Clinical trial NCT02579096
Conditions: Gout Chronic Kidney Diseases
Keywords: Gout Allopurinol Febuxostat CKD
Sponsor: VA Office of Research and Development
Start date: 2017-03-06; Completion date: 2021-04-15
Enrollment: 950 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will compare two effective therapies, allopurinol and febuxostat, to lower serum uric acid and therefore prevent further gout attacks. These therapies have never been compared at appropriate doses. Further, they will be studied in patients with kidney disease for the first time.

Detailed description:
Gout is the most common form of inflammatory arthritis affecting adults (1), with a disease frequency that continues to increase dramatically (2). Gout is associated with substantial morbidity and mortality which are concentrated in older men and magnified in patients with chronic kidney disease (CKD) (3-6), demographics common to the Veterans Affairs (VA) Health System. Effective gout therapies are readily available and are centered primarily on the use of approved urate lowering therapy (ULT). Despite having excellent ULT options available to patients (7), gout is extremely poorly managed especially in patients with CKD (8-10).

The two most widely used ULTs in clinical practice, allopurinol and febuxostat, have recently been endorsed as the two acceptable first-line treatment strategies in chronic gout (7). Although both agents appear to be efficacious and generally well-tolerated, allopurinol and febuxostat have significantly different costs and have never been compared to each other at appropriate doses. Randomized controlled trials completed to date comparing allopurinol with febuxostat in gout have used 'fixed' and, in many cases, insufficient doses of allopurinol (11-13), an approach that is contrary to current guideline recommendations (7). Furthermore, these studies have included only very small proportions of gout patients with CKD even though CKD is present in approximately 1 of every 2 gout sufferers (14).

To test the hypothesis that allopurinol is non-inferior to febuxostat in the treatment of gout, the investigators propose a randomized open-label non-inferiority trial, which for the first time compares allopurinol with febuxostat using appropriately titrated doses and a "treat-to-target" approach. Further, the investigators will assess the comparative effectiveness of these agents in a significant number of gout patients with co-morbid CKD.

The investigators plan to enroll 950 participants with a diagnosis of gout, including participants with stage 3 CKD, who are hyperuricemic defined as a serum uric acid concentration (sUA) above 6.8 mg/dl. Participants will be recruited from 18 Veteran Affairs and 5 Rheumatology and Arthritis Investigational Network (RAIN) sites. The total duration of the trial will be 4 years. Recruitment will occur over 24 months. Participants will be followed for 72 weeks. This will include a 24 week Dose Titration Phase (Phase 1) followed by a 24 week Maintenance and Optimization Phase (Phase 2) and then a 24 week Steady State Flare Observation Phase (Phase 3). The investigators will use a "treat-to-target" approach with specified titration of ULT dosing to obtain goal sUA. Maximal daily drug doses will be 800 mg/day for allopurinol or 120 mg/day for febuxostat.

The primary outcome will be the proportion of participants who have at least one gout flare in the allopurinol group compared to the febuxostat group during Phase 3. This primary outcome was endorsed by the patient and VA provider groups that were surveyed (see below). All participants will be followed during Phase 3 regardless of the achievement of sUA goal. The primary hypothesis will test the non-inferiority of allopurinol with regards to proportions of flares. The investigators anticipate that approximately 15 to 20% of patients will flare during Phase 3.

Arms: arm 1: Patients will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Febuxostat will be given with allopurinol arm 2: Febuxostat will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Allopurinol will be given with Febuxostat
Interventions: intervention 1: allopurinol capsule, 100-800 mg by mouth once daily intervention 2: febuxostat tablet 40-120 mg by mouth once daily intervention 3: Placebo, vehicle control (febuxostat-shaped) intervention 4: Placebo, vehicle control (allopurinol-shaped)
Intervention descriptions: intervention 1: Patients will be up-titrated up to the dose required to reach target uric acid levels. intervention 2: Patients will be up-titrated to the dose required to reach target uric acid levels. intervention 3: Placebo tablets resembling febuxostat will be given with allopurinol. intervention 4: Placebo capsules resembling allopurinol will be given with febuxostat.

Protocol documents:
ICF_000.pdf: 
 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 1 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
INTRODUCTION 
 
You are being invited to take part in a research study that is being funded by the Department of 
Veterans Affairs.  Before you decide to take part, it is important for you to know why the 
research is being done and what it will involve.  This includes any potential risks to you, as well 
as any potential benefits you might receive.    
 
Read the information below closely; if you wish, you can discuss it with family and friends. If 
there is anything that is not clear or if you would like more details please ask one of the study 
staff to explain them to you.  Take your time to decide.  If you do decide to take part in this 
study, your signature on this consent form will show that you received all of the information 
below, and that you were able to discuss any questions and concerns you had with a member of 
the study team.   
 
BACKGROUND AND PURPOSE 
 
What is the purpose of this research study? 
The purpose of this research study is to find out whether the two medications Allopurinol and 
Febuxostat work as well as each other for preventing gout attacks. This is a double blind 
placebo controlled study meaning you will not know which treatment you are receiving during 
the duration of the study.  Both of these medications have been approved and are currently 
used to prevent gout attacks, though the FDA recommends that allopurinol be tried first.. They 
work by lowering the level of uric acid in your body that causes gout attacks. However, we do 
not know which medication is best, what doses are needed to gain the most benefit, or whether 
certain patients may do better with one medication or the other.  
 
We will also determine which medication may be more effective in treating patients who have 
gout and who also have decreased kidney function.  Gout is a common disease among Veteran 
patients and treating it more effectively and efficiently to prevent gout attacks is an important 
goal for the VA.    
 
Why am I being asked to participate in this research study? 
You are being asked to participate in this research study because you have a history of gout 
and your recent blood uric acid level is at a high level when gout attacks may occur.  
 
 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 2 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
What kind of treatment would I receive if I wasn’t in this research study? 
If you were not in the research study, the treatment you would receive for your gout would be 
handled by your regular doctor. That  treatment may include allopurinol or febuxostat or any 
other medications used to lower uric acid or prevent gout attacks.    
 
What are the treatments I will receive as part of this research study and are these treatments 
approved by the Food and Drug Administration (FDA)? 
As part of this study, you will be assigned by chance (like a flip of a coin) to receive either 
allopurinol or febuxostat. You would have a 50:50 chance of receiving either medication.  
Allopurinol and febuxostat have both been shown to be effective in gout and are approved by 
the FDA; however, febuxostat is only recommended for patients whose gout is not controlled 
with or cannot tolerate allopurinol. 
 
Who will be conducting the research study and who is sponsoring this research? 
This study is being conducted at < insert VA name > as well as other VA and non-VA hospitals 
across the United States and is being sponsored by the Department of Veterans Affairs.  
 
How many people are going to participate in this research study? 
There will be about 950 participants in the study from about 20 VA Medical Centers  located all 
across the US.  Locally at <insert VA name>. 
 
DURATION OF THE RESEARCH   
 
Your individual participation in the project will take 72 weeks (approximately 18 months), during 
which you will be taking study medications.  We will check your medical records 30 days later to 
see if you report any gout related issues. This research study overall is expected to take 
approximately 4 years (48 months) for all participants to complete.  We will continue to review 
your medical records for 10 years to track your health (review will be conducted up to10 years 
after the last participant’s final study visit); however, we will not need to contact you during this 
time.  This is a 72 week blinded study, therefore the blind will be broken and care will be 
returned to your primary care doctor. Information on your gout control will be available to your 
doctor and the study drug that you were receiving will be known.  Treatment decisions after the 
study will be up to your primary care doctor’s discretion. Data will be revealed at the end of the 
72 weeks. 
 
 
 
 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 3 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
STUDY PROCEDURES 
 
Initial/Screening Visit  
After you sign this consent form, we need some additional information to see if you can continue 
in the full study.  We will ask you questions about your gout condition to determine your 
eligibility.  You will be asked about any prescribed and over-the-counter medications you are 
taking. We will draw a sample of blood (about 2 tablespoons) to check your uric acid level, liver 
and kidney function. Drawing blood involves venipuncture (a small needle is inserted into a vein 
in your forearm). This visit will take approximately 1 hour of your time.   
 
Initial/Screening Visit (cont’d) 
If any information from the initial screening visit indicates that you are not eligible for the study, 
you will be referred to your doctor to continue your regular care based on his or her advice.  If 
after the screening tests you are considered eligible to continue in the study, you will be 
scheduled for a study entry visit. This visit can be done either at the same time as your 
screening visit if your eligibility is confirmed then, or you will be asked to return within 2 weeks of 
your screening visit.   
 
Study entry visit  
You will be randomized to receive either allopurinol or febuxostat, having a 50:50 chance to 
receive either medication. You will receive two sets of study pills to take at the same time. One 
set will be the actual medication; the other set will look like the other medication, but it will in fact 
be a placebo (an inactive sugar pill). Neither you, the research team nor your regular doctors 
will know which active medication and which placebo you are receiving. This visit will take up to 
2 hours.  
 
While in the research study, you will be asked to take the study medications for 72 weeks.  Both 
sets of pills (active and placebo) can be taken at the same time, morning or evening, with or 
without food.  While in this study you will be asked not to make any changes in any of your other 
medications unless absolutely necessary, and only with permission of your doctor.  The 
research team will be available to you for any questions regarding the study medications and 
how you should take them.  
 
At the study entry visit, you will be asked to complete several questionnaires about your health-
related quality of life and alcohol use, have blood pressure and weight measured, and have a 
blood test (about two tablespoons) to measure blood counts and inflammation in your body. 
These blood tests will include: 
 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 4 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
• 
Complete blood count (CBC)  
• 
Tests to measure the level of uric acid in your blood 
• 
Tests to measure the function of your liver and kidneys (standard blood tests your doctor 
would order to monitor the effect of the medications on your body). 
• 
Tests to measure inflammation in the body 
 
In-person study visits (until week 48) 
You will come to the Study Center every six (6) weeks for blood tests and evaluation by the 
study doctor and/or study coordinator.  At each visit you will have your blood pressure taken, 
and you will talk with the physician and discuss any side effects you may be having and any 
changes in your medications, your gout and your general health. You will also be asked about 
taking your study medication, and may have your dose increased based on the results of your 
blood tests.  At the week 24 visit, you will be asked to complete questionnaires about your 
health (the same as at the beginning of the study). These visits will take approximately 30 
minutes of your time and are very important to make sure you are receiving the correct dose of 
study medication to treat your symptoms. 
 
Blood tests: To monitor for side effects and how well the medication is working, the same 
amount of blood (approximately 2 tablespoons) will be drawn again every 6 weeks for 48 
weeks. You may also need to have blood tests for uric acid level done at weeks 9, 15 and 
21 if your uric acid level remains too high. These blood tests will include those you will 
receive during your study entry visit. 
 
Phone visits  
Starting at week 3, the study coordinator will call you every six weeks until week 21 (weeks 3, 6, 
9, 15, 21), then again at weeks 30 and 42 to discuss medication side effects, any changes in 
your gout, and whether you have been taking the study medication as prescribed. These phone 
calls will occur on the weeks between your in-person visits to the Study Center (for example, 
phone call at week 3 and in-person study visit at week 6). These phone calls will take 
approximately 5-10 minutes of your time.  
 
In-person 48-week visit 
At the 48 week visit, or if you leave the study early, you will have blood pressure and weight 
measurements, blood tests done, and you will complete the same questionnaires about your 
health and alcohol use as at the beginning of the study. You will also be asked about any side 
effects, medication changes, taking your study medications, and will be asked to return your 
unused study medications. This visit will take up to 2 hours.  
 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 5 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
Study visits (phone and in-person) after 48 weeks 
Active treatment with the study medications ends at 72 weeks. After you have had your 48 week 
visit, we will be calling you every 4 weeks to ask about any gout attacks that you may have had 
and whether you have been taking the study medication as prescribed. These phone calls will 
take approximately 5-10 minutes of your time at weeks 52, 56, -, 64, and 68. At week 60 and 72, 
or if you leave the study early we will ask you to come for an in-person study visit.  You will have 
blood pressure and weight measurements taken, blood tests done, you will also be asked about 
any side effects, medication changes, taking your study medication,and any gout attacks.  You 
will also be asked to return your unused study medications. This visit will take up to 2 hours. In 
addition, at week 72 you will complete the same questionnaires about your health and alcohol 
use as at the beginning of the study.. 
 
Gout Attack Diary 
We will ask you to keep a diary of gout attacks that occur in between study visits and phone 
calls so that it’s easier for you to remember information about the gout attack when they are 
discussed during your study visits. These diaries will ask you a few specific questions about 
your gout attacks that occur in between study visits.   
 
After study participation has ended 
After you complete study participation, during which you will be taking study medications, you 
and your doctor will be told which drug you were taking (allopurinol or febuxostat). This is so 
that after the study your provider has the information to treat your gout appropriately. We will 
check your medical record 30 days later to see how you are doing and whether you reported 
any gout-related complaints to your doctor.  
 
POSSIBLE RISKS OR DISCOMFORTS 
 
Any procedure has possible risks and discomforts. The procedures in this study may cause all, 
some or none of the risks or side effects listed.  Rare, unknown, or unforeseeable (unexpected) 
risks also may occur. The following is not an all-inclusive list, but includes conditions that are 
more likely to occur than others. Rare, unknown, or unforeseeable (unexpected) risks also may 
occur.  For more information about allopurinol or febuxostat you may consult further with the 
study doctor or refer to a standard text such as the Physicians’ Desk Reference (PDR) or the 
United States Pharmacopoeia Dispensing Information (USPDI).  
Risks and side effects related to allopurinol are listed below:  
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 6 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
• 
The most common side effects reported by patients or detected by doctors include: mild 
skin rash, gout attack, loose stools (diarrhea), upset stomach, nausea, and increased 
liver proteins.  
o 
As we adjust the dose to lower your uric acid levels, allopurinol may cause you 
to experience an increase in gout attacks, but this should go away after the first 
few weeks. You will be given medications to minimize this temporary risk of gout 
attacks.  
• 
Less frequent side effects, reported by patients or detected by doctors less than 1% of 
the time, include moderate to severe skin reactions, decreased blood cell or platelet 
count, liver damage, kidney problems, and general allergic reaction. Although these side 
effects are very rare, some may be more serious than the more common side effects. 
o 
Skin reactions can range from a mild rash to a severe skin reaction. Symptoms 
of this allergic reaction may include bumps, spots or blisters on the skin, large 
areas of peeling skin, and sores in and around the eyes and mouth. The skin 
and eye reactions may also be accompanied by other whole-body symptoms 
such as itching, body aches, and fever, and can damage your liver and kidneys. 
You will be monitored closely for skin reactions. 
o 
Symptoms of general allergic reaction can include similar symptoms to skin 
reaction but also swelling and/or tightening of the chest, face and/or throat. Very 
rarely, these reactions can be life threatening.  Please notify your study doctor 
immediately if you are having an allergic reaction. Promptly stopping the 
medications reduces the risk of life threatening complications. 
o 
Liver problems can range from mildly increased liver proteins to severe liver 
damage. Signs of liver problems include dark urine, feeling tired, not hungry, 
upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin 
or eyes. Please notify your study doctor immediately if you are having any of 
these symptoms. 
Risks and side effects related to febuxostat are listed below:  
• 
The most common side effects reported by patients or detected by doctors between 1 to 
10% of the time include: mild skin rash, joint pain, gout attack, upset stomach, nausea, 
dizziness, and increased liver proteins.  
o 
As we adjust the dose to lower your uric acid levels, febuxostat may cause you 
to experience an increase in gout attacks, but this should go away after the first 
few weeks. You will be given medications to minimize this temporary risk of gout 
attacks.  


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 7 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
• 
Less frequent side effects, reported by patients or detected by doctors less than 1% of 
the time, include moderate to severe skin reactions, decreased blood cell or platelet 
count, liver damage, mood changes, heart and blood vessel problems including a heart 
attack or stroke, and general allergic reaction. Although these side effects are very rare, 
some may be more serious than the more common side effects.  
o 
Skin reactions can range from a mild rash to a severe skin reaction. Symptoms 
of this allergic reaction may include bumps, spots or blisters on the skin, large 
areas of peeling skin, and sores in and around the eyes and mouth. The skin 
and eye reactions may also be accompanied by other whole-body symptoms 
such as itching, body aches, and fever, and can damage your liver and kidneys. 
You will be monitored closely for skin reactions. 
o 
Symptoms of general allergic reaction can include similar symptoms to skin 
reaction but also swelling and/or tightening of the chest, face and/or throat. Very 
rarely, these reactions can be life threatening.  Please notify your study doctor 
immediately if you are having an allergic reaction. Promptly stopping the 
medications reduces the risk of life threatening complications. 
o 
Liver problems can range from mildly increased liver proteins to moderate liver 
damage. Signs of liver problems include dark urine, feeling tired, not hungry, 
upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin 
or eyes. Please notify your study doctor immediately if you are having any of 
these symptoms. 
o May increase the risk of heart-related death and death from all causes 
compared to allopurinol, in people who already have heart disease. This study 
will help us understand any difference in heart and blood vessel problems 
between these two approaches to treating your gout.You should call your doctor 
or get emergency help right away if you have any of the following symptoms: 
▪ 
Chest pain  
▪ 
Numbness or weakness in one side of your body  
▪ 
Shortness of breath or trouble breathing  
▪ 
Slurring of speech  
▪ 
Dizziness, fainting or feeling lightheaded  
▪ 
Rapid or irregular heartbeat 
 
Contact your study doctor right away if you experience any of these side effects or any other 
unusual symptoms. Your study doctor will be following you to see if any side effects from any of 
these medications occur, and will manage these symptoms with treatments that are appropriate 
for you.  We will also follow your blood counts, kidney and liver function test closely during the 
study.  It is important that you report promptly any side effect experienced to your study doctor.  
If you or your study doctors feel that the side effects are not acceptable, study medications may 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 8 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
be stopped altogether. There may be some risk for those patients taking higher doses of 
febuxostat that have not yet been approved by the FDA, but it is approved and widely used 
outside the U.S. The study team will continue to monitor your health throughout the study in 
order to minimize this risk. If toxicity develops and the toxicity is severe enough to require your 
removal from the protocol then the blind will be broken meaning you and your physician will be 
informed of the drug you were receiving during your participation in this study. 
 
Prophylatic medications such as colchicine, naproxen or prednisone will be given to you to help 
prevent flares.  These medications are given to you while you are at an increased risk of flares, 
including while your uric acid levels are going down.  For this study these medications will be 
stopped at week 48.  Stopping these prophylactic medications, for some subjects, may slightly 
increase the chance of experiencing the symptoms of a gout flare.  Importantly, the urate 
lowering medications, Allopurinol or Febuxostat will of course be continued.  If flare symptoms 
occur, contact the appropriate study staff personnel for further guidance. 
 
We will make every effort to make study visits and phone calls as convenient for you as possible 
by scheduling your research visits during your regular clinic visits. You will have blood drawn up 
to 14 times over the course of the study to review and adjust your medications. The needle 
sticks from having blood drawn may cause pain (like a pinch), or bruising, and, rarely, infections.  
Very rarely, patients become lightheaded or faint from having blood drawn.     
 
We do not anticipate side effects from the placebo for Allopurinol or for Febuxostat.  It has been 
shown in some studies that the psychological impact of a placebo may cause side effects 
similar to those described for a study treatment in some participants. 
 
Blood draw may cause pain and a bruise. Some people may become light-headed (dizzy) or 
faint after blood drawing. There is also a rare risk of infection at the site of the blood draw. 
 
As this study involves the use of your identifiable, personal information, there is a chance that a 
loss of confidentiality will occur. The researchers have procedures in place to lessen the 
possibility of this happening (see “Confidentiality” section below) 
 
Risks of the usual care you receive are not risks of the research.  Those risks are not included 
in this consent form.  You should talk with your health care providers if you have any questions 
about the risks of usual care.   
 
 
 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 9 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
POTENTIAL BENEFITS 
 
• 
Advancement in knowledge regarding treatment practices in gout will be of scientific and 
public health value  
• 
Participating subjects may benefit from increased monitoring that is related to study 
participation  
• 
Participating subjects may also benefit from better control of uric acid and therefore fewer 
gout attacks. 
 
ALTERNATIVES TO PARTICIPATING IN THIS RESEARCH 
 
If you chose not to participate your doctor will continue to treat you just as they did before. Both 
of the medications studied in this trial are available to be used.  In some cases at the VA, 
physicians are required to use allopurinol before febuxostat is tried.  
 
You may discuss these options with your doctor.   
 
CONFIDENTIALITY 
 
Taking part in this study will involve collecting private information about you.  Confidentiality 
cannot be guaranteed, but your private information will be protected in a number of ways. The 
study team will keep all research records that contain your identifiable health information 
confidential to the extent allowed by law.  All hard-copy study forms with the information we 
collect from you as part of this study will be stored in locked cabinets to which only approved 
study staff will have access. Data will be entered on computers that are protected with 
passwords to which only approved study personnel will have access. Only approved study staff 
at the study’s Coordinating Center will have access to participant identifying information.  This 
study is being conducted in multiple VA Medical Centers nationwide. Information shared among 
researchers will not be able to identify you individually. This study is also being conducted in 
multiple sites in the Rheumatology and Arthritis Investigational Network (RAIN) across the US.   
 
The study team will collect your Social Security number for this research study. The study team 
will use your Social Security number only as necessary within the VA to search your medical 
records or when there is a need to check your non-VA hospitalizations during the study or to 
check your status with other healthcare and vital status databases. We use a unique code 
instead of your name or Social Security number to identify you in our study database. If you 
choose to withhold your Social Security number, you will not be able to participate in the study. 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 10 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
Information about you will be combined with information from other people taking part in the 
study.  We will write about the combined data we have gathered.  Any talks or papers about this 
study will not identify you individually. 
 
Research records, just like hospital medical records, may be released or disclosed according to 
applicable federal and state law as well as to federal and state agencies that are responsible for 
oversight of medical research.  We will not share your records or identify you unless we have to 
by law. A researcher with IRB approval may gain access to a dataset that includes your 
information but does not identify you.  There are times when we may have to show your records 
to other people including representatives of the sponsors of this study or the Food and Drug 
Administration (FDA).  In addition someone from the Department of Health and Human 
Services, Office of Human Research Protections, the Government Accountability Office, the 
Office of the Inspector General, the VA Office of Research Oversight, the VA Central IRB, our 
local Research and Development Committee, and other study monitors may look at or copy 
portions of records that identify you. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S.Law.  This website will not include information that can identify you.  At most, the website 
will include a summary of the results. You can search this website at any time. 
 
We will put information about you from this study into your medical record.  This includes putting 
a progress note in your computerized VA medical record that states you are participating in a 
research study. 
 
COSTS TO PARTICIPANTS AND PAYMENT 
 
Costs to Participants:  You will not be charged for any treatments or procedures that are part 
of this study.  If you usually pay co-payments for VA care and medications, you will still pay 
these co-payments for VA care and medications that are not part of this study.   
 
Payment Offered for Participation: You will not be paid for participation in this study, but we 
will pay for transportation, parking, or other expenses related to participation, up to $40 per visit. 
The amount that you are reimbursed will be based on the number of miles that you travel for 
your visits.  Specifically, participants who travel less than 50 miles will receive $20 and 
participants who travel 50 miles or more will receive $40.  Reimbursement will be made 
available by <insert site specific info>. Due to limitations in the Financial Management System, 
payments made to participants through Austin Financial Services Center generate Internal 
Revenue Service Form 1099 regardless of amount.  Your SSN will be used for this purpose in 
reimbursement. 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 11 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
MEDICAL TREATMENT AND COMPENSATION FOR INJURY   
 
Every reasonable safety measure will be used to protect your well-being.  If you are injured as a 
result of taking part in this study, the VA will provide necessary medical treatment at no cost to 
you unless the injury was due to your not following the study procedures.                           
 
If you should have a medical concern or get hurt or sick as a result of taking part in this study, 
call:   
 
DURING THE DAY: 
 
Dr./Mr./Ms.                                                       at                                                 and  
 
 
AFTER HOURS: 
 
Dr. /Mr./Ms. _____                                           at ________________________.  
 
Emergency and ongoing medical treatment will be provided as needed.   
 
The major complications of uric acid lowering therapy, either allopurinol or febuxostat, are gout 
attacks and rashes.  Medications to treat any gout attacks will be provided as part of the study 
and all participants will be monitored closely for rashes. Study medications may be stopped or 
doses decreased if any rashes occur. 
You do not give up any of your legal rights and you do not release the VA from any liability by 
signing this form.    
 
PARTICIPATION IS VOLUNTARY 
 
It is up to you to decide whether or not to take part in this study. If you decide to take part you 
may still withdraw at any time.  If you do not wish to be in this study or leave the study early, you 
will not lose any benefits to which you are entitled.  If you don’t take part, you can still receive all 
usual care that is available to you.  Your decision not to take part will not affect the relationship 
you have with your doctor or other staff, and it will not affect the usual care that you receive as a 
patient.   
 
If you decide to not take your medications your blood uric acid level will increase and you will 
again be likely to experience attacks of your gout which could include painful and swollen joints. 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 12 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
If it is necessary to withdraw from the study your rheumatologist or primary care doctor will treat 
your gout.  
 
You may contact study personnel at any time if you would like to withdraw from the study.  
Contact information can be found in the section below titled, “Persons to Contact About This 
Study”  If you withdraw, study personnel may continue to review the study data already 
collected prior to your withdrawal, but they cannot collect further information about you, except 
from public records, such as survival data.  Specimens that have already been used cannot be 
withdrawn. 
 
RIGHT OF INVESTIGATOR TO TERMINATE PARTICIPATION  
 
The investigator(s) may stop your participation in this study, without your consent, for reasons 
such as: it will be in your best interest; you do not follow study procedures; or you experience a 
study-related injury.  
 
PERSONS TO CONTACT ABOUT THIS STUDY 
 
If you have any questions, complaints, or concerns about this study, you may contact the study 
investigator at your VA Medical Center or the <insert info> during regular business hours. 
 
The investigator is Dr./Mr./Ms.                        at____________________________                                              
 
The <insert info> is Dr. /Mr./Ms. _____                        at ________________________.                                   
 
If you have questions about your rights as a study participant, or you want to make sure this is a 
valid VA study, you may contact the VA Central Institutional Review Board (IRB). This is the 
Board that is responsible for overseeing the safety of human participants in this study.  You may 
call the VA Central IRB toll free at 1-877-254-3130 if you have questions, complaints or 
concerns about the study or if you would like to obtain information or offer input.   
 
FUTURE USE OF DATA AND RE-CONTACT  
 
After this study ends, your study data will be stored indefinitely at the Cooperative Study 
Program, Massachusetts Veterans Epidemiology Research and Information Center (The future 
use and re-contact for this data will be different than the data storage of the biobanking of 
specimens described below). 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 13 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
Study data will be available for use for approved research protocols by investigators who may or 
may not be associated with this study.  Researchers may link your study data with existing data 
sets, including but not limited to those maintained by the Social Security Administration, 
Department of Veterans Affairs or other organizations.  Any use of your data will comply with 
existing regulations and be approved by appropriate oversight bodies including an Institutional 
Review Board (IRB).  The IRB is a group of people, unrelated to the study, who review research 
studies to make sure your rights are protected.  The IRB may require that you be contacted for 
your consent prior to the use of your data in a new study if it decides such consent is required 
for your protection. By signing this consent form you are agreeing to be re-contacted in the 
future to request your permission for the use of your data in a new study, you may deny this 
permission for future use and still be eligible to participate in this study. 
 
BIO-BANKING OF SPECIMENS FOR AN OPTIONAL PART OF THE STUDY 
 
You are being invited to participate in an optional part of the study that will collect blood for 
future research on how your genes and markers of inflammation in the blood influence gout 
attacks, your response to gout therapies and the overall health of patients with gout.  
Please read each sentence below, think about your choice, and mark “YES” or “NO”. No matter 
what you decide to do, your decision will not affect your medical care or your 
participation in the study already described. 
 
If you agree to participate, we will collect  2 tablespoons of blood at your screening and/or 
baseline,  24 week and 48 week visits.. If you are eligible to participate in this study this extra 
blood will be banked at the Experimental Immunology Laboratory (EIL) centered at the VA 
Nebraska-Western Iowa Health Care System indefinitely.  This is VA a approved biobank. The 
long-term storage of your samples will be overseen by the Omaha VAMC Institutional Review 
Board, which is a group of people, unrelated to the study, who review research studies to make 
sure your rights are protected.  Only approved study personnel will have access to your 
specimens for this study. No samples will be removed or used from the bank until completion of 
the research study.  Any future proposal to test your blood and/or DNA samples will need to be 
approved by the appropriate oversight bodies.  If any information from the initial screening visit 
indicates that you are not eligible for the study, the extra blood will not be stored and will be 
destroyed following local policies and procedures. 
 
You will not be re-contacted about any future use of your samples. All samples sent for 
biobanking will be  marked only with a unique study ID but will not include any Protected Health 
Information.   These samples, however, can be linked with data collected as part of this 
research study. The research results from future use of these samples will not be conveyed to 
you, your family, or physician. If you agree to have your sample(s) stored in the Repository, you 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 14 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
can change your mind up until the end of the research study.  If you change your mind before 
the research ends you can send a letter to:  
Dr. Ted Mikuls MD 
983025 Nebraska Medical Center 
Emile at 45th Street 
Omaha NE 68198-3025  
 
requesting withdrawl from the biobank study.  When study researchers receive written 
instructions from you, they will destroy your samples and all information in the repository that 
identifies you.  After the research study ends, you will not be able to withdraw your samples 
because the Repository will not know which one is yours.  The samples will stay in the 
Respository indefinitely.  
 
As this study involves the use of your identifiable, personal information, there is a chance that a 
loss of confidentiality will occur. The researchers have procedures in place to lessen the 
possibility of this happening. 
Federal laws and policies provide you with protection from discrimination by health insurance 
companies, group health plans, and most employers based on your genetic information.  A new 
federal law, the Genetic Information Nondiscrimination Act (GINA) generally will protect you in 
the following ways: 
 
• 
Health insurance companies and group health plans may not request your genetic 
information obtained from this research. 
• 
Health insurance companies and group health plans may not use your genetic 
information obtained from this research when making decisions regarding your eligibility 
or premiums. 
• 
Employers with 15 or more employees may not use your genetic information obtained 
from this research when making a decision to hire, promote, or fire you or when setting 
the terms of your employment. 
 
Be aware that this new Federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 
 
 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 15 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
If you have any questions or concerns about biobanking of your samples you may contact Dr. 
Ted Mikuls M.D. during during regular business hours at 402-888-0515 
 
    YES  
My specimen(s) may be saved for future research without any 
restrictions. 
 
 
OR   
 
    YES  
My specimen(s) may be saved for future research with the following 
restrictions. 
 
Check ALL the restrictions that apply: 
 
 
  My specimens can only be used for research by the current principal 
investigator 
 
 
  My specimens can only be used for research that does not involve 
genetic testing 
 
            
  My specimens can only be used for research that involves the 
disease or condition to which this study pertains 
                       OR 
 
     NO  
I do not wish to participate. 
 
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY 
 
A member of the study staff has explained the research study to you.  You have been told of the 
risks or discomforts and possible benefits of the study. You have been told of other choices of 
treatment available to you.  You have been given the chance to ask questions and obtain 
answers.   
 
By signing this document below, you voluntarily consent to participate in this study.  You also 
confirm that you have read this consent, or it has been read to you.  You will receive a copy of 
this consent after you sign it.  A copy of this signed consent will also be put in your medical 
record. 
 


 
RESEARCH  CONSENT  FORM 
Version Date: 01APRIL2019 
Participant Name:                                                                                                           Date:  _________ 
Title of Study: CSP#594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat                
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study:   James O’Dell,  MD      
 
SUBJECT’S IDENTIFICATION 
                                                                      
  
 
 
 
VA Form    10-10-86 
 
                                               Page 16 of 16 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:     04/05/2019 
 
LSI Approval Date:         N/A 
 
LSI Verification Date:     N/A 
                      
 
I agree to participate in this research study as has been explained in this document. 
 
 
 
_________________________ 
Participant’s Name 
____________________________ 
Participant’s Signature 
___________ 
Date 
___________________________ 
Name of person obtaining consent 
______________________________ 
Signature of person obtaining consent 
____________ 
Date 
 

SAP_002.pdf: 
CSP594 Comparative Effectiveness in Gout: Allopurinol 
vs. Febuxostat 
 
NCT02579096 
08.07.2019 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 1 of 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSP 594  
Comparative Effectiveness in Gout:  
Allopurinol vs. Febuxostat 
 
Statistical Analysis Plan 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 2 of 48 
 
Abbreviations 
ACR = American College of Rheumatology 
AE = Adverse Event 
AHS = Allopurinol Hypersensitivity Syndrome 
CKD = Chronic Kidney Disease 
CRF = Case Report Forms 
CSP = Cooperative Studies Program 
eGFR = estimated Glomerular Filtration Rate 
RAIN = Rheumatology and Arthritis Investigational Network 
SAE = Serious Adverse Event 
sUA = serum Uric Acid 
SAP =  Statistical Analysis Plan 
ULT = Urate Lowering Therapy 
 
1. Introduction 
This document outlines the statistical methods for the analysis of data collected in the Department of 
Veterans Affairs Cooperative Studies Programs (CSP) study #594 entitled “Comparative Effectiveness in 
Gout: Allopurinol vs Febuxostat”.  The purpose of this document is to provide guidelines from which the 
analysis will proceed.  Deviations from these guidelines will be documented and filed electronically in the 
study central file SharePoint site. 
The following documents were used in preparation of this statistical analysis plan (SAP): 
 
Clinical Study Protocol CSP #594 
 
Case Report Forms (CRF) from above entitled Protocol 
 
Global CSP SOP 2.9: “Developing and Conducting Statistical Analyses” 
 
Local Work Instruction WI 201 Statistical Analysis Plan and Biostatistical Research Data Processing Plan 
Creation and Amendment 
 
Local Job Aid No. 036: Guide to Writing Statistical Analysis Plans 
 
 
2. Overview of the Study Design and Objectives 
The proposed study is a double-blinded, two-arm intervention trial testing whether appropriately titrated 
allopurinol is non-inferior to appropriately titrated febuxostat.   
Participants will be recruited from 19 Veteran Affairs and 5 RAIN sites.  Individuals with a history of gout 
who continue to be hyperuricemic (sUA ≥ 6.8mg/dl) and fulfill entry criteria will be invited to participate. A 
total of 950 participants will be randomized in a 1:1 ratio to receive either allopurinol or febuxostat. 
Recruitment will occur over 24 months. The total duration of the trial will be 4 years.  


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 3 of 48 
 
Participants will be followed for 72 weeks: a 24-week Dose Titration Phase (Phase 1) followed by a 24-week 
Maintenance and Optimization Phase (Phase 2) and then a 24-week Steady State Flare Observation Phase 
(Phase 3).   Patients will undergo active surveillance during Phases 1 and 2 with scheduled in-person study 
visits, while Phase 3 observation will be conducted remotely using telephone encounters. There will be one 
study visit at week 60 to return bottles and diaries and pick up a new three-month supply of study 
medication. 
The primary objective: 
To compare the efficacy of appropriately titrated doses of two ULTs, allopurinol and febuxostat, in reducing 
gout flares during Phase 3, weeks 49-72, in participants with gout who are hyperuricemic prior to study 
entry. 
Secondary Objective:  
1) To compare the efficacy and tolerability of allopurinol and febuxostat in reducing gout flares among 
participants with gout who have stage 3 chronic kidney disease (CKD 3) and are hyperuricemic at 
baseline. 
 
2) To compare the efficacy of the two ULT dosing regimens in achieving sUA < 6.0 mg/dL   between weeks 
36 and 48 (i.e., during Phases 1 and 2: the dose titration phase, and the dose maintenance and 
optimization phase). 
 
3) To determine if the number of gout flares in phase 3 in participants who achieve a sUA < 6.0 mg/dl by 
48 weeks differ compared with those who do not, regardless of treatment assignment. 
 
4) To determine whether health-related quality of life measures differ between participants randomized 
to allopurinol compared to febuxostat and differ by achievement of sUA < 6.0 mg/dL, regardless of 
treatment assignment. 
 
5) To determine whether change in tophi area differ by location between participants randomized to 
allopurinol compared to febuxostat, and between participants who achieve or do not achieve sUA < 6.0 
mg/dL, regardless of treatment assignment. 
 
6) To determine whether the number of gout flares during each of the trial’s 3 phases differ between 
participants randomized to allopurinol compared with febuxostat and then extend this analysis to the 
entire 72-week period. 
 
7) To explore the tolerability/toxicity of the two ULT dosing regimens. 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 4 of 48 
 
8) To describe the effects of baseline covariates and time-dependent covariates on the primary results.  
 
3. Investigational Plan 
 
3.1. Description of the Study Population 
The study will include gout patients not only receiving first-time ULT but will also allow for the inclusion 
of gout patients who remain hyperuricemic (serum urate ≥ 6.8 mg/dl) despite ongoing therapy with 
uricosurics (e.g. probenecid) or allopurinol at daily doses ≤ 300 mg.  Uricosurics will require a 14-day 
wash-out prior to study enrollment.  Because febuxostat is non-formulary in the VA and considered 
only for patients failing or intolerant to allopurinol, patients already taking this agent will be excluded 
from study participation.   
 
Inclusion Criteria: 
1. Age ≥18 years 
2. History of gout – crystal proven or historical as defined by ACR criteria listed above 
3. Serum urate level ≥ 6.8 mg/dl 
 
Exclusion Criteria: 
1. Stage 4 or 5 Chronic Kidney Disease (CKD) – defined as eGFR of <30 ml/min/1.73 m2 
2. Women younger than 50 years of age 
3. Patients with a history of prior solid organ / hematopoietic transplantation 
4. Previous allergy or intolerance to allopurinol 
5. Patients who are not candidates for any of the recommended prophylactic medications 
(colchicine, naproxen or glucocorticoids) 
6. Patients who in the opinion of the investigator have a high genetic risk for allopurinol 
hypersensitivity syndrome (AHS*) unless they have been found to be negative for HLA B5801. 
7. Previous history of failure to reach target uric acid levels despite therapy with allopurinol at 
dose > 300 mg/day 
8. Prior febuxostat use 
9. Patients with malignancies that are currently active with exception of non-melanoma skin 
cancer 
10. Patients with serum uric acid levels >15 mg/dl 
11. Patients with myelodysplasia and hemoglobin of < 8.5 g/dL 
12. Patients with chronic liver disease with two or more of the following occurring within the past 
six months: 
a. INR ≥1.7, not on Warfarin therapy 
b. Bilirubin ≥2 mg/dL 
c. Serum albumin <3.5 g/dL 
d. Ascites 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 5 of 48 
 
e. Encephalopathy 
13. Current use of azathioprine, mercaptopurine, didanosine, cyclophosphamide, probenecid**, 
lesinurad or pegloticase*** 
14. Enrollment in another randomized interventional clinical trial**** 
15. Any severe medical condition that, in the enroller's opinion, is likely to compromise the 
participant's ability to complete the trial (e.g. unable to give informed consent). 
 
*Please see operational manual for further discussion on genetic risk for AHS. 
** Participants on probenecid may be enrolled in the study provided that they undergo a 14-day 
wash-out period before study entry. 
*** Urate-lowering therapies approved after study kickoff are also excluded. 
**** Unless the randomized interventional clinical trail is approved for dual enrollment by VACO 
 
3.2. Description of the Intervention Strategy 
Eligible patients who consent to participate will be randomized in a 1:1 ratio to receive either 
allopurinol or febuxostat.  
Specified titration of ULT dosing, adhering to the currently recommended initial dosing in gout patients 
with both normal renal function and CKD stage 3 [1] will be used in Phase 1 (see Table 1 for dose 
titration schedule).   
 
Specified dose titration will occur until:  
1) achievement of sUA concentrations at target level < 6.0 mg/dl (5.0 for participants with tophi);  
2) an adverse event occurs mandating drug discontinuation or dose reduction;  
3) maximal daily drug dose has been achieved (800 mg/day for allopurinol or 80 mg/day for 
febuxostat).   
 
During the 24-week ‘Maintenance and Optimization Phase’ (Phase 2) ongoing dose titration will be 
allowed if sUA level remains above 6.0 mg/dl, as long as maximal daily drug doses have not been 
achieved.  Dose escalation will not be allowed during the final three study visits of Phase 2 occurring at 
weeks 36, 42, and 48, to allow for steady-state assessment through week 72 (Phase 3).  During Phase 3, 
participants will be actively followed by monthly phone interviews for flare reporting. In order to 
reduce the frequency of acute gout flares that may complicate ULT initiation and titration, anti-
inflammatory prophylaxis that conforms to recently published guidelines in gout management [2] will 
be used in Phase 1 and 2. 
 
 
Table 1: Phase 1 Dose Titration for weeks 0 to 24 (maximum ULT dose in mg/day by study week) 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 6 of 48 
 
Baseline 
3 wks. 
6 wks. 
9 wks. 
12 wks. 
15 wks. 
18 wks. 
21 wks. 
24 wks. 
Allopurinol 
100 
200 
300 
400 
500 
600 
700 
800 
800 
Febuxostat 
40 
40 
40 
80 
80 
80 
80 
80 
80 
 
Prophylaxis 
 
All participants required to be on prophylactic medication for a minimum of 6 months  
 
3.3. Definition of Intention to Treat Sample 
 
All consented and randomized subjects will be accounted for and reported in the CONSORT diagram for 
the study. By definition, all those randomized subjects will be considered as an intention to treat (ITT) 
subjects. And all subjects who initiated intervention (i.e., did not drop out or withdraw prior to start of 
the allocated intervention) will be included in the Data Monitoring Committee (DMC) reports. 
However, in keeping with clinical practice, only subjects who can tolerate the medications will be 
considered as our primary analysis subjects. They belong in the phase 3 comparison wherein 
participants are asked to maintain their level of medication for 24 weeks.    
 
Thus, our primary hypothesis evaluates response during phase 3, while treating phases 1 and 2 as the 
induction period which identifies those who can tolerate the medications at more than minimum 
doses.  In the secondary analyses we will re-analyze the data using the ITT population to determine if 
dropout patterns during the induction phases appear to change the results of the comparison.   We 
anticipate that participants who experience severe side effects or who struggle to maintain the 
medication regimen will drop out during these early phases.  Thus, in phase 3 nearly all the remaining 
patients should find the regimen easy to maintain and have only minor side effects. 
 
Moreover, the ITT analysis that regards any gout flare as a treatment failure is not interpretable. 
Typically, during titration and stabilization many participants experience flares as the medications 
reduce sUA level and bring long-term disease under control.   These flares are not treatment failures, 
but instead expected side effects of the titration.   Thus, the phase 2 stabilization period is a time buffer 
that allows us to assert that failures during phase 3 are solely due to treatment (as opposed to 
titration).   
Two analytic sample files consisting of the “ITT” subjects and “Primary Analysis” subjects as defined 
above will be created and maintained throughout the study.  These files will be called the “CSP594_ITT” 
file and “CSP594_PA” file. 
 
3.4. Definition of per-Protocol sample 
Participant adherence to protocol-directed study treatment will be assessed via dosage review and 
participant interview.  We will use the question and pill count data to determine if a participant took 
80% or more of treatment medication.  The per-protocol population will be defined as participants 
remaining on the same treatment in phase 3 of the study with 80% adherence.   


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 7 of 48 
 
We will compare the primary results with the analogous results for the per-protocol participants.  
3.5. Description of the Efficacy Endpoints 
 
3.5.1. 
 Primary outcomes 
The primary outcome will be the proportion of participants who have at least one gout flare in the 
allopurinol group compared with the febuxostat group during Phase 3.  
 
Gout flares   
Prior randomized trials have used varying definitions of gout flares.  In this study, the occurrence of 
gout flares will be documented according to recently published criteria; this approach is consistent with 
the approach used in gout RCTs.  Subjects will be asked to keep a diary of flares. Information about the 
occurrence of flares will be reviewed at all ULT clinic visits and telephone encounters occurring at 
monthly intervals in Phase 3 with the aid of these diaries to avoid recall bias that could affect this 
measurement if longer intervals were used.  A gout flare questionnaire will be used during each visit 
(Phase 1 and 2) and each call (Phase 3) to capture information on: 1) the presence of a ‘warm’ joint; 2) 
the presence of a swollen joint; 3) a corresponding pain at rest score > 3 (0 to 10 scale); 4) patient-
reported gout flare; and 5) medications used to treat flares, if any.  Participants will be considered to 
have an acute gout flare if 3 of the first 4 criteria are satisfied. This method has been demonstrated to 
have a sensitivity of 91% and a specificity of 82%.  In addition to examining the proportion of patients 
with at least one flare, we will also examine the number of one-month intervals during Phase 3 with 
gout flares requiring treatment.  Treatment of gout flares will be done at the discretion of the site 
investigator with guidelines provided within the protocol (See Section X. Treatment Regimens below). 
Because gout patients may treat their attack at the first symptoms of attack onset, which can abort the 
full presentation of an attack, a secondary flare definition will be used of patient-reported flare of 
typical characteristics above plus use of appropriate gout anti-inflammatory medication; this is a 
standard approach used in gout RCTs in which flares are an outcome of interest. 
 
3.5.2. 
Secondary outcomes 
The secondary outcomes will include:  
1) The efficacy and tolerability in patients with CKD 3. 
 
i. To determine whether the efficacy of allopurinol and febuxostat differ among 
those with Stage 3 CKD, a planned secondary endpoint will be the occurrence of 
gout flares during Phase 3 in this patient subset.   
 


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ii. Tolerability of the two treatments will also be compared in this patient subset and 
will include comparisons of adverse events, serious adverse events, and related 
study withdrawal.   
 
2) The proportion of patients achieving a sUA < 6.0 mg/dl during Phase 2 (mean level assessed at 
weeks 36, 42, and 48) across treatment groups. 
 
3) The proportion of having at least one gout flares in Phase 3 differ in those who reach a target 
sUA of < 6.0 mg/dl compared with those who do not by 48 weeks. 
 
4) The impact of study treatments and sUA levels on health-related quality of life. 
 
Both the five-item EurQol (EQ-5D-3L) and Veterans RAND 12 (VR-12) will be collected from all 
participants at baseline, 24, 48 and 72 weeks.   
 
5) The changes in tophi area by location among those with tophaceous gout across treatment 
groups and sUA levels. 
 
We anticipate that ~20% of study participants will have tophi at enrollment.  The sentinel 
tophus will be defined as the most prominent and/or most readily measured tophus found at 
the time of the baseline evaluation on the hands, elbows, feet, or ears (i.e., the most common 
sites for tophi).Change in tophi area will be examined at week 24, week 48, and week 72 as a 
secondary outcome among this informative subset of patients with tophaceous gout.  
 
6) The impact of treatment on the flare rate over time. 
 
To determine whether the total number of gout flares differs between the two treatment 
groups the total flare numbers occurring during observation (week 0 to 72) will be compared. 
 
Recognizing that the duration of a gout flare typically extends from several days to 2-3 weeks, 
and that it may sometimes be difficult for patients to distinguish between two or more back-
to-back flares and one persistent but fluctuating flare, a maximum of one gout flare will be 
counted for each one-month observation period. Thus, as an example, during Phase 3 (24 
weeks) patients could experience a number of gout flares ranging from 0 to 6 flares. 
 
7) The tolerability/toxicity of the two ULTs. 
 
Toxicity data will be carefully collected throughout the 72 weeks of the study and compared 
across treatment arms. Toxicity data include rises in sUA levels, serum creatinine, CBC, liver 
function tests (LFTs), blood pressure, cardiovascular safety events of interest, hospitalization, 


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and reports of skin rashes. 
 
8) The effects of baseline covariates and time-dependent covariates on the primary results.  
 
3.6. Description of Baseline Data  
 
Demographic details (e.g., age, sex, race, ethnicity, military service), medical history (e.g., co-
morbidities), and baseline labs will be evaluated overall, and by intervention group. 
 
3.7. Safety Data 
 
The safety information to be collected for this study include the description of the event, distinction 
between serious and non-serious adverse event, severity and expectedness of the event, relatedness to 
the study intervention, and outcome of the event.  In addition, data on all events will be classified using 
the Medical Dictionary for Regulatory Activities (MedDRA) (Version 9.0) coding dictionary. 
 
Related AE data will be collected for all consented subjects from the time of consent until the end of 
participation in the study. If a patient receives care at a non-VA facility for an adverse event they 
experience, research personnel will obtain the requisite release of information form(s) from the patient 
and once received, acquire the pertinent medical records from the facility.  
 
SAE reporting will start at the time of patient consent and continue until 30 days after the patient’s 
involvement in the study.  
 
For reporting to the DMC and inclusion in the final report safety data will be aggregated for the sample 
as described in 3.3.  Data will be summarized as follows. 
 
 
Frequency and percentages of all non-serious and serious adverse events overall and by 
intervention group 
 
Frequency and percentages of all unique subjects with non-serious and serious adverse events 
overall and by intervention group 
 
Rates of non-serious and serious adverse events overall, by intervention group, and by center, 
calculated as # events/ person-time in years 
 
Tabulation of event type, MEDRA classification, severity, expectedness, relatedness and 
outcome of all events overall and by intervention group 
 
4. Sample Size and Power 
 


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The results for the primary hypothesis will be analyzed by using a one-sided 95% confidence interval on 
the difference in proportion of participants with one or more gout flare events during phase 3.  The test 
of the difference between proportions will have one-sided type I error of 5%.   
 
Starting with a total of 950 participants and allowing up to 10% dropout, the test has 90% power to 
reject the null hypothesis of inferiority with a total of 850 participants, 425 participants per treatment 
arm. 
 
Sample recruitment and subsequent event rates will be summarized and presented to the DMC bi-
annually.  These reports will be used for monitoring the progress of the study and any modification to 
the recruitment schedule or the statistical analysis plan will be at the recommendation of the DMC.  
 
5. Statistical Methods 
 
5.1. Handling of Missing Data in Analysis 
 
During phase 3, 2% of subjects have been estimated to drop out. This is less than the dropout rate in 
phase 1 and 2 because no one is having dose titration. For purpose of making the power calculation 
conservative, the rate of attrition has been estimated as being up to 10%, and sample size has been 
adjusted accordingly to maintain 90% statistical power for the primary analysis.   
 
The high dropout rate reflects clinical practice and not the more vigilant patient monitoring in a clinical 
trial. Distribution of participants lost to follow-up and missing data on key variables across the 
treatment groups will be monitored throughout the study.  Missing primary endpoint data will not be 
imputed.  All those with missing endpoint data either due to attrition or active withdrawal of consent 
will be excluded from primary analysis. Missing covariate data will be imputed in selected 
circumstances as described in [3].  We will explore the possibility of non-random dropout on endpoint 
data [4]. 
 
5.2. Balancing During Randomization 
 
Simple randomization will be used to ensure that equal proportions of participants with the following 
characteristics are in the two treatment arms:  
 
1) CKD Stage 3; 
2) marked hyperuricemia defined as a sUA ≥ 9.0 mg/dl;  
3) presence of tophi (focused examination involving the hands, elbows, feet, and ears, which are 
the most common sites for tophaceous deposits); and  
4) participants with current receipt of allopurinol.   
 


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Furthermore, to guarantee enrollment of a sufficient number of gout participants with CKD stage 3 
(eGFR ≥30 but <60 ml/min/1.73 m2) to address a key secondary objective (see Section 2), we will 
randomize at least one participant with CKD Stage 3 for every two participants with preserved renal 
function (eGFR ≥ 60 ml/min/1.73 m2). 
 
Distribution of all these variables across the treatment groups will be closely monitored throughout the 
study.  If any unbalancing happens on one or more characteristics listed above, a biased coin algorithm 
will be implemented to remedy the condition. 
 
5.3. Univariate and Bivariate Distributions of Baseline, Safety and Follow-up data 
 
 
In general, the number of observations, mean, median, standard deviation, minimum, and 
maximum will be calculated for continuous variables. The number of decimals places will be two 
decimal places. 
 
Frequencies and percentages will be calculated for categorical data. 
 
Distribution of continuous variables and proportions of categorical variables will be tabulated by 
intervention group, and t-test and chi-square tests will be performed to evaluate if these variables 
are balanced between 2 intervention groups. 
 
For the primary analysis, baseline is defined as the starting date of Phase 3. 
 
5.4. Primary Efficacy Analysis 
 
Primary efficacy analysis will include patients who remain on study when phase 3 begins. 
The primary outcome is the difference (D) in proportion of patients with one or more gout flares during 
Phase 3.  Seven rheumatologists on our Planning Committee, selected for their expertise in gouty 
arthritis and clinical trial design, chose B = 8%. 
Formal statement of the primary hypothesis 
H0:  Allopurinol is inferior to febuxostat.  The Phase 3 proportion of one or more gout flare 
events among Allopurinol participants is more than the Phase 3 proportion of one or more gout 
flare events among Febuxostat participants by 8% or more (D ≥ 8%). 
Ha:  Allopurinol is non-inferior to febuxostat. The Phase 3 proportion of one or more gout flare 
events among Allopurinol participants is not more than the Phase 3 proportion of one or more 
gout flare events among Febuxostat participants by 8% or more (D < 8%). 
The estimate of D, 𝐷̂, is the observed treatment difference.  The difference is defined so that it is 
positive when febuxostat has the higher success rate (lower gout flare proportion).  To test the null 
hypothesis, we will compute the upper limit of a one-sided 95% confidence interval for 𝐷: 


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U = 𝐷̂ + 1.645*stderr(𝐷̂). 
The graphic below displays the decision process. In Figure 1 the upper limit (U) is less than B, and we 
reject the null hypothesis of non-inferiority; allopurinol is non-inferior to febuxostat. In   Figure 2,  U 
exceeds B indicating that the true difference may be larger than the posited value of D;  we cannot 
reject the null hypothesis that allopurinol is inferior to febuxostat. 
Figure 1: One-Sided 95% Confidence Interval for the Non-inferiority Test Depicting 
‘Rejection’ of the Null Hypothesis 
 
 
 
Figure 2: One-Sided 95% Confidence Interval for the Non-inferiority Test Depicting 
‘Acceptance’ of the Null Hypothesis 
 
 
 
SAS 9.4 will be used to carry out the analysis. Analytic reports will provide the proportions, the 
differences among proportions, and the upper limit of a one-sided 95% confidence interval, the bound, 
followed by a report of the results. 
 
5.4.1. Sensitivity Analysis 
 
(1) The primary analysis will be repeated on the “per-Protocol” sample with adherence as defined 
in 3.4 to evaluate efficacy among those adherent to the protocol. We will compare the primary 
results with the analogous results for the per-protocol participants.   
 
(2) On the “Primary Analysis” cohort assuming all allopurinol patients with missing primary 
outcome had at least one gout flare during phase 3 of our study while none of febuxostat 
patients with missing primary outcome had any gout flare during phase 3 (the worst-case 
scenario). 
 
(3) On the “Primary Analysis” cohort assuming all febuxostat patients with missing primary 
outcome had at least one gout flare during phase 3 of our study while none of allopurinol 
0 
𝐷̂
𝑈 
𝐵 
0 
𝐷̂
𝑈 
𝐵 


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patients with missing primary outcome had any gout flare during phase 3 (the best case 
scenario). 
 
5.5. Secondary Analysis 
All secondary analyses are descriptive exploratory analyses and will be done with and without covariate 
adjustment (age, sex, disease severity, comorbidities, etc.).  In some secondary analyses, we will 
impute values to explicitly explore the effect of missing data. 
We describe the proposed analysis for each of the eight secondary objectives: 
1) To compare the efficacy and tolerability of allopurinol and febuxostat in hyperuricemic participants 
with gout and stage 3 chronic kidney disease (CKD 3) in reducing gout flares.  
 
a. We will carry out the analogues non-inferiority analysis proposed for the primary objective 
but restricted to participants with stage 3 CKD, using only gout flares observed during 
Phase 3.  Using the full cohort, we will compare gout flare rates of participants with stage 3 
CKD to participants with an eGFR ≥60 mL/min/1.73m2 with a logistic regression model.  
 
b. Tolerability of the two treatments will also be compared in this patient subset and will 
include comparisons of proportions of adverse events, serious adverse events, and related 
study withdrawal during the whole study using logistic regression. 
 
2) To explore the efficacy of the two ULT dosing regimens in achieving the goal of sUA < 6.0 mg/dl 
evaluated at the end of phase 2.   Besides treatment, the primary predictors include the series of 
sUA measures and dose titrations prior to 48 weeks.  This longitudinal analysis will model 
deviations from the titration protocol. 
 
a. The analysis for these longitudinal data will be the mixed effects model with a variance-
covariance structure that assumes auto correlated AR(1) sUA measurements over time.  
We will use PROC MIXED in SAS.   At each clinical visit a binary factor will indicate if the 
titration protocol is or is not maintained.  Besides baseline factors such as age, sex, and 
duration of disease, the model will incorporate time-dependent factors including side 
effects.  Missing data methods will address potential censoring of events among patients 
who fail to attend clinic visits.   
 
b. We will run the same analysis using the biological threshold of sUA < 6.8 mg/dl at the end 
of phase 2. 
 


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3) To determine if there are gout flares in phase 3 in participants who achieve a sUA < 6.0 mg/dl by 48 
weeks differ compared to those who do not, regardless of treatment assignment. 
 
The binary outcome for this logistic regression analysis will be the presence of gout flares in phase 3. 
The analysis will use gout flares in phase 1 and phase 2 as baseline covariates. 
 
4) To determine whether health-related quality of life measures differ between participants 
randomized to allopurinol compared to febuxostat and differ by achievement of sUA < 6.0 mg/dL, 
regardless of treatment assignment. 
 
a. EQ-5D-3L & VR-12 instruments will be administered at baseline, 24, 48, and 72 weeks.  At 
each time we will compare the mean scores by treatment groups, using both an unadjusted 
t-test and linear regression with adjustment for baseline covariates.     
 
b. With outcome change from baseline to later weeks, we will compare mean changes by 
treatment group with and without covariates using linear regression.    
 
c. We will carry out a repeated measures analysis using all time points.  Missing data methods 
will address potential censoring of events among patients who fail to complete the 
instrument at a particular time.  
 
d. Analogous analyses will be carried out controlling for sUA levels. 
 
5) To determine whether change in tophi area differ by location between participants randomized to 
allopurinol compared to febuxostat and differ by achievement of sUA < 6.0 mg/dL, regardless of 
treatment assignment. 
 
a. Tophi area will be assessed at baseline, 24, 48, and 72 weeks.  At each time point we will 
compare the mean areas by location by treatment groups, using an unadjusted t-test and 
linear regression with adjustment for baseline covariates.     
 
b. With area change from baseline to later weeks, we will compare mean changes by location 
with and without covariates using linear regression.    
 
c. We will carry out a repeated measures analysis using all time points.  Missing data methods 
will address potential censoring of events among patients who fail to complete the 
instrument at a particular time.  
 
d. Analogous analyses will be carried out controlling for sUA levels. 
 


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6) To determine whether the number of gout flares during all three phases differ between 
participants randomized to allopurinol compared to febuxostat and then extend this analysis to the 
entire 72-week period.  
 
a. We will model the number of gout flares, which can have substantial variation, as Poisson 
random variables.   We will use Poisson regression to compare treatments using a 
longitudinal repeated measure (PROC GLIMMAX and GENMOD in SAS). Missing data 
methods will address potential censoring of events among patients who appear to fail to 
report flares.   
 
b. Flare counts will be analyzed separately during Phases 1, 2, and 3 because dose titration 
during Phase 1 tends to increase the counts, and this effect may still persist in Phase 2, 
particularly for those still undergoing dose titration; participants are expected to be in 
steady-state by Phase 3.    
 
c. Phase 2 analysis will consider prophylactic treatment after a gout flare and severe side 
effects of treatment as predictors of subsequent counts.    
 
d. During Phase 3 the same set of factors as well as Phase 2 counts will be used to predict 
gout flare counts. These time-dependent associations will require a mixed effects model 
using an auto correlated AR(1) variance-covariance to model the series of events.   
 
e. For these analyses we may treat the counts as continuous measures in order to introduce 
more subtle variance-covariance structure and a variety of random effects. 
 
7) To determine the patterns of tolerability/toxicity for each treatment during Phase 3 and then 
overall from weeks 1-72. 
 
a. Toxicity events include rises in sUA levels, adverse changes in serum creatinine, CBC, liver 
function tests (LFTs), blood pressure, and the incidence of skin rashes. The incidence of 
cardiovascular events of interest will also be included in this analysis.  
 
b. Within each Phase we will determine if the incidence of such events differs between 
treatments.  In the Phase 3 analysis baseline covariates will include the summary of toxicity 
events during Phases 1 and 2 as well as the week 48 sUA level.  As in the sixth secondary 
analysis the same statistical methods for Poisson counts will be used.    
 
c. At each clinic visit we will assess the count of each type of major side effect episodes 
between visits. The analyses will compare treatments using a longitudinal repeated 
measures analysis with Poisson count, negative binomial counts, and binary outcomes 


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(PROC GLIMMAX and GENMOD in SAS).   Missing data methods will address potential 
censoring of events among patients who fail to attend clinic visits.   
 
8) To describe the effects of baseline covariates and time-dependent covariates on the primary results.  
 
a. We will carry out logistic regression analyses adjusting for covariates and use GEE model. 
 
b. Baseline data include demographic characteristics (e.g. age, sex), disease history including 
CKD level, presence of tophi at baseline, height, weight, laboratory values, medications, 
other comorbidities, and quality-of-life measures.    
 
c. Time-dependent variables include data obtained after baseline include sUA measures, 
titration levels, and side effects. 
 
d. All data obtained before Phase 3 may be used as baseline factors for Phase 3 analyses. 
 
6. Data Monitoring Committee Reports 
 
Data and study progress will be monitored by the study executive committee and by the Data 
Monitoring Committee.  The DMC will review the study progress and safety semiannually with 
additional meetings and communications as needed.  
 
All reports will be generated in conjunction with the Data Management department using SQL and SAS. 
 
6.1. Analytic Sample for DMC Reports 
 
All subjects randomized more than six weeks prior to the DMC meeting date who initiated intervention 
(i.e., did not drop out or withdraw prior to start of the allocated intervention) will be included in the 
analytic cohort for the upcoming DMC report, and all data collected up to four weeks prior to the DMC 
meeting date will be analyzed. This allows for two weeks lag time for submission of data from sites. 
 
6.2. Outline of DMC Reports 
   
The report is divided into four sections to cover subject disposition, baseline assessment, follow-up 
assessment, and safety assessment.  
 
Section A: Subject Disposition 
 
Figure A1. CONSORT Diagram 
Figure A2. Overall Study Enrollment 


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Figure A3. Enrollment by Site 
Table A4. Pre-Screening Log Data. 
Table A5. Protocol Deviations 
Table A6. Terminations 
Table A7. Form Completion, by Form Type 
Table A8. Form Completion, by Site 
 
Section B: Baseline Assessment 
 
Table B1. Patient Characteristics 
Table B2. Military Service, VA sites only   
Table B3. Relevant Medical History 
Table B4. Baseline Labs and Assessment  
Table B5. Week 24 Labs and Assessment  
Table B6. Week 48 Labs and Assessment 
Table B7. Study Medication Adherence 
Table B8. Study Medication Dose Change 
Table B9. Concomitant Medications 
Section C: Follow-up Assessment 
 
Table C1. Study Primary Outcome Events 
Table C2. Study Secondary Outcome Events – Part I 
Table C2. Study Secondary Outcome Events – Part II 
Table C2. Study Secondary Outcome Events – Part III 
Table C2. Study Secondary Outcome Events – Part IV 
Table C2. Study Secondary Outcome Events – Part V 
 
Section D: Safety Assessment 
 
Table D1. Rates of Non-Serious Adverse Events (NAEs) and Serious Adverse Events (SAEs), by Site   
Table D2. Summary of Non-Serious Adverse Events 
Table D3. Summary of Serious Adverse Events   
Table D4. Non-Serious Adverse Events by System Organ Class and Preferred Term   
Table D5. Serious Adverse Events by System Organ Class and Preferred Term  
 
 
 


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7. Shell DMC Tables (subject to change) 
 
Figure A1. CONSORT Diagram 
 


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Table A2. Recruitment by Site 
Site ID 
Site Name 
Actual Accrual 
Expected 
Accrual 
Percentage of 
Expected 
101 
Nebraska-WesternIowa 
N 
N 
XX% 
102 
CharlesGeorge 
N 
N 
XX% 
103 
RAIN5-UNMC 
N 
N 
XX% 
104 
Portland 
N 
N 
XX% 
105 
RAIN1-Mayo 
N 
N 
XX% 
106 
Pittsburgh 
N 
N 
XX% 
107 
SaltLakeCity 
N 
N 
XX% 
108 
Salem 
N 
N 
XX% 
109 
SanFrancisco 
N 
N 
XX% 
110 
SanDiego 
N 
N 
XX% 
111 
EdwardHines 
N 
N 
XX% 
112 
NYU 
N 
N 
XX% 
113 
Philadelphia 
N 
N 
XX% 
114 
Cincinnati 
N 
N 
XX% 
116 
Minneapolis 
N 
N 
XX% 
117 
KansasCity 
N 
N 
XX% 
118 
RAIN3-Yankton 
N 
N 
XX% 
119 
Dallas 
N 
N 
XX% 
120 
LomaLinda 
N 
N 
XX% 
121 
WhiteRiverJunction 
N 
N 
XX% 
122 
Miami 
N 
N 
XX% 
123 
Boston 
N 
N 
XX% 
124 
RAIN2-Bismark 
N 
N 
XX% 
125 
WRJ-Manchester 
N 
N 
XX% 
 
 


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Figure A2. Overall Study Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
0
100
200
300
400
500
600
700
800Mar-17Apr-17May-17Jun-17Jul-17Aug-17Sep-17Oct-17Nov-17Dec-17Jan-18Feb-18
Expected
Actual


CSP #594 Statistical Analysis Plan v3.0 
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Page 21 of 48 
 
Figure A3. Enrollment by Site 
 
0
5
10
15
20
25
30
35
40
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
Number of Participants
Site Number 
Actual
Expected


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Table A4. Pre-Screening Log Data.  
 
 
 
 
 
 
Reason Why no tEnrolled 
Eligible but 
did not 
enroll (N= ) 
% 
Cumulative % 
A. Refusal 
N 
% 
% 
B. Provider decision 
N 
% 
% 
C. Dual Enrollment Issue 
N 
% 
% 
D. Missing – No reason given 
N 
% 
100% 


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Table A5. Protocol Deviations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1See Appendix B. 
Description of Protocol 
Deviation 
Sample 
(N= ) 
Form 
Location 
Element Codes 
Informed consent and/or HIPAA 
authorization not signed until 
after study procedures started 
N (%) 
PD 
DVDECOD=1 
Eligibility criteria violated 
N (%) 
PD 
DVDECOD=2 
Allopurinol/Febuxostat not 
prescribed and/or not 
dispensed as per protocol 
N (%) 
PD 
DVDECOD=3 
Required study procedure not 
completed 
N (%) 
PD 
DVDECOD=4 
SAE not reported per protocol 
N (%) 
PD 
DVDECOD=5 
Lab blood draws not obtained 
as per protocol 
N (%) 
PD 
DVDECOD=6 
Participant took Probenecid and 
or/ Lesinurad   
N (%) 
PD 
DVDECOD=7 
Participant took other excluded 
medication  after randomization 
N (%) 
PD 
DVDECOD=8 
Required source documentation 
could not be obtained 
N (%) 
PD 
DVDECOD=9 
Patient seen outside visit 
window (Study visits will have a 
window +/- 1 week in Phase 1 
and +/- 2 weeks in Phase 2 and 
3) 
N (%) 
PD 
DVDECOD=10 
Other protocol deviation1 
N (%) 
PD 
DVDECOD=11 


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Table A6. Early Terminations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1See Appendix C. 
 
 
Reason for 
Termination 
Sample 
(N= ) 
Form Location 
Element Codes 
Death 
N (%) 
EOS 
DSDECOD=1 
Side effects with 
study medications 
N (%) 
EOS 
DSDECOD=2 
Provider decision 
N (%) 
EOS 
DSDECOD=3 
Participant decision 
N (%) 
EOS 
DSDECOD=4 
Participant lost to 
follow-up 
N (%) 
EOS 
DSDECOD=5 
Study site closure 
N (%) 
EOS 
DSDECOD=6 
Participant required 
to take exclusion 
medication on a 
regular basis 
N (%) 
EOS 
DSDECOD=7 
Other reasons for 
early termination 
N (%) 
EOS 
DSDECOD=8 


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Table A7. Form Completion, by Form Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Expectation: >=90% submission 
 
 
 
 
Form Name 
#Forms 
Expected 
#Forms 
Completed 
Adverse Event Follow Up 
N 
N (%) 
Adverse Event 
N 
N (%) 
Alcohol Use Questionnaire 
N 
N (%) 
Change in Study Medication Dosage 
N 
N (%) 
Clinical Biochemistry Laboratory Test 
N 
N (%) 
Concomitant Medications 
N 
N (%) 
Demographics 
N 
N (%) 
Eligibility and Randomization 
N 
N (%) 
End of Study 
N 
N (%) 
EQ5D-3L 
N 
N (%) 
Gout Attack Diary and Questionnaire 
N 
N (%) 
Index Tophus Location and Area 
N 
N (%) 
Military History 
N 
N (%) 
Participant Contact Information 
N 
N (%) 
Protocol Deviation 
N 
N (%) 
Rash Adverse Event Form 
N 
N (%) 
Relevant Medical History 
N 
N (%) 
Serious Adverse Event Follow Up 
N 
N (%) 
Serious Adverse Event 
N 
N (%) 
Study Medication Adherence  
N 
N (%) 
sUA unscheduled 
N 
N (%) 
Vital Signs 
N 
N (%) 
VR-12 
N 
N (%) 


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Table A8. Form Completion, by Site 
 
 
*Expectation: >=90% submission 
 
 
 
 
Site# 
Site Name 
#Forms 
Expected 
#Forms 
Completed 
101 
Nebraska-WesternIowa 
N 
N (%) 
102 
CharlesGeorge 
N 
N (%) 
103 
RAIN5-UNMC 
N 
N (%) 
104 
Portland 
N 
N (%) 
105 
RAIN1-Mayo 
N 
N (%) 
106 
Pittsburgh 
N 
N (%) 
107 
SaltLakeCity 
N 
N (%) 
108 
Salem 
N 
N (%) 
109 
SanFrancisco 
N 
N (%) 
110 
SanDiego 
N 
N (%) 
111 
EdwardHines 
N 
N (%) 
112 
NYU 
N 
N (%) 
113 
Philadelphia 
N 
N (%) 
114 
Cincinnati 
N 
N (%) 
116 
Minneapolis 
N 
N (%) 
117 
KansasCity 
N 
N (%) 
118 
RAIN3-Yankton 
N 
N (%) 
119 
Dallas 
N 
N (%) 
120 
LomaLinda 
N 
N (%) 
121 
WhiteRiverJunction 
N 
N (%) 
122 
Miami 
N 
N (%) 
123 
Boston 
N 
N (%) 
124 
RAIN2-Bismark 
N 
N (%) 
125 
WRJ-Manchester 
N 
N (%) 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 27 of 48 
 
Table B1. Patient Characteristics 
Characteristic  
Sample  
VA 
(N= ) 
Sample  
RAIN 
(N= ) 
Form Location 
Element Codes 
Age (years) 
 
 
 
 
     Mean ± SD 
Mean ± SD 
Mean ± SD 
Eligibility and 
Demographics 
Average, Stddev 
( floor(Randdt-Brthdat)/365.25) 
     Range 
(Range) 
(Range) 
Eligibility and 
Demographics 
Range=(min-max(Randdt-Birthdat)) 
Sex 
 
 
 
 
Male  
N (%) 
N (%) 
Demographics 
SEX = 1 
Female 
N (%) 
N (%) 
Demographics 
SEX = 2 
Race  
 
 
 
 
American 
Indian/Alaskan Native 
N (%) 
N (%) 
Demographics 
RaceAl = 1 
Asian 
N (%) 
N (%) 
Demographics 
RaceAs = 1 
Black/African 
American 
N (%) 
N (%) 
Demographics 
RaceAA=1 
Native Hawaii/Pacific 
Islander 
N (%) 
N (%) 
Demographics 
RacePl=1 
White / Caucasian  
N (%) 
N (%) 
Demographics 
RaceW=1 
Other / Multiple 
Selected  
N (%) 
N (%) 
Demographics 
RaceO=1 
Ethnicity 
 
 
 
 
Not Hispanic or 
Latino 
N (%) 
N (%) 
Demographics 
Ethnic=1 
Hispanic or Latino 
N (%) 
N (%) 
Demographics 
Ethnic =2 
Participant chose not 
to answer 
N (%) 
N (%) 
Demographics 
Ethnic =-99 
Education 
 
 
 
 
Less than High School 
Diploma 
N (%) 
N (%) 
Demographics 
Educatn = 1 
High School Diploma 
N (%) 
N (%) 
Demographics 
Educatn = 2 
Some College credit 
but no Degree 
N (%) 
N (%) 
Demographics 
Educatn = 3 
Associate's Degree 
N (%) 
N (%) 
Demographics 
Educatn = 4 
Bachelor’s Degree 
N (%) 
N (%) 
Demographics 
Educatn = 5 
Master’s Degree 
N (%) 
N (%) 
Demographics 
Educatn = 6 
Doctoral Degree 
N (%) 
N (%) 
Demographics 
Educatn = 7 
Other 
N (%) 
N (%) 
Demographics 
Educatn = 8 
Marital Status 
 
 
 
 
Married  
N (%) 
N (%) 
Demographics Marital=1 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 28 of 48 
 
 
 
 
Divorced  
N (%) 
N (%) 
Demographics 
Marital=2 
Civil Commitment  
N (%) 
N (%) 
Demographics 
Marital=3 
Never Married  
N (%) 
N (%) 
Demographics 
Marital=4 
Widowed  
N (%) 
N (%) 
Demographics 
Marital=5 
Separated  
N (%) 
N (%) 
Demographics 
Marital=6 
Cohabitating  
N (%) 
N (%) 
Demographics 
Marital=7 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 29 of 48 
 
Table B2. Military Service, VA sites only   
 
 
*Number of subjects from VA sites only 
 
Characteristic  
Sample* (N= ) 
Form Location 
Element Codes 
Military Service 
 
 
 
Army 
N (%) 
Military History 
MilBranchA  =1 
Navy 
N (%) 
Military History 
MilBranchN  =1 
Air Force 
N (%) 
Military History 
MilBranchAF  =1 
Marine Corps 
N (%) 
Military History 
MilBranchM  =1 
Coast Guard 
N (%) 
Military History 
MilBranchCG  =1 
Other 
N (%) 
Military History 
MilBranchOth =1 
Service Periods 
 
 
 
Prior to World War II (Nov 
1941 or earlier) 
N (%) 
Military History 
MilWartimePWW  =1 
World War II Era (Dec 
1941-Dec 1946) 
N (%) 
Military History 
MilWartimeWW  =1 
Jan 1947-June 1950 
N (%) 
Military History 
MilWartime47 =1 
Korean Conflict Era (July 
1950-Jan 1955) 
N (%) 
Military History 
MilWartimeK  =1 
Feb 1955-July 1964 
N (%) 
Military History 
MilWartime55 =1 
Vietnam Conflict Era (Aug 
1964-April 1975) 
N (%) 
Military History 
MilWartimeV  =1 
May 1975-July 1990 
N (%) 
Military History 
MilWartime75 =1 
Persian Gulf War Era(Aug 
1990-Feb 1991) 
N (%) 
Military History 
MilWartimePG  =1 
March 1991-Sep 2001 
N (%) 
Military History 
MilWartime91 =1 
Afghanistan/Iraq Conflict 
Era (Oct 2001-Present) 
N (%) 
Military History 
MilWartimeAI =1 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 30 of 48 
 
Table B3. Relevant Medical History 
 
 
Does 
participant 
currently 
have the 
problem? 
Is 
participant 
currently 
receiving 
treatment? 
Does it limit 
the 
participant’s 
activities? 
 
Characteristic  
(N= ) 
 (N= ) 
 (N= ) 
Form Location 
Congestive Heart Failure  
 
 
 
 
Coronary Artery Disease or 
Myocardial Infarctions.  
N (%) 
N (%) 
N (%) 
Relevant Medical History 
High Blood Pressure 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Lung Disease 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Diabetes 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Gastrointestinal Disease 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Kidney Disease 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Liver Disease 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Blood Disorder 
 
 
 
Relevant Medical History 
Cancer (with exception of non-
melanoma skin cancer) 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Arthritis or Musculoskeletal 
Disorder (other than Gout) 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Thyroid Disease 
N (%) 
N (%) 
N (%) 
Relevant Medical History 
Chronic Rash 
 
 
 
Relevant Medical History 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 31 of 48 
 
Table B4. Baseline Labs and Assessment 
 
Characteristic  
Sample (N= ) 
Form Location 
Creatinine  (mg/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
White Blood Cell (K/CMM) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Platelet Count (K/CMM) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Hemoglobin (Hgb) (g/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
C-reative Protein (CRP) (mg/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Alanine Aminotransferase (ALT) 
(U/L) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Weight (kg) 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 
Systolic BP 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 
Diastolic BP 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 32 of 48 
 
 Table B5. Week 24 Labs and Assessment 
 
 
 
Characteristic  
Sample (N= ) 
Form Location 
Creatinine  (mg/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
White Blood Cell (K/CMM) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Platelet Count (K/CMM) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Hemoglobin (Hgb) (g/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
C-reative Protein (CRP) (mg/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Alanine Aminotransferase (ALT) 
(U/L) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Weight (kg) 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 
Systolic BP 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 
Diastolic BP 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 33 of 48 
 
Table B6. Week 48 Labs and Assessment 
 
 
Characteristic  
Sample (N= ) 
Form Location 
Creatinine  (mg/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
White Blood Cell (K/CMM) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Platelet Count (K/CMM) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Hemoglobin (Hgb) (g/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
C-reative Protein (CRP) (mg/dl) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Alanine Aminotransferase (ALT) 
(U/L) 
 
 
     Mean ± SD 
Mean ± SD 
Clinical Bio Lab 
     Range 
Range 
Clinical Bio Lab 
Weight (kg) 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 
Systolic BP 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 
Diastolic BP 
 
 
Mean ± SD (N) 
Mean ± SD (N) 
Vital Signs 
Range 
(Range) 
Vital Signs 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 34 of 48 
 
Table B7. Study Medication Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Adherence is compusted as (Total capsules/Tablets taken/Total capsules/tablets given) * 100 
Adherence1 
Baseline  
(n= ) 
Form Location 
Phase 1 
 
 
<80% 
N (%) 
Study Medication Adherence 
>= 80% 
N (%) 
Study Medication Adherence 
Phase 2 
 
 
<80% 
N (%) 
Study Medication Adherence 
>= 80% 
N (%) 
Study Medication Adherence 
Phase 3 
 
 
<80% 
N (%) 
Study Medication Adherence 
>= 80% 
N (%) 
Study Medication Adherence 
Overall 
 
 
<80% 
N (%) 
Study Medication Adherence 
>= 80% 
N (%) 
Study Medication Adherence 
 
 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 35 of 48 
 
Table B8. Study Medication Dose Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence1 
Baseline  
(n= ) 
Form Location 
Baseline 
 
 
< 100/40mg 
N (%) 
Change in Study Medication dosage 
= 100/40mg 
N (%) 
Change in Study Medication dosage 
> 100/40mg 
N (%) 
Change in Study Medication dosage 
3 weeks 
 
 
< 200/40mg 
N (%) 
Change in Study Medication dosage 
= 200/40mg 
N (%) 
Change in Study Medication dosage 
> 200/40mg 
N (%) 
Change in Study Medication dosage 
6 weeks 
 
 
< 300/40mg 
N (%) 
Change in Study Medication dosage 
= 300/40mg 
N (%) 
Change in Study Medication dosage 
> 300/40mg 
N (%) 
Change in Study Medication dosage 
9 weeks 
 
 
< 400/80mg 
N (%) 
 
= 400/80mg 
N (%) 
 
> 400/80mg 
N (%) 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 36 of 48 
 
Table B9. Concomitant Medications 
 
 
Characteristic 
Baseline  
(n= ) 
Form Location 
Probenecid 
 
N (%) 
Concomitant Medications 
Lesinurