section 9.3.3 Treatment Phase
Existing Text
9.3.3.9
End of Study Treatment
Subjects who have withdrawn from study medication treatment but have not withdrawn consent 
will continue to be followed. Subjects will be contacted by telephone every 2 months (±10 days) to 
determine if any potential CV events have occurred (see Section 7.5 for telephone contact details). 
If the subject has had a potential CV event, he/she should bring the event related documents (labs, 
hospital discharge summary, etc) to the clinic. If after two attempts a subject cannot be reached 
then the subject’s emergency person will be contacted. Before a subject is considered lost to 
follow-up, a minimum of two documented telephone contact attempts must have been made and 
1 certified letter must have been sent within 4 weeks of the most recently missed telephone call in 
an effort to contact the subject. Subjects who prematurely discontinue from the study and 
experience a CV event that is positively adjudicated as a MACE will no longer be followed. 
Further, at each telephone contact, sites will ask the subject if they have taken any new 
medications (OTC or Prescription) since the last contact, or have stopped taking any ongoing 
medications recorded at the last contact. If yes, the generic medication name, start date, end date 
and reason for use will be recorded on the eCRF.
Sites will also ask the subject at each telephone contact if they have had any SAEs or any potential 
cardiovascular adverse events since the last telephone contact. If yes, these will be recorded on the 
AE eCRF, and sites should follow the instructions in the Protocol Section 10.2.2, Collection and 
Reporting of SAEs if applicable. All SAEs should be followed up until resolution or permanent 
outcome of the event.
9.3.3.10 Month 60 Final Visit/End of Treatment or Early Termination
The following procedures will be performed and documented at the Final Visit/End of Treatment 
or Early Termination Visit.

Call IVRS/IWRS to complete the subject or for Early Termination.

Physical examination.

Vital signs.

Weight.

Tophus assessment.

AE assessment.

Gout flare assessment.

Laboratory assessments.

12-lead ECG.

Concomitant medication assessment.


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
Collect unused study medication and assess compliance.

Collect unused prophylaxis medication (EoT or Early Termination).
For all subjects receiving any Sponsor supplied medication, the investigator must complete both 
the End of Study Drug CRF page and the End of Study Visit eCRF page.
Revised Text
9.3.3.10 End of Study/Discontinuation of Treatment/Early Termination
All efforts should be made to prevent any subject being lost to follow-up during the conduct 
of the study.
Subjects who either discontinue study drug treatment, or who fully withdraw consent, 
should complete the following procedures at their Discontinuation of Treatment Visit or 
Early Termination Visit, respectively. For subjects who are active in the study (taking study 
medication) at the time the independent CV Endpoints Committee determines that the 
targeted number of adjudicated MACE have been reached, instructions will be provided by 
the Sponsor regarding the scheduling of the End of Study Visit, which includes the following 
procedures. 

Access IVRS/IWRS to complete the subject or for Early Termination.

Physical examination.

Vital signs.

Weight.

Tophus assessment.

AE assessment.

Gout flare assessment.

Laboratory assessments (fasting if at all possible, however if the subject is not fasting
continue with visit).

12-lead ECG.

Concomitant medication assessment.

Collect unused study medication and assess compliance.

Collect unused prophylaxis medication (if applicable).
For all subjects receiving any Sponsor supplied medication, the investigator must complete both 
the End of Study Drug eCRF page and the End of Study Visit eCRF page.
Rationale for Amendment
Removed text redundant with other sections. Revised visit name and section text to more 
accurately reflect the purpose and procedures being performed; and to delineate the differences 


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between the three visit types. Added instruction around subjects who are active in the study at the 
time that the last MACE is adjudicated. Included a reminder instruction around requirements for 
fasting at the final visit. Added text to clarify when drug return is not applicable.
Page 71, Section 10.2.5 Evaluation of CV Safety
Existing Text
Each death, all CV serious adverse events and selected non-serious adverse events which are 
considered by the investigator to be potentially of cardiovascular nature, including any medically 
significant updates, will be sent by Takeda to a blinded CV Endpoints committee (see 
Section 11.2) for adjudication. Potential non-serious (non-hospitalized) cardiovascular adverse 
events may include, but are not limited to, events such as chest pain, angina, dyspnea/shortness of 
breath, arrhythmias, and syncope.
All investigational sites will be required to collect relevant clinical information required for 
adjudication of all deaths, all SAEs and selected nonserious events that are considered by the 
investigator to be potentially of CV nature. The adjudication committee may also identify 
additional events for adjudication through periodic data review. A CV worksheet will be provided 
to the investigational sites as a guide to ensure that supporting clinical information for each of 
these events are collected and compiled by the site and forwarded by fax or mail to Takeda 
Pharmacovigilance when available. The worksheet is not intended to be all inclusive and 
investigators should use medical judgment to determine what additional supporting documentation 
should be collected.
Revised Text
Each death and selected serious cardiovascular adverse events, including any medically 
significant updates, will be sent by Takeda to a blinded CV Endpoints committee (see 
Section 11.2) for adjudication. The final selection of the CV events for adjudication is done by 
the adjudication committee chair. Non-serious, potential CV events will not be adjudicated. 
All investigational sites will be required to collect relevant clinical information required for 
adjudication of all deaths and selected CV SAEs. A CV worksheet will be provided to the 
investigational sites as a guide to ensure that supporting clinical information for each of these 
events are collected and compiled by the site and forwarded to Takeda Pharmacovigilance when 
available. The worksheet is not intended to be all inclusive and investigators should use medical 
judgment to determine what additional supporting documentation should be collected.
Rationale for Amendment
Clarified the adjudication process, deleted requirement for adjudication of non-serious events.
Non-serious adverse events are not likely to be adjudicated to a MACE endpoint and the FDA 
agreed to remove the requirement for adjudication of non-serious events.


Febuxostat
Study No. TMX-67_301
Page 115 of 115
Protocol Incorporating Amendment No. 6
27 August 2013
CONFIDENTIAL
Page 75, Section 13.1.3 Safety Analyses
Existing Text
A blinded CV Endpoints Committee will adjudicate each death and major cardiovascular adverse 
event to determine if it meets the MACE criteria.
Revised Text
A blinded CV Endpoints Committee will adjudicate each death and selected serious
cardiovascular adverse event to determine if the event meets the MACE criteria.
Rationale for Amendment
Non-serious adverse events are not likely to be adjudicated to a MACE endpoint and the FDA 
agreed to remove the requirement for adjudication of non-serious events.
Page 85, Appendix A Schedule of Study Procedures
Added Text
Review Gout Flare Brochure
X
X
Rationale for Amendment
Included as a reminder to sites to formally perform a review of the gout flare information with all 
subjects.
Page 86, Appendix A Schedule of Study Procedures, footnotes
Existing Text
(b) For those subjects with tophi present, assessments will be done at Day 1, Month 12, 24, 36, 48 and Final Visit/ EoT or Early 
Termination.
(f) Fasting labs required at Day 1/Randomization Visit, Month 12, 24, 36, 48 and Final Visit/ EoT or Early Termination.
(i) EoT will have procedures as at Month 60 visit.
Revised Text
(e) For those subjects with tophi present, assessments will be done at Day 1, Month 12, and annually thereafter until End of 
Study/DoT/Early Termination.
(j) Fasting labs required at Day 1/Randomization Visit, Month 12, and annually thereafter until End of Study/DoT/Early 
Termination. However, if the subject is not fasting, assessment should still be conducted.
Rationale for Amendment
All footnote numbering was updated to facilitate easier flow and reference within the table. 
Footnotes regarding tophi and laboratory assessments were updated to remove reference to 
specific visit months because subject participation will vary due to the endpoint nature of the 
study; also added reminder instruction around the necessity for fasting during laboratory 
assessment visits. Removed unnecessary and potentially confusing footnote appended to the End 
of Study/DoT/Early Termination visit.


 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
Amendment 6 - A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate
the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects with Gout and
Cardiovascular Comorbidities
Clinical Operations Approval
28-Aug-2013 14:28
Pharmacovigilance Approval
28-Aug-2013 15:13
Biostatistics Approval
28-Aug-2013 15:19
Clinical Operations Approval
28-Aug-2013 15:22
Clinical Science Approval
28-Aug-2013 15:33
PPD


Febuxostat
Study No. TMX-67_301
Page 4  of 95
Protocol 
20 January 2010
CONFIDENTIAL
1.3 Protocol Amendment TMX-67_301.001
This document describes changes in reference to Protocol TMX-67_301.001, dated 20 January 
2010. Please note that this amendment includes major changes to the overall study design and 
conduct of the study; therefore only an overview of the changes is provided in this section.
Change in Protocol
Rationale
Secondary Efficacy Endpoints Moved to 
Additional Endpoints
Since the majority of subjects will receive ULT that 
will decrease sUA <6.0 mg/dL, differences between 
treatment groups are no longer a relevant secondary 
endpoint
Removed ECGs from Safety Assessments
ECGs will be performed at the Screening Visit and 
per the investigator’s discretion should a 
cardiovascular event occur
Study Duration Changed to Approximately 
5 Years and the Number of Subjects 
Increased to 7500 
Complete event-driven trial in a shorter period of 
time
Change enrollment criteria to include 
subjects with (1) a serum urate level (sUA) 
≥7 mg/dL or (2) with a sUA ≥6 mg/dL 
AND at least one flare in the 12 months 
prior to screening and/or the presence of 
tophi 
Increase participation of gout subjects in safety 
study that may not have otherwise qualified due to 
sUA levels
Shortened washout period for prior urate 
lowering therapy to 7 days from 14 days
To make washout period consistent with duration 
appropriate for drug clearance and not to achieve 
hyperuricemic state
Introduce allopurinol titration (in 100 mg 
increments) based on sUA response to a 
maximum of 400 mg in subjects with 
moderate renal impairment and 600 mg in 
normal/mild renal impairment subjects 
(NOTE: Additional visits have been added 
at Weeks 6, 8 and 10 to monitor sUA 
response for those subjects who do not 
achieve sUA <6.0 mg/dL at the previous 
visit.)
Prevent subjects randomized to allopurinol from 
withdrawing from the study due to inadequate sUA 
response
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Febuxostat
Study No. TMX-67_301
Page 5  of 95
Protocol 
20 January 2010
CONFIDENTIAL
Change in Protocol
Rationale
Investigator and sponsor will be unblinded 
to sUA levels until Week 12 visit (NOTE: 
both parties will remain blinded to study 
treatment.)
Assist in ensuring that subjects are titrated to a dose 
of study treatment that will maintain sUA 
<6.0 mg/dL for the 5 year study duration
Updated entry criteria for females to be 
≥55 years of age and removed requirement 
for FSH testing
Women over age 55 are post-menopausal and 
confirmation via laboratory testing is not required
Updated protocol to remove any 
restrictions related to thiazide diuretic use
Any required allopurinol titration will occur in 
100 mg increments and subjects will be monitored 
every 6 months during the course of the study
Revised Study Medication and Treatment 
Section due to inclusion of higher 
allopurinol doses and addition of placebo
capsules
To maintain blinding, all subjects will be required to 
take 2 capsules of study medication daily
Updated schedule of events to reflect yearly 
physical exams 
To follow typical clinical practice
Updated criteria for causality of adverse 
events 
Align with company policy to utilize Yes or No 
response
Updated proposed CV event rate to 2.8%
Limited available information on true CV rate in 
high risk populations
Updated colchicine dosing 
recommendations for acute gout flares
Recently approved US labeling providing specific 
guidance regarding colchicine dosing
Deleted thyroid, and hs-crp 
To streamline the study conduct; hematology and 
urinalysis will be done at screening and chemistry 
(including liver function tests) will be done at 
screening and at least every 6 months during the 
study
Added additional visits at Month 9 and 
Month 15 for elderly subjects and subjects 
with moderate renal impairment
To more frequently monitor LFTs and renal 
function in elderly subjects and subjects with 
moderate renal impairment
Removed the telephone contacts every 
2 months after Month 12 visit for subjects 
still receiving study medication
Subjects will be seen in the clinic at least every 
6 months; telephone contacts will still be made 
every 2 months for subjects who have discontinued 
study medication but are being followed for 
potential CV events.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Febuxostat
Study No. TMX-67_301
Page 6  of 95
Protocol 
20 January 2010
CONFIDENTIAL
Change in Protocol
Rationale
Clarified that detailed information on 
aspirin and NSAID use will be collected 
and specified how the analyses will account 
for use of these medications
Use of these medications could potentially 
confound the interpretation of study events
Specified details of signs and symptoms to 
be collected for gout flares
To apply the standardized definition of acute gout 
flare under development by the ACR
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Febuxostat
Study No. TMX-67_301.002
Page 4 of 144
Protocol Incorporating Amendment No. 2
24 February 2010
CONFIDENTIAL
1.3 Protocol Amendment TMX-67_301.001 Summary of Changes
This document describes changes in reference to Protocol TMX-67_301.001, dated 20 January 
2010. Please note that this amendment includes major changes to the overall study design and 
conduct of the study; therefore only an overview of the changes is provided in this section.
Change in Protocol
Rationale
Secondary Efficacy Endpoints Moved to 
Additional Endpoints
Since the majority of subjects will receive ULT that 
will decrease sUA <6.0 mg/dL, differences between 
treatment groups are no longer a relevant secondary 
endpoint
Removed ECGs from Safety Assessments
ECGs will be performed at the Visit and per the 
investigator’s discretion should a cardiovascular 
event occur
Study Duration Changed to Approximately 
5 Years and the Number of Subjects 
Increased to 7500 
Complete event-driven trial in a shorter period of 
time
Change enrollment criteria to include 
subjects with (1) a serum urate level (sUA) 
≥7 mg/dL or (2) with a sUA ≥6 mg/dL 
AND at least one flare in the 12 months 
prior to screening and/or the presence of 
tophi 
Increase participation of gout subjects in safety 
study that may not have otherwise qualified due to 
sUA levels
Shortened washout period for prior urate 
lowering therapy to 7 days from 14 days
To make washout period consistent with duration 
appropriate for drug clearance and not to achieve 
hyperuricemic state
Introduce allopurinol titration (in 100 mg 
increments) based on sUA response to a 
maximum of 400 mg in subjects with 
moderate renal impairment and 600 mg in 
normal/mild renal impairment subjects 
(NOTE: Additional visits have been added 
at Weeks 6, 8 and 10 to monitor sUA 
response for those subjects who do not 
achieve sUA <6.0 mg/dL at the previous 
visit.)
Prevent subjects randomized to allopurinol from 
withdrawing from the study due to inadequate sUA 
response
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Febuxostat
Study No. TMX-67_301.002
Page 5 of 144
Protocol Incorporating Amendment No. 2
24 February 2010
CONFIDENTIAL
Change in Protocol
Rationale
Investigator and sponsor will be unblinded 
to sUA levels until Week 12 visit (NOTE: 
both parties will remain blinded to study 
treatment.)
Assist in ensuring that subjects are titrated to a dose 
of study treatment that will maintain sUA 
<6.0 mg/dL for the 5 year study duration
Updated entry criteria for females to be 
≥55 years of age and removed requirement 
for FSH testing
Women over age 55 are post-menopausal and 
confirmation via laboratory testing is not required
Updated protocol to remove any 
restrictions related to thiazide diuretic use
Any required allopurinol titration will occur in 
100 mg increments and subjects will be monitored 
every 6 months during the course of the study
Revised Study Medication and Treatment 
Section due to inclusion of higher 
allopurinol doses and addition of placebo 
capsules
To maintain blinding, all subjects will be required to 
take 2 capsules of study medication daily
Updated schedule of events to reflect yearly 
physical exams 
To follow typical clinical practice
Updated criteria for causality of adverse 
events 
Align with company policy to utilize Yes or No 
response
Updated proposed CV event rate to 2.8%
Limited available information on true CV rate in 
high risk populations
Updated colchicine dosing 
recommendations for acute gout flares
Recently approved US labeling providing specific 
guidance regarding colchicine dosing
Deleted thyroid, and hs-crp 
To streamline the study conduct; hematology and 
urinalysis will be done at screening and chemistry 
(including liver function tests) will be done at 
screening and at least every 6 months during the 
study
Added additional visits at Month 9 and 
Month 15 for elderly subjects and subjects 
with moderate renal impairment
To more frequently monitor LFTs and renal 
function in elderly subjects and subjects with 
moderate renal impairment
Removed the telephone contacts every 
2 months after Month 12 visit for subjects 
still receiving study medication
Subjects will be seen in the clinic at least every 
6 months; telephone contacts will still be made 
every 2 months for subjects who have discontinued 
study medication but are being followed for 
potential CV events.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Febuxostat
Study No. TMX-67_301.002
Page 6 of 144
Protocol Incorporating Amendment No. 2
24 February 2010
CONFIDENTIAL
Change in Protocol
Rationale
Clarified that detailed information on 
aspirin and NSAID use will be collected 
and specified how the analyses will account 
for use of these medications
Use of these medications could potentially 
confound the interpretation of study events
Specified details of signs and symptoms to 
be collected for gout flares
To apply the standardized definition of acute gout 
flare under development by the ACR
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Febuxostat
Study No. TMX-67_301
Page 4 of 132
Protocol Incorporating Amendment No. 3
26 January 2011
CONFIDENTIAL
1.3
Protocol Amendment 3 Summary of Changes
This document describes changes in reference to Protocol TMX-67_301 Amendment 3, dated 
26 January 2011.
Change in Protocol
Rationale
Update contacts for medical monitoring (medical 
advice on protocol, compound and medical 
management of subjects) and data management.
Takeda Global Research and Development, Inc. has contracted 
with vendors for medical monitoring and changed contracted 
vendor for data management responsibilities.
Update the approximate number of study sites from 
450 sites to 465 sites.
Sites in Canada will be added to the study.
The follow up of subjects who discontinue 
prematurely from the study is clarified.
Subjects who prematurely discontinue study drug treatment 
and experience a CV event that is positively adjudicated as a 
MACE will no longer be followed.
Exclusion Criteria updated.
Criteria updated to eliminate possibility of subjects entering 
this study more than once.
Phone Follow-Ups clarified.
Clarification of expectations for collection of data at Phone 
Follow-ups.
Gout Flare and CV Event Sample Worksheets 
modified.
Text has been added to record investigator and subject 
information on all pages.
End of study Drug/End of Study Visits clarified.
Clarified the independence of the End of Study Drug and End 
of Study Visits eCRF.
Significant Protocol Deviations clarified.
Clarified that Significant Protocol Deviations should be 
captured in the eCRF.
Clarification on how the double-blinded nature of 
the study will be maintained added.
Clarification is response to FDA comment.
Additional Colchicine safety and drug interaction 
verbiage added.
Inform investigators of potential safety concerns and drug 
interactions in subjects who are given colchicine for 
prophylaxis.


Febuxostat
Study No. TMX-67_301
Page 4 of101
Protocol Incorporating Amendment No. 4
19 May 2011
CONFIDENTIAL
1.3
Protocol Amendment TMX-67_301 Summary of Changes
This document describes changes in reference to Protocol TMX-67_301 Amendment 4, dated 
19 May 2011.
Change in Protocol
Rationale
Remove the HIPAA regulation language throughout 
the protocol 
HIPAA Privacy Rule provides federal protections for personal 
health information for the USA subjects only.


Febuxostat
Study No. TMX-67_301
Page 4 of112
Protocol Incorporating Amendment No. 5
26 September 2011
CONFIDENTIAL
1.3
Protocol Amendment TMX-67_301.003 Summary of Changes
This document describes changes in reference to Protocol TMX-67_301 Amendment 4, dated
19 May 2011.
Change in Protocol
Rationale
Remove the HIPAA regulation language throughout 
the protocol 
HIPAA Privacy Rule provides federal protections for personal 
health information for the USA subjects only.

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the 
Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular 
Comorbidities
NCT Number: NCT01101035
SAP Approve Date: 22 February 2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TMX-67_301
A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the 
Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and 
Cardiovascular Comorbidities
PHASE 3B
TAKEDA DEVELOPMENT CENTER AMERICAS INC
Version: Amendment 3
Date: 22 February 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.


TMX-67_301
Page 2 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
APPROVAL SIGNATURES
SIGNATURES
Date
Date
Date
PPD
PPD
PPD


TMX-67_301
Page 3 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
TABLE OF CONTENTS
1.0
LIST OF ABBREVIATIONS..........................................................................................5
2.0
INTRODUCTION...........................................................................................................6
3.0
OBJECTIVES .................................................................................................................7
3.1
Primary Objectives ....................................................................................................7
3.2
Study Design .............................................................................................................7
4.0
ANALYSIS VARIABLES ............................................................................................10
4.1
Primary Endpoint.....................................................................................................10
4.2
Secondary Endpoints ...............................................................................................10
4.3
Additional Endpoints ...............................................................................................10
5.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
6.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
6.1
General Considerations............................................................................................13
6.1.1
Baseline, Study Day, and Window Conventions.................................................13
6.2
Major Protocol Violations........................................................................................13
6.3
Analysis Sets ...........................................................................................................13
6.4
Disposition of Subjects ............................................................................................14
6.5
Demographic and Baseline Characteristics...............................................................15
6.5.1
Gout Disease History .........................................................................................15
6.5.2
Cardiovascular History.......................................................................................16
6.5.3
Medical History and Concurrent Medical Conditions .........................................16
6.5.4
Medication History and Concomitant Medications .............................................16
6.6
Study Drug Exposure and Compliance.....................................................................17
6.7
Efficacy Analysis.....................................................................................................18
6.7.1
Efficacy Endpoints.............................................................................................18
6.8
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................20
6.9
Quality-of-Life Analysis..........................................................................................20
6.10
Pharmacoeconomic Analysis ...................................................................................20
6.11
Other Outcomes.......................................................................................................20
6.12
Safety Analysis........................................................................................................20
6.12.1 Primary Safety Endpoint ....................................................................................21
6.12.2 Secondary Safety Endpoints...............................................................................22
6.12.3 Other Safety Endpoints ......................................................................................22
6.12.4 Adverse Events ..................................................................................................23
6.12.5 Clinical Laboratory Evaluations .........................................................................25
6.12.5.1
Mean Change from Baseline...................................................................25


TMX-67_301
Page 4 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
6.12.5.2
Markedly Abnormal Laboratory Values..................................................25
6.12.5.3
Shifts Relative to Normal Range.............................................................25
6.12.6 Vital Signs .........................................................................................................25
6.12.7 12-Lead ECGs ...................................................................................................26
6.13
Interim Analysis ......................................................................................................26
6.13.1 DMC and Independent Statistical Group ............................................................27
6.14
Changes in the Statistical Analysis Plan from the Protocol Analysis Plan.................27
6.14.1 Amendment 1 ....................................................................................................27
6.14.2 Amendment 2 ....................................................................................................28
6.14.3 Amendment 3 ....................................................................................................29
7.0
REFERENCES..............................................................................................................30
8.0
LIST OF APPENDICES................................................................................................31
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values ......31
Appendix B
Criteria for Identification of Markedly Abnormal Vital Sign Values........32
LIST OF IN-TEXT TABLES
Table 6.a
Visit Windows for Efficacy and Safety Variables...............................................14
Table 6.b
Time Intervals and Steps to Calculate Tophus Resolution Rate ..........................19
Table 6.c
O’Brien-Fleming Spending Function..................................................................26
LIST OF IN-TEXT FIGURES
Figure 3.a
Dose Titration Based on sUA Response and By Baseline Renal Function in 
the First Three Months of the Study .....................................................................8


TMX-67_301
Page 5 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
1.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
APTC
Antiplatelet Trialists’ Collaborative
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical classification system
BMI
body mass index
BUN
blood urea nitrogen
CHF
congestive heart failure
CI
confidence interval
CPH
Cox proportional hazard
CV
cardiovascular
DMC
data monitoring committee
DVT
deep vein thrombosis
ECG
electrocardiogram
eCLcr
estimated creatinine clearance
FAS
full analysis set
HLT
high level term
IBW
Ideal body weight
ISG
independent statistical group
IVRS
interactive voice-activated response system
IWRS
interactive web-activated response system
LDH
lactate dehydrogenase
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
NSAIDs
nonsteroidal anti-inflammatory drugs
PE
pulmonary embolism
PT
preferred term
PY
patient-year
QD
once daily
SAE
serious adverse event
sUA
serum uric acid
SAP
statistical analysis plan
SOC
System organ class
TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
ULN
Upper limit of normal
ULT
urate lowering therapy
WHO
World Health Organization


TMX-67_301
Page 6 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
2.0
INTRODUCTION
This document describes the statistical analyses and data presentations to be performed for this 
multicenter, randomized, double-blind, active-controlled study designed to evaluate the 
cardiovascular (CV) safety of febuxostat compared with allopurinol in subjects with gout and 
CV comorbidities.
This statistical analysis plan (SAP) and amendments were developed based on information 
provided in the following protocol:

Protocol TMX-67_301 (Amendment 6), dated 27 August, 2013.
Amendment 3 of this SAP will remain sequestered to the blinded team until database lock and 
un-blinding.


TMX-67_301
Page 7 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
3.0
OBJECTIVES
3.1
Primary Objectives
The primary objective of this study is to compare the risk of predefined major cardiovascular 
adverse events (MACE) during treatment with febuxostat and allopurinol in subjects with gout 
and CV comorbidities.
3.2
Study Design
This is a phase 3B multicenter, randomized, double-blind, active-controlled study designed to 
evaluate the CV safety of febuxostat compared with allopurinol in subjects with gout and 
significant CV comorbidities. Approximately 7500 subjects will be randomly assigned to study 
drug treatment.
The overall duration of the study is dependent on the number of predefined MACE. The length 
of the study is expected to be approximately 9 years. The length of study participation for each 
subject will vary due to the event driven study design. This study is designed to have a maximum 
of 624 MACE.
On Study Day 1, eligible subjects will be randomized in a 1:1 ratio to receive either febuxostat 
once daily (QD) or allopurinol QD. Randomization will be stratified based on baseline renal 
function (normal renal function or mild renal impairment versus moderate renal impairment). 
Baseline renal function will be defined using the following criteria based on estimated creatinine 
clearance (eCLcr):

Normal renal function: defined as an eCLcr ≥90 mL/min.

Mild renal impairment: defined as an eCLcr 60 to 89 mL/min, inclusive.

Moderate renal impairment: defined as an eCLcr 30 to 59 mL/min, inclusive.
where estimated creatinine clearance (eCLcr) is calculated using the Cockcroft-Gault formula 
corrected for ideal body weight (IBW); IBW is 50 kg for males and 45.5 kg for women, plus 
2.3 kg for each inch in height >5 feet (60 inches)]:






140-Age[yr]
IBW[kg]
women multiply by 0.85
eCLcr 
 
72
serum creatinine [mg/dL]



Subjects randomized to febuxostat will initially receive the 40 mg dose QD. Subjects will remain 
on 40 mg for the remainder of the study if their serum uric acid (sUA) is <6.0 mg/dL at the Week 
2 Visit. If their sUA is ≥6.0 mg/dL at the Week 2 Visit they will receive febuxostat 80 mg QD at 
the Week 4 visit, and will remain on this dose for the remainder of the study.
Subjects randomized to allopurinol who have normal renal function or mild renal impairment
will initially receive allopurinol 300 mg QD with the dose increased in 100 mg increments 
monthly until either a sUA <6.0 mg/dL or an allopurinol dose of 600 mg QD is achieved. 
Subjects randomized to allopurinol who have moderate renal impairment will initially receive 
allopurinol 200 mg QD with the dose increased in 100 mg increments monthly until either a sUA 


TMX-67_301
Page 8 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
<6.0 mg/dL or an allopurinol dose of 400 mg QD is achieved. The randomization and dosing 
schema are displayed in Figure 3.a.
Figure 3.a
Dose Titration Based on sUA Response and By Baseline Renal Function in 
the First Three Months of the Study
Serum urate levels will be unblinded to the investigator and Takeda during the first 10 weeks of 
the study to facilitate dose increases based on sUA response. After the Week 10 Visit, sUA 
measurements will be blinded to Takeda and the investigator. The interactive voice-activated 
response system/interactive web-activated response system (IVRS/IWRS) will manage the 
treatment assignment after randomization and throughout the study medication treatment.
To maintain the double-blind nature of the study, febuxostat and allopurinol tablets will be 
over-encapsulated and matching placebo capsules will be manufactured which are identical in 
appearance. Subjects will orally self administer 2 capsules each morning in the appropriate 
combination for their assigned dose and treatment.
Subjects currently on urate-lowering therapy (ULT) will discontinue treatment at the Day -7
Screening Visit, and will begin colchicine 0.6 mg QD for gout flare prophylaxis. Subjects not on 
ULT will begin colchicine 0.6 mg QD on the Day 1/Randomization Visit. All subjects will 
receive gout flare prophylaxis for the first six months of the study medication treatment period. 
Alternatively, if colchicine is not tolerated and the subject’s eCLcr is ≥50 mL/min, they will be 
administered naproxen 250 mg twice daily with lansoprazole 15 mg QD. If a subject has been 


TMX-67_301
Page 9 of 32
Statistical Analysis Plan Amendment 3
22 February 2017
CONFIDENTIAL
maintained on an appropriate dose (as determined by the investigator) of another proton pump 
inhibitor other than lansoprazole, he/she may continue treatment with it during this study. In 
instances when subjects should not receive colchicine or naproxen, other nonsteroidal 
anti-inflammatory drugs (NSAIDs) or prednisone may be provided at the investigator’s 
discretion.
Following the Day 1/Randomization Visit, subjects will return for study visits during the first 
3 months of the study based on the subject’s sUA response. Once a subject’s sUA <6.0 mg/dL,
there will be no further visits until Month 3.
All subjects will return at Week 2 for measurement of sUA and all subjects will return for a 
Week 4 and Month 3 visit. If the Week 2 sUA level is <6.0 mg/dL, the subject will be dispensed 
study medication at Week 4, and the next visit will occur at Month 3. If the Week 2 sUA level is 
≥6.0 mg/dL, the subject will be dispensed study medication at Week 4, and the next visit will 
occur at Week 6.
For the subset of subjects who have a Week 6 visit, if the Week 6 sUA level is <6.0 mg/dL, the 
subject will be dispensed study medication at Week 8, and the next visit will occur at Month 3. If 
the Week 6 sUA level is ≥6.0 mg/dL, the subject will be dispensed study medication at Week 8
and the next visit will occur at Week 10.
For the subset of subjects who have a Week 10 visit, the subject will be dispensed study 
medication at the Month 3 visit. After the Month 3 visit, no further dose adjustments will be 
made. All subjects will have Month 3 and Month 6 visits.
Following the Month 6 visit, all subjects will have visits every 6 months for the duration of the 
study. In addition, subjects with moderate renal impairment (eCLcr <60mL/min) and/or subjects 
who are elderly (≥65 years of age) will have visits at Month 9 and Month 15 to monitor liver 
function tests. Subjects who are withdrawn from study medication treatment but have not 
withdrawn consent will be followed via phone calls every 2 months until the end of the study or 
until the subject experiences a CV event that is positively adjudicated as a MACE.
A Data Monitoring Committee (DMC) will periodically review results obtained in the study, 
including results at 3 planned interim analyses. They will monitor the progress and the on-going 
safety of subjects enrolled into the study. An Independent CV Endpoints Committee will be 
established to prospectively review all suspected CV events using blinded data. A periodic 
review of all serious adverse events and specific CV adverse event terms will be performed by 
the Chair of the CV Endpoints Committee. The Chair, not the sponsor, will designate cases for 
comprehensive review by the CV Endpoints Committee. All investigational sites will be required 
to collect relevant clinical information required for adjudication of all deaths and potential CV 
serious adverse events (SAE).


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4.0
ANALYSIS VARIABLES
4.1
Primary Endpoint
The primary endpoint is the time from randomization to the first occurrence of any event in the 
predefined MACE composite, which includes:

CV death.

Non-fatal myocardial infarction (MI).

Non-fatal stroke.

Unstable angina with urgent coronary revascularization.
4.2
Secondary Endpoints
The secondary endpoints are:

The time from randomization to the first occurrence of any Antiplatelet Trialists’
Collaborative (APTC) event, which includes:
–
CV death.
–
Non-fatal MI.
–
Non-fatal stroke.

The time from randomization to the occurrence of each individual event in the pre-defined 
MACE composite.
4.3
Additional Endpoints
The following are additional endpoints:

The time from randomization to the first occurrence of any event in the pre-defined MACE 
composite plus any of the following events:
–
Urgent Cerebral revascularization [non-elective].
–
Hospitalized congestive heart failure (CHF).
–
Arrhythmias not associated with ischemia.
–
Venous and peripheral arterial thromboembolic events; eg, Deep Vein Thrombosis 
(DVT) and Pulmonary Embolism (PE).
–
Transient Ischemic Attack (TIA).

The time from randomization to the occurrence of all-cause death.

The time from randomization to the occurrence of all-cause death during treatment (from 
randomization to last dose of study medication).

The time from last dose of study medication to the occurrence of all-cause death.

Percentage of subjects whose average sUA levels from the end of the first year of treatment 
to the end of the study are <4.0 mg/dL, ≥4 to <5.0 mg/dL, ≥5 to <6.0 mg/dL, and 
≥6.0 mg/dL.


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
The mean number of flares requiring treatment from the end of the first year of treatment to 
the end of the study.

Percentage of subjects with tophi resolution by the end of Years 1, 2, 3 and 4 for subjects 
with a primary palpable tophus at the Day 1 Visit.

Other safety assessments will include:
–
Adverse events (including rash events),
–
Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis),
–
Vital signs measurements (blood pressure and heart rate), and
–
Electrocardiogram (ECG) findings.


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5.0
DETERMINATION OF SAMPLE SIZE
A total of 7500 subjects (3750 per treatment group) are planned to be enrolled in this study. The 
sample size will provide at least 90% power to meet a non-inferiority margin of 1.3 for the 
hazard ratio (febuxostat relative to allopurinol) of the primary endpoint. The sample size 
calculation assumed a true hazard ratio of 1.0 at a 1-sided 2.5% significance level with 3 interim 
analyses at approximately 25%, 50% and 75% of the events based on critical values obtained 
using the Lan-DeMets - O’Brien-Fleming alpha spending function.
For the determination of non-inferiority between the febuxostat treatment group and the 
allopurinol treatment group, the sample size calculation further assumed:

Constant proportional hazards and exponential survival curves,

Annual adjudicated MACE composite rate of 2.8%,

Maximum length of participation of 5 years,

Accrual time of 2.5 years, and

Annual drop-out rate of 10%.
This study is designed to have a maximum of 624 MACE.


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6.0
METHODS OF ANALYSIS AND PRESENTATION
6.1
General Considerations
The SAS System with the HP-Unix operating system, will be used to perform the statistical 
analyses. Unless otherwise specified, all statistical tests and confidence intervals (CIs) will be 
two-sided and conducted at the 0.05 significance level. All computations will be performed prior 
to rounding. Statistical significance will be determined using p-values which have been rounded 
to 3 decimal places. Unless otherwise specified, descriptive statistics on continuous variables 
will consist of the number of subjects (N), mean, standard deviation, minimum, 25th percentile, 
median, 75th percentile, and maximum.
For the purpose of this document study drug will refer exclusively to the double-blind treatment 
namely: febuxostat (40 mg QD or 80 mg QD) or allopurinol (200 mg to 600 mg QD in 100 mg 
increments). Unless specified otherwise all statistical tables will be presented by febuxostat and 
allopurinol treatment groups with no summaries by dose.
6.1.1
Baseline, Study Day, and Window Conventions
For the time to event endpoints, time to event will be the time from the date of randomization to 
the first occurrence of any event in the respective endpoint.
A windowing convention will be used to determine the analysis value for a given study visit and 
will be applicable for all by-visit summaries and analyses, unless otherwise specified. The 
convention to be used for the analysis of efficacy and safety is summarized in Table 6.a.
Unless otherwise specified, baseline will be defined as the last observation prior to receiving the 
first dose of study drug on Day 1, and post-baseline values will be defined as those values 
collected within the specified window for that visit.
If a subject has more than one measurement in the same visit window, the measurement closest 
to the target day will be used. If two measurements in the same window are of equal distance to 
the target day, the measurement that occurs after the target day will be used. If two or more 
measurements occur on the same day, the last repeat value will be used.
6.2
Major Protocol Violations
No statistical analyses will be planned using the Per Protocol Set. Major protocol violations will 
be summarized for this study.
6.3
Analysis Sets
The primary endpoint and all other analyses by treatment group will be analyzed according to the 
randomized treatment using the Full Analysis Set (FAS). The FAS will consist of all subjects 
who were randomized and received at least one dose of double-blind study medication. If a 
subject reports a composite MACE after treatment discontinuation, then the reported event will 
be counted toward the treatment to which they were randomized.


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Table 6.a
Visit Windows for Efficacy and Safety Variables
Visit ID
Target Day
Window
Baseline
1
Day 1
Week 2
14
Days 2 to 21
Week 4
28
Days 22 to 35
Week 6
42
Days 36 to 49
Week 8
56
Days 50 to 63
Week 10
70
Days 64 to 81
Month 3
91
Days 82 to 137
Month 6
182
Days 138 to 228
Month 9
273
Days 229 to 319
Month 12
364
Days 320 to 410
Month 15
455
Days 411 to 501
Month 18
546
Days 502 to 637
Month 24
728
Days 638 to 819
Month 30
910
Days 820 to 1001
Month 36
1092
Days 1002 to 1183
Month 42
1274
Days 1184 to 1365
Month 48
1456
Days 1366 to 1547
Month 54
1638
Days 1548 to 1729
Month 60
1820
Days 1730 to 1911
Month 66
2002
Days 1912 to 2093
Month 72
2184
Days 2094 to 2275
Month 78
2366
Days 2276 to 2457
Month 84
2548
Days≥2458
6.4
Disposition of Subjects
Subject eligibility will be summarized by number of subjects screened and by number and 
percentage of subjects randomized and not randomized. For subjects not randomized, the number 
and percentage of subjects by primary reason for not being randomized will be summarized.
Subject disposition will be summarized for each treatment group and overall based on the FAS. 
The number and percentage of subjects randomized but not treated, randomized subjects who 
completed study drug, and randomized subjects who discontinued study drug by reason for 
discontinuation will be summarized. In addition, the number and percentage of randomized 
subjects who completed planned study visits, and who discontinued the study prematurely by 
reason for premature discontinuation will be summarized.
The timing of premature discontinuation from study drug will also be summarized within the 
following intervals: Day 1 to Day 182 [Month 6], Day 183 to Day 364 [Month 12], Day 365 to 
Day 546 [Month 18], Day 547 to Day 728 [Month 24], Day 729 to Day 910 [Month 30], 


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Day 911 to Day 1092 [Month 36], Day 1093 to Day 1274 [Month 42], Day 1275 to Day 1456 
[Month 48], Day 1457 to Day 1638 [Month 54], Day 1639 to Day 1820 [Month 60], Day 1821 to 
Day 2002 [Month 66], Day 2003 to Day 2184 [Month 72], Day 2185 to Day 2366 [Month 78], 
≥Day 2367 [≥Month 78].
In addition, the timing of premature discontinuation summary during the first 6 months will 
further be summarized using three month intervals: Day 1 to Day 91 and Day 92 to Day 182.
Comparisons between treatment groups of the rate of premature discontinuation will be assessed 
using Fisher’s exact test both overall and by reason for discontinuation.
6.5
Demographic and Baseline Characteristics
Demographic and baseline variables will be summarized to assess the comparability of the 
treatment groups by randomization. Summary statistics will be generated overall and by 
treatment group based on the FAS. No inferential statistics will be presented.
Descriptive statistics will be provided for continuous variables (age, height, weight, and body 
mass index [BMI]). The BMI (in kg/m2) is defined as the subject’s weight (in kilograms) divided 
by the square of their height (in meters).
The number and percentage of subjects will be presented by treatment group for categorical 
variables: race, ethnicity, gender, age (<65, 65<75, ≥75 years), BMI (<25, 25<30, ≥30 kg/m2), 
alcohol history, smoking history, baseline renal function (moderate renal impairment, mild renal 
impairment, and normal renal function), and history of kidney stone, hypercholesterolemia, use 
of low dose aspirin, use of NSAIDs, or use of clopidogrel and other anti-platelet drugs.
Subjects’ baseline renal function will be categorized as moderately impaired, mildly impaired, or 
normal based on their baseline estimated creatinine clearance value (eCLcr). Subjects with 
eCLcr values of 30 to 59 mL/min will be classified as having moderately impaired renal 
function, 60 to 89 mL/min as having mildly impaired renal function, and ≥90 mL/min as having 
normal renal function.
In addition, summary statistics for demographic variables (Age, Gender, Ethnicity, and Race) 
will be provided for screen failure subjects.
6.5.1
Gout Disease History
Summaries of gout disease history will be presented by treatment group and based on the FAS. 
No inferential statistics will be presented.
Descriptive statistics will be provided for continuous variables (baseline serum urate, years with 
gout, total number of tophi at baseline, pain scale rating of last gout flare). The number and 
percentage of subjects will be presented by treatment group for the following categorical 
variables: baseline serum urate (<7.0, 7.0<8.0, 8.0<9.0, 9.0 <10.0, and ≥10.0 mg/dL), 
approximate number of gout flares during the past year (1 to 3, 4 to 6, and >6), time since last 
gout flare (<1 month ago, 1<4 Months Ago, 4<6 Months Ago, 6<12 Months Ago, and 
≥1Year Ago), use of previous urate-lowering therapy, signs and symptoms of previous gout 
flares (Redness, Tenderness, Swelling, Joint Warmth, and Other), pain scale rating of last gout 


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flare (0 (no pain), 1-5, 6-10), presence of tophus at baseline, and site of primary tophus 
(wrist/hand, Ankle/Foot/Toe/Instep, Elbow, Knee, and Other).
6.5.2
Cardiovascular History
Summaries of cardiovascular history will be presented by treatment group and based on the FAS. 
No inferential statistics will be presented.
For each of the following cardiovascular (CV) history categories, the number and percentage of 
subjects will be presented: myocardial infarction (MI), hospitalized unstable angina, cardiac 
revascularization, cerebral revascularization, stroke, hospitalized transient ischemic attack (TIA), 
peripheral vascular disease (ankle brachial index 0.6), peripheral vascular disease with 
revascularization, peripheral vascular disease with claudication, deep vein thrombosis (DVT), 
pulmonary embolism (PE), history of diabetes mellitus, coronary artery bypass graft procedure,
percutaneous transluminal coronary angioplasty, cardiac arrhythmia, pacemaker or defibrillator, 
and congestive heart failure. For subjects with a history of diabetes, a summary will also be 
provided by evidence of micro- or macrovascular disease (retinopathy, neuropathy, nephropathy, 
or small vessel vascular disease). For subjects with a history of congestive heart failure, a 
summary will also be provided by classification type (Class I-IV).
In addition, the number and percentage of subjects with hypertension and hyperlipidemia will be 
presented by treatment group.
6.5.3
Medical History and Concurrent Medical Conditions
Summaries of medical history and concurrent medical conditions will be presented by treatment 
group and based on the FAS. No inferential statistics will be presented.
Medical history will consist of any significant conditions or diseases that stopped at or prior to 
time of informed consent. Ongoing conditions will be considered concurrent medical conditions.
Concurrent medical conditions are significant ongoing conditions or diseases present at time of 
informed consent through end of study. These include clinically significant laboratory, ECG, or 
physical examination abnormalities.
Medical history and concurrent medical conditions will be coded using the latest Medical 
Dictionary for Drug Regulatory Activities (MedDRA). The number and percentage of subjects 
with medical history and concurrent medical conditions will be reported by system organ class 
and preferred term.
6.5.4
Medication History and Concomitant Medications
Summaries of prior and concomitant medications will be presented by treatment and based on 
the FAS. No inferential statistics will be presented.
Any medication that was stopped prior to screening will be considered prior medication. 
Medication taken at any time between the date of screening and the date of last contact, 
inclusive, will be considered concomitant medication. Prior and concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary and will be summarized 
according to their anatomical therapeutic chemical classification system (ATC) classes.


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The number and percentage of subjects taking prior medication and concomitant medication will 
be summarized separately. The table for concomitant medications will be presented in four
separate components, namely: concomitant medications that stopped at or prior to baseline
(Day 1); concomitant medications that were ongoing at baseline; concomitant medications that 
started after baseline; and concomitant medications that were ongoing at baseline or started after 
baseline.
Summary will be generated overall and by treatment group sorted in decreasing frequency by the 
overall Preferred Term. In Drug Class and Preferred Term summarizations, a subject will be
counted once if the subject reports one or more medications.
6.6
Study Drug Exposure and Compliance
Summaries of study drug exposure, study participation, and compliance will be presented by 
treatment group and based on the FAS. No inferential statistics will be presented.
A subject’s extent of drug exposure will be calculated as the duration of treatment in the 
double-blind treatment period. Duration of study drug exposure in days will be defined as (date 
of last dose - date of first dose + 1). If the date of last dose is missing and a subject has 
discontinued from the study, then, for summary purposes, the last dose date will be estimated as 
the last drug dispense date plus the number of days in the dosing interval or date of last contact, 
whichever comes first. The study participation will begin on the day of randomization and end 
on the day of last contact. Duration of study participation in days will be defined as (date of last 
contact – date of randomization +1). For subjects who report a MACE event after treatment 
discontinuation, the start date of the event will be used as the date of last contact.
Treatment duration and study participation will be summarized overall and by treatment group 
using descriptive statistics and subject counts at the intervals: Day 1 to Day 364 [Year 1], 
Day 365 to Day 728 [Year 2], Day 729 to Day 1092 [Year 3], Day 1093 to Day 1456 [Year 4], 
Day 1457 to Day 1820 [Year 5], Day 1821 to Day 2184 [Year 6], and ≥Day 2185 [≥Year 6]. In 
addition, within each treatment group, the duration of treatment by each dose will be 
summarized.
Study drug compliance will be calculated and summarized with descriptive statistics and subject 
counts within compliance categories (<80%, 80<90%, ≥90%). Compliance (%) will be 
calculated as the number of capsules taken divided by two times the number of days on drug.
The number and percentage of subjects on the final dose and with dose adjustment from initial 
dosing will be summarized by treatment group. The final doses based on sUA response and by 
baseline renal function are summarized in Figure 3.a.
The number and percentage of subjects with use of each type of prophylactic medication based 
on the initial dosing and dose adjustment from initial dosing will be summarized by treatment 
group. In addition, descriptive statistics on the total number of days (date of last dose - date of 
first dose + 1) of prophylactic dosing will be summarized by treatment group.


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6.7
Efficacy Analysis
Efficacy analyses will be summarized by the level of average post baseline sUA achieved using 
the Full Analysis Set (FAS). The FAS will consist of all subjects who were randomized and 
received at least one dose of double-blind study medication. The average post-baseline sUA level 
during the period from the end of the first year of treatment up to 1-day after a subject’s last dose 
of study drug, will be grouped using the following categories <4.0 mg/dL, ≥4 to <5.0 mg/dL, 
≥5 to <6.0 mg/dL, and ≥6.0 mg/dL.
Efficacy analyses will not be summarized by treatment group. Since subjects will have their dose 
of study drug adjusted based on sUA response, the majority of subjects will have sUA values 
less than 6.0 mg/dL during treatment.
6.7.1
Efficacy Endpoints
There are no primary or secondary efficacy endpoints in the study. However, the following 
efficacy related other endpoints will be summarized.

Percentage of subjects whose average sUA levels from the end of the first year of treatment 
to the end of the study are <4.0 mg/dL, ≥4 to <5.0 mg/dL, ≥5 to <6.0 mg/dL, and 
≥6.0 mg/dL.
Average sUA will be computed based on all post-baseline sUA values collected from the 
end of the first year of treatment to the end of the study. For subjects with at least a year of 
study treatment exposure, all sUA values up to 1-day after a subject’s last dose of study 
drug will be included in the analyses.

The mean number of flares requiring treatment from the end of the first year of treatment to 
the end of the study.
The flare rate from the end of the first year of treatment (>=365 Days) to the end of the 
study will be summarized. Flare rate will be calculated as the number of flares from the end 
of the first year of treatment to the end of the study divided by the length of time on 
treatment during the period after the first year and through the end of study. The flare rate 
and 95% CI will be computed using Poisson regression model adjusted for treatment 
exposure with average sUA category as a factor in the model.
For subjects with at least a year of study treatment exposure, all flares up to 30 days after a 
subject’s last dose of study drug will be included in the analyses.

Percentage of subjects with tophi resolution by in Years 1, 2, 3, 4, 5, 6, and 7 for subjects 
with a primary palpable tophus at the Day 1 Visit.
For subjects with a primary tophus at baseline (Day 1 assessment), the percentage of 
subjects with tophi resolution at the end of Years 1, 2, 3, 4, 5, 6, and 7 of treatment will be 
summarized. The estimate for tophi resolution rate will be calculated using the life-table 
method. In calculating the percentage of subjects with tophi resolution, yearly intervals will 
be used in the life-table analysis. All tophus data up to 30 days after a subject’s last dose of 
study drug will be included in the analyses.


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The time intervals that will be used in the life table method relative to the first day of study drug 
and steps to calculate the resolution rate at the end of each interval are summarized in Table 6.b.
Table 6.b
Time Intervals and Steps to Calculate Tophus Resolution Rate
Time Interval
(Years)
Interval
Number
tn
tr
t
w
tn
tP
0 – 1
1
1n
1r
1
w
1
1
1
2
w
n
n


1
1
1
P
Q

1 – 2
2
2
1
1
1
n
n
r
w



2r
2
w
2
2
2
2
w
n
n


2
2
1
P
Q

2 – 3
3
3
2
2
2
n
n
r
w



3r
3
w
3
3
3
2
w
n
n


3
3
1
P
Q

3 – 4
4
4
3
3
3
n
n
r
w



4r
4
w
4
4
4
2
w
n
n


4
4
1
P
Q

For 
1,  2, 3, 4
t 
, 
tn is the number of subjects who have not had a resolved primary tophus at 
the beginning of the
tht
interval,
tr is the number of subjects whose tophus resolved during the
tht
interval,
tw is the number of subjects who were censored or lost during the
tht
interval, 
tnis 
the number of subjects who have not had a resolved primary tophus at the end of the 
tht
interval 
adjusted for early withdrawal, and 
tP is resolution rate at the end of the 
tht
interval. 


1 1
t
t
i
i
i
Q
r n





is the conditional probability of no resolution at the end of the 
tht
interval, 
where is the product notation.
In addition, the relationship between average serum urate concentration and occurrence of any 
gout flare requiring treatment (at least 1 occurrence versus no occurrence) from the end of the 
first year of treatment to the end of the study will further be evaluated using logistic regression 
model adjusting for baseline sUA. Descriptive summary of the baseline and average 
post-baseline sUA values will also be provided by occurrence of any gout flare (at least 
1 occurrence versus no occurrence).
The following additional gout flare summaries will also be performed. The windows convention 
for the gout flare summaries by 6 month intervals [days] are: 6 [Days 2 to 182], 6-12 [Days 183 
to 364], 12-18 [Days 365 to 546], 18-24 [Days 547 to 728], 24-30 [Days 729 to 910], 30-36 
[Days 911 to 1092], 36-42 [Days 1093 to 1274], 42-48 [Days 1275 to 1456], 48-54 [Days 1457
to 1638], 54-60 [Days 1639 to 1820], 60-66 [Days 1821 to 2002], 66-72 [Days 2003 to 2184], 
72-78 [Days 2185 to 2366], and 78-84 [Days >2366]. All flare data collected from baseline and 
up to 30 days after a subject’s last dose of study drug will be included in the analyses.

The number and percentage of subjects requiring treatment for gout flare will be summarized 
by prophylaxis medication use and overall by 6 Month intervals. A subject who reports more 
than one flare during the same time interval will be counted only once for that time interval.


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
The total number of flares and the flare rate per subject year of treatment exposure will be 
summarized by 6 month intervals. Within the time intervals, subject year is the total number 
of days of drug exposure for all subjects with exposure for the interval divided by 365.

The number and percentage of subjects requiring treatment for gout flare will also be 
summarized by signs and symptoms of gout flare (Swelling, Redness, Tenderness, Joint 
Warmth, and Other Signs/Symptoms).
If a subject reports more than one signs and symptoms category, then for summary purpose 
the subject will be counted within each reported signs and symptoms category. However, if a 
subject reports the same signs and symptoms more than once during the study period then the 
subject will be counted only once in that category. Summary in each signs and symptoms 
category will also be provided by severity level (Mild, Moderate, Severe). If a subject reports 
different severity level for the same signs and symptoms category during the study period, 
the most severe level will be used for summary purposes.
6.8
Pharmacokinetic/Pharmacodynamic Analysis
Not Applicable.
6.9
Quality-of-Life Analysis
Not Applicable.
6.10
Pharmacoeconomic Analysis
Not Applicable.
6.11
Other Outcomes
Not Applicable.
6.12
Safety Analysis
Safety will be assessed by evaluating the incidence of adverse events including cardiovascular 
adverse events such as predefined MACE composite, and evaluating ECGs; laboratory tests and 
vital signs. A CV Endpoints Committee blinded to treatment assignment will adjudicate potential 
cardiovascular adverse events and each death to determine if it meets MACE criteria. The 
procedures and rules of adjudication of these events by the CV Endpoints Committee is
described in a separate charter.
For the primary, secondary, and additional safety endpoints, time to event will be the time from 
the date of randomization or the date of last dose of study medication to the date of first 
occurrence of any event in the respective endpoint. If a subject reports an event for a given safety 
endpoint after treatment discontinuation, the reported event will be counted toward the treatment 
to which they were randomized. Subjects who are lost to follow-up during the study or who do 
not exhibit an episode of an event for the specific safety endpoint throughout the study will be 
censored at the day of last contact.


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All safety endpoints will be analyzed using the Full Analysis Set (FAS). The FAS will consist of 
all subjects who were randomized and received at least one dose of double-blind study 
medication. Non-inferiority will be assessed only for the primary safety endpoint.
6.12.1 Primary Safety Endpoint
The primary safety variable is the time from randomization to the first occurrence of any event in 
the predefined MACE composite. The goal of the primary safety analysis is to compare the risk 
of a predefined MACE during treatment with febuxostat to that of allopurinol.
Survival analysis using the Cox Proportional Hazards (CPH) model will be fitted on the time to 
the first occurrence of any event in the predefined MACE composite. The hazard ratio
(febuxostat versus allopurinol) for the primary safety endpoint will be computed based on 
febuxostat and allopurinol estimated hazard rates. The febuxostat treatment group will be 
compared to the allopurinol treatment group to test for non-inferiority in the MACE composite 
rate using a CPH model with treatment as factor in the model and baseline renal function as a 
stratification factor. Non-inferiority of febuxostat to allopurinol will be declared (at an interim or 
at the final analysis) if the current upper 1-sided CI for the hazard ratio calculated with critical 
values obtained using the Lan-DeMets-O’Brien-Fleming alpha spending function, which 
preserves an overall 1-sided false-rejection rate of 2.5%, is less than 1.3.
Kaplan-Meier plot for the time to first occurrence of any event in the adjudicated MACE 
composite will be produced by treatment group (overall and within the levels of the stratification 
factor, baseline renal function).
A sensitivity analysis on the primary safety endpoint will also be performed by excluding MACE 
that occur more than 30 days after treatment discontinuation.
Assessment of the proportional hazards assumption will be made by inspection of the 
Kaplan-Meier curves and using plots of Schoenfeld residuals. In the Kaplan-Meier curves, if the 
proportional hazard assumption is satisfied then the graph of the survival function versus the 
survival time should result in a graph with parallel curves. In the plots of Schoenfeld residuals, if 
the proportional hazard assumption is satisfied then the graph of the Schoenfeld residuals 
obtained from the primary CPH model versus the ordered time of events along with smoothing 
spline should result in a horizontal line.
Alternative methods of analysis may be considered should some of the underlying model 
assumptions seem inappropriate (e.g., non-proportional hazards). The reasons for any changes to 
the planned approach and methods will be fully documented.
An additional analysis on the primary safety endpoint will be performed using Cox-proportional 
hazards model controlling for the effect of NSAIDs use. The model will include treatment group, 
baseline renal function, and use of NSAIDs as explanatory variables. A similar analysis will 
control for the effect of low-dose aspirin use.
To identify risk factors an additional exploratory analysis on the primary safety endpoint will be 
performed using multivariate CPH modeling. The multivariate model will include treatment 
group and the following covariates jointly in the model with baseline renal function as the 
stratification factor: age, gender, BMI, NSAIDs use, low-dose aspirin use, smoking history, 


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baseline sUA, and history of diabetes, hypertension, non-fatal MI, or non-fatal stroke. No 
interaction terms will be introduced in the multivariate model. The backward elimination 
technique with a significance level to stay (SLS) in the model of SLS = 0.05 will be 
implemented for variable selection while always retaining treatment group and baseline renal 
function as stratification factor in the model.
In addition, the number and percentage of subjects with predefined MACE will be summarized 
within the levels of each subgroup variable. The relative risk (febuxostat versus allopurinol) and 
95% CI based on the normal approximation will be calculated within the levels of each subgroup 
variable. Homogeneity among the levels of the subgroup variables will be assessed using the 
Cochran-Mantel-Haenszel test. A forest plot indicating the point and 95% CI estimates of the 
risk ratios within the levels of each subgroup variable will also be presented.
6.12.2 Secondary Safety Endpoints
The following secondary safety endpoints will be assessed:

The time from randomization to the first occurrence of any Antiplatelet Trialists’ 
Collaborative (APTC) event (CV Death, Non-fatal MI, and Non-fatal Stroke).

The time from randomization to the occurrence of each individual event in the pre-defined 
MACE composite.
Survival analysis using the CPH model will be performed on the time to the first occurrence of 
any APTC event and on the time to occurrence of each individual event in the pre-defined 
MACE composite. Parameter estimates and 2-sided 95% CIs for the hazard ratio will be 
computed. A graphical display indicating the point and 95% CI estimates of the hazard ratios for 
the primary MACE components will also be presented.
To identify risk factors for the time to first occurrence of APTC event, an exploratory analysis 
will also be performed using multivariate CPH modeling. The multivariate model will include 
treatment group and the following covariates jointly in the model with baseline renal function as 
the stratification factor: age, gender, BMI, NSAIDs use, low-dose aspirin use, smoking history, 
baseline sUA, and history of diabetes, hypertension, non-fatal MI, or non-fatal stroke. No 
interaction terms will be introduced in the multivariate model. The backward elimination 
technique with a significance level to stay (SLS) in the model of SLS = 0.05 will be 
implemented for variable selection while always retaining treatment group and baseline renal 
function as stratification factor in the model.
In addition, Kaplan-Meier plots for the time to first occurrence of APTC event and the time to 
first occurrence of each individual event in the pre-defined MACE will be presented by treatment 
group.
6.12.3 Other Safety Endpoints
The following additional safety endpoints will also be assessed:

The time from randomization to the first occurrence of any event in the pre-defined MACE 
composite plus any of the following events:


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–
Urgent Cerebral revascularization [non-elective].
–
Hospitalized congestive heart failure (CHF).
–
Arrhythmias not associated with ischemia.
–
Venous and peripheral arterial thromboembolic events; eg, Deep Vein Thrombosis 
(DVT) and Pulmonary Embolism (PE).
–
Transient Ischemic Attack (TIA).

The time from randomization to the occurrence of all-cause death,

The time from randomization to the occurrence of all-cause death during treatment (from 
randomization to last dose of study medication),

The time from last dose of study medication to the occurrence of all-cause death,
Survival analysis using the CPH model will be performed for these additional endpoints. 
Parameter estimates and a 2-sided 95% CI for the hazard ratio will be computed. 
Kaplan-Meier plots will also be presented by treatment group.
The following other additional safety analyses will also be performed:

The number of subjects with first occurrence of predefined MACE that occur no more than 
30 days after a subject’s last dose of study drug and the associated incidence rate by 
100 patient-years of exposure along with 95% confidence intervals will be summarized by 
treatment group. The 95% CIs will be calculated based on the Poisson distribution. For a 
given treatment total patient-years (PY) of exposure will be calculated by summing across all 
subjects the total number of days on the treatment and dividing by 365.
The same analysis will be performed for each component of the MACE composite.

Mortality analyses for the overall and by CV and Non-CV cause. The total number deaths 
and the death rate with 95% CI will be presented. The 95% CIs for the death rate will be 
calculated based on the Binomial distribution using exact method.

The number and percentage of subjects with first occurrence of a pre-defined MACE 
composite will be presented by number of days in the study.

List of CV risk factors for subjects with a predefined MACE composite comprising diabetes, 
hypertension, hyperlipidemia, obesity, and smoking will be provided by treatment group.
Listings include subject number, age, gender, baseline renal function, primary MACE 
component, disposition, primary reason for discontinuation if disposition is early term, and 
CV risk factors.
6.12.4 Adverse Events
An adverse event (AE) will be defined as any AE, regardless of relationship to study drug, that 
occurs on or after the date of randomization and up to 30 days after the last dose. An event with a 
reported onset date after the subject has signed the informed consent document but prior to the 
date of randomization will be considered a pre-treatment event. Treatment-emergent adverse 
events (TEAEs) are defined as AEs whose onset occurs, severity worsens or intensity increases 
after receiving the study medication and up to 30 days after the last dose. Treatment-related 


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adverse events will be defined as treatment-emergent AEs which were identified by the 
investigator to be related to study drug.
Treatment-emergent adverse events will be summarized using the latest Medical Dictionary for 
Regulatory Agencies (MedDRA) coding dictionary. In general all AEs will be tabulated at each 
of the following levels by treatment group and overall: overall summary (subject with at least 
1 AE), the MedDRA system organ class (SOC), the MedDRA high level term (HLT), and the 
MedDRA preferred term (PT). Tabulations at each level of a term will present count (n) and 
percentage of subjects reporting any event for that term. Subjects reporting more than one 
occurrence for the term (level) being summarized will be counted only once. Summaries 
involving severity (or relationship to study drug) will use the most severe (or most related) event 
when a subject has more than one event for a term. If the severity level of an AE is missing, the 
intensity of AE is considered to be severe.
Adverse events will be summarized as follows:

A high-level summary of AEs which include the numbers and percentages of subjects for the 
following categories:
–
Any TEAE, any treatment-related TEAE, any TEAE leading to study drug withdrawal, 
any treatment-emergent serious adverse event (SAE), any treatment-related SAE, and any 
death.

All treatment-emergent/ treatment-related treatment-emergent AEs.

Treatment-Emergent Adverse Events by System Organ Class.

Treatment-Emergent Adverse Events by Preferred Term.

All TEAEs by relationship to study drug.

All treatment-emergent/ treatment-related treatment-emergent AEs for subjects in each of the 
following subgroups:
–
Baseline Renal function.
–
Prophylactic medication taken.

All treatment-emergent/treatment-related treatment-emergent AEs by MedDRA system 
organ class and high level term versus severity.

Rash treatment-emergent/ treatment-related treatment-emergent AEs.

Treatment-emergent/ treatment-related treatment-emergent serious AEs.

Treatment-emergent/treatment-related treatment-emergent AEs Leading to Study Drug 
Withdrawal.

Treatment-emergent/treatment-related treatment-emergent serious AEs Leading to Study 
Drug Withdrawal.

All pre-treatment AEs.
The following listings will also be provided:

All unique MedDRA terms.

Adverse Events Leading To Study Drug Withdrawal During Treatment Period.


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
Serious Adverse Events.

Adverse Events Resulting in Deaths.
The number of AEs per 100 subject-years will be displayed for each level of summarization in 
all AE Tables. This calculation counts all episodes of an AE, including multiple events for the 
same subject. For a given treatment total patient-years (PY) of exposure will be calculated by 
summing across all subjects total number of days on the treatment and dividing by 365.
6.12.5 Clinical Laboratory Evaluations
Laboratory data include hematology, chemistry, and urinalysis variables. Laboratory data will be 
summarized at baseline and each post-baseline visit. The laboratory analyses will be performed 
on values obtained on study and no more than 7 days after last dose of study drug. For 
Hematology and Urinalysis since laboratory assessments are done only at screening, only 
baseline descriptive summaries will be provided.
6.12.5.1 Mean Change from Baseline
For serum chemistry laboratory variables, descriptive statistics will be presented for baseline, 
post-baseline, and change from baseline. 
6.12.5.2 Markedly Abnormal Laboratory Values
For chemistry serum laboratory variables, the number and percentage of subjects with at least 
one markedly abnormal value at each post-baseline visit and the end of study will be presented. 
In addition, the number and percentage of subjects with any markedly abnormal value for serum 
chemistry variables will also be presented at each post-baseline visit.
Criteria for identifying markedly abnormal values have been established by Takeda
Pharmacovigilance and Clinical Science Departments, and values meeting the criteria will be 
listed by subject.
6.12.5.3 Shifts Relative to Normal Range
Shift tables showing the number of subjects with low, normal, or high values at each 
post-baseline visit according to the central laboratory’s reference ranges will be presented.
6.12.6 Vital Signs
Descriptive statistics for baseline, post-baseline, and change from baseline will be computed by 
treatment group for all vital sign parameters (pulse rate, systolic blood pressure, and diastolic 
blood pressure). Data collected from baseline and up to 7 days after a subject’s last dose of study 
drug will be included.
For each vital sign parameter, the number and percentage of subjects with at least one markedly 
abnormal value at each post-baseline visit and the end of study will be presented. In addition, the 
number and percentage of subjects with any markedly abnormal value for a vital sign parameter 
will also be presented at each post-baseline visit. Listing of Markedly Abnormal Laboratory 
Values will also be presented.


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6.12.7 12-Lead ECGs
The number and percentage of subjects in each overall ECG interpretation category (normal, 
clinically significant abnormal, non-clinically significant abnormal) at baseline and Final Visit/ 
Early Termination will be summarized. Percentages will be based on the number of subjects with 
values at each visit. Data collected from baseline and up to 7 days after a subject’s last dose of 
study drug will be included.
In addition, shift tables showing the number of subjects with normal, clinically significant 
abnormal, or non-clinically significant abnormal ECG interpretation results at post-baseline visit 
will be provided.
For the ECG interpretation summaries, if a subject has multiple interpretations at a particular 
visit, the most significant result will be selected for summary.
6.13
Interim Analysis
This study is designed to have a maximum of 624 MACE composite events for assessing 
non-inferiority of febuxostat relative to allopurinol with regard to cardiovascular risk assuming a 
true hazard ratio of 1.0 and 90% power. Interim analyses will be conducted when approximately 
25%, 50% and 75% of the events or equivalently approximately 156, 312, and 468 events have 
occurred, followed by a final analysis. In this group sequential trial with 4 equally-spaced 
analyses and a one-sided overall significance level of 0.025, the Lan-DeMets alpha spending 
approach with an O’Brien-Fleming stopping boundary will be used. Table 6.c displays the 
projected critical boundaries and the overall 1-sided 2.5% significance level spending at each 
interim analysis obtained from the O’Brien-Fleming spending function. East®5.3 was used to 
determine the critical boundaries.
Table 6.c
O’Brien-Fleming Spending Function
Interim 
Look
Information
Fraction
Critical 
Boundary
Alpha Spending at 
Each Interim
Cumulative Alpha 
Spending
1
156/624 = 0.25
4.333
0.000
0.000
2
312/624 = 0.50
2.963
0.002
0.002
3
468/624 = 0.75
2.359
0.008
0.010
4
624/624 = 1.00
2.014
0.015
0.025
Therefore, at the 3 interim and at the final analyses, one-sided confidence intervals for the hazard 
ratio of febuxostat relative to allopurinol for the primary endpoint will be constructed using 
critical values obtained using the Lan-DeMets -O’Brien-Fleming alpha spending function. At 
each analysis, if the upper confidence limit of the hazard ratio is ≤1.3, the study will be stopped 
and the non-inferiority of febuxostat relative to allopurinol with regard to cardiovascular risk will 
be declared. If non-inferiority is declared at an interim analysis, subsequent analyses of the 
primary endpoint will be considered sensitivity analyses.
Periodically during the course of the study, a blinded assessment of the annual adjudicated 
MACE rate will be made. The number of subjects planned to be enrolled in this study was based 


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on an event rate of 2.8%, which was based on limited information. Based on the overall blinded 
MACE rate observed, an assessment will be made to determine whether or not to adjust the 
number of subjects planned for enrollment.
At the DMC meeting on 
, the 75% interim analysis results based on 468 
adjudicated MACE for the primary MACE endpoint to assess cardiovascular safety was
reviewed by the DMC. At the DMC meeting on 
, the DMC informed Takeda that 
the non-inferiority criterion for the primary endpoint was met at the 75% interim analysis 
conducted in
. According to the study design, the study should have been stopped and 
the non-inferiority of febuxostat relative to allopurinol with regard to cardiovascular risk should 
have been declared. However the DMC recommendation was to continue the trial without 
modification until the maximum 624 unique events were achieved to further assess all cause 
mortality (which was not a protocol specified endpoint) and CV mortality (which is specified 
only as a component of the MACE endpoint). Takeda agreed to follow the DMC 
recommendation and continue the study.
Based on the group sequential design, the 75% interim analysis will be the primary analysis for 
the primary MACE endpoint for the purpose of statistical inference. The continuation of the 
study to protocol-specified maximum events (624 unique MACE) is for the assessment of all 
cause mortality and CV mortality. The analyses of all cause mortality and CV mortality with and 
without death events after discontinuation of treatments will be added to the end of study 
analysis. An updated sensitivity analysis for the primary MACE endpoint based on 624 unique 
MACE will also be conducted to provide additional supportive evidence for the primary 
endpoint.
6.13.1 DMC and Independent Statistical Group
An Independent Statistical Group (ISG), 
, has been appointed to support 
statistical activities for all the interim analyses as well as for routine Data Monitoring Committee 
(DMC) reviews. The independent statistician is external to TGRD and will neither be involved in 
the direct conduct of the study nor be involved in activities related to the adjudication of CV 
events. Further, the CV adjudication committee (CEC) members are not involved in the conduct 
of any of the febuxostat clinical trials or in the DMC.
The blinded data required for the DMC reviews and for the three interim analyses will be sent to 
the ISG by Takeda. The randomized treatment assignment for each subject will be provided 
directly to the independent statistician by the IVRS vendor. The ISG will perform the unblinded 
analyses and will provide the unblinded results to the DMC directly.
6.14
Changes in the Statistical Analysis Plan from the Protocol Analysis Plan
6.14.1 Amendment 1 
There are no changes from the protocol analysis plan. The statistical analysis plan provides 
further details regarding the planned analysis of this study.
The following changes from the original SAP were made in this amendment. 
 
PPD
PPD
PPD
PPD
PPD


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In Section 3.2 Study Design, details were added to specify how the double-blind nature of the 
study will be maintained and to clarify that subjects who prematurely discontinue treatment will 
continue to be followed until the end of the study or until the subject experiences a CV event 
positively adjudicated as a MACE.
In Section 6.4 Disposition of Subjects, comparisons between treatment groups were added for 
the rate of premature discontinuation both overall and by reason for discontinuation using 
Fisher’s exact test.
In Sections 6.5.1 - 6.5.4 and Section 6.6, clarification that summaries will be presented by 
treatment group was added.
In Section 6.12 Safety Analysis, the SAP was amended to clarify that subjects who are lost to 
follow-up during the study will be censored in the primary safety analysis at the day of last 
contact.
In Section 6.12.1 Primary Safety Endpoint, the method that will be used to examine the Cox 
Regression model proportional hazards assumptions was added. In addition, the purpose of the 
multivariate CPH model was clarified as exploratory and the variable selection method was 
added.
To be consistent with the analysis specified in the protocol, an additional analysis on the primary 
safety endpoint using Cox-proportional hazards model controlling for the effect of NSAIDs use
was included. A similar analysis controlling for the effect of low-dose aspirin was also added.
In Section 6.12.2 Secondary Safety Endpoint; an exploratory analysis was added using a 
multivariate CPH model to identify risk factors for the time to first occurrence of APTC event.
In Section 6.12.4 Adverse Events, it was specified that the latest version of the MedDRA coding 
dictionary will be used to summarize adverse events.
In Section 6.13 Interim Analyses, the critical values from the Lan-DeMets-O’Brien-Fleming 
alpha spending function to be used for the interim analyses were provided. Subsection, 
Section 6.13.1 was renamed from ‘Independent Statistical Group’ to ‘DMC and Independent 
Statistical Group’. The subsection provides details regarding who will be conducting the interim 
analysis and that the ISG will be independent from the adjudication committee and other study 
related activities.
6.14.2 Amendment 2
In Section 4.3, the time from randomization to the occurrence of all-cause death, the time from 
randomization to the occurrence of all-cause death during treatment, and the time from last dose 
of study medication to the occurrence of all-cause death were added as additional endpoints. In 
Section 6.12.3, survival analysis using the CPH model and Kaplan-Meier plots for these 
additional endpoints were added.
In Section 6.2, the summarization of major protocol violations was clarified.
In Section 6.5, an additional summary of concomitant medications that were ongoing at baseline 
or started after baseline was added.


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In Section 6.6, the duration of study participation in days was clarified as the date of last contact 
- date of randomization +1. The summary of adjustments to dosing was also clarified.
In Section 6.7.1, clarification was made that the estimate of the tophi resolution rate using the 
life-table method will be based on the first resolved primary tophus. Additional summaries of 
tophi resolution by the end of Years 5, 6 and 7 were also added.
In Section 6.12.3, diabetes, hypertension, hyperlipidemia, obesity, and smoking were specified 
as CV risk factors.
The planned statistical inference between treatment groups for adverse events, laboratory 
evaluations, and vital signs was deleted from Sections 6.12.4, 6.12.5, and 6.12.6, respectively. 
In Section 6.13, clarification was added that if non-inferiority is declared at an interim analysis, 
subsequent analyses of the primary endpoint will be considered sensitivity analyses.
Throughout the SAP, updates were made to reflect the longer expected duration of the study. 
This included additional visits and corresponding visit windows added to Table 6.a as well as 
additional intervals for summarization of premature discontinuations in Section 6.4, of treatment 
duration in Section 6.6, and of gout flares in Section 6.7.1.
6.14.3 Amendment 3
In Section 6.13, language about the primary analysis of the study report was added by the un-
blinded team (Amendment 3 of this SAP will remain sequestered to the blinded team until 
database lock and un-blinding).
Approval signature page for the un-blinded team was added on Page 2.


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7.0
REFERENCES
1. Marcus R, Peritz E, Gabriel KR. On closed testing procedures with special reference to 
ordered analysis of variance. Biometrika. 1976;63(3):655-660. TAP-08-000744.
2. Kalbfleisch, J.D., Prentice, R.L. The statistical analysis of failure time data. New York: John 
Wiley & Sons, Inc, 1980.
3. Keene ON, Jones MR, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and 
chronic obstructive pulmonary disease: example from the TRISTAN study. Pharm Stat 2007; 
6(2):89-97.
4. Jennison C, Turnbull B. W. Group sequential methods with applications to clinical trials. 
Chapman & Hall/CRC, 2000.
5. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 
35:549–56.
6. Schoenfeld, D. Partial residuals for the proportional hazards regression model. Biometrika, 
1982, 69:239-241.


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8.0
LIST OF APPENDICES
Appendix A Criteria for Identification of Markedly Abnormal Laboratory Values
Chemistry - Criteria for Markedly Abnormal Values
Parameter (Units)
Low Abnormal
High Abnormal
Albumin (g/dL)
≤2.4

Alkaline Phosphatase (IU/L)

>=1.5 x ULN
ALT (IU/L)

(a) ≥3 x ULN
(b) ≥5 x ULN
(c) ≥10 x ULN
(d) ≥20 x ULN
(e) ≥3 x ULN and Total Bilirubin >1.5 x ULN and
(f) ≥3 x ULN and Total Bilirubin >2 x ULN
AST (IU/L)

(a) ≥3 x ULN
(b) ≥5 x ULN
(c) ≥10 x ULN
(d) ≥20 x ULN
(e) ≥3 x ULN and Total Bilirubin >1.5 x ULN and
(f) ≥3 x ULN and Total Bilirubin >2 x ULN
Total Bilirubin (mg/dL)

≥2.0
Bicarbonate (mEq/L)
≤17
≥41
BUN (mg/dL)

≥31
Calcium (mg/dL)
≤7.0
≥12.0
Chloride (mEq/L)
≤79
≥121
Creatinine (mg/dL)

≥1.5 and increased from baseline by ≥0.3
Glucose (mg/dL)
≤49
≥301
Inorganic Phosphorus (mg/dL)
≤1.5
≥9.0
LDH (IU/L)

≥3 x ULN
Potassium (mEq/L)
≤2.9
≥5.9
Sodium (mEq/L)
≤124
≥151
Total Cholesterol (mg/dL)

≥350 and increased from baseline by ≥100
Total Protein (g/dL)
≤4.5

Triglyceride (mg/dL)

≥2 x ULN and increased from baseline by ≥100
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, LDH=lactate 
dehydrogenase, ULN=upper limit of normal.


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Appendix B Criteria for Identification of Markedly Abnormal Vital Sign Values
Vital Signs - Criteria for Markedly Abnormal Values
Parameters (Units)
Low Abnormal
High Abnormal
Systolic Blood Pressure (mm Hg)
<85 or drop >30 From Baseline
>180
Diastolic Blood Pressure (mm Hg)
<45 or drop >20 From Baseline
>110
Pulse (Beats/min)
<50
>120
Baseline is defined as the last measurement prior to the first dose of study drug.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d68056cc01
TMX-67_301 Statistical Analysis Plan Amendment #3 2017-02-22
Biostatistics Approval
23-Feb-2017 21:59 UTC
Clinical Science Approval
23-Feb-2017 23:21 UTC
Pharmacovigilance Approval
24-Feb-2017 19:38 UTC
PPD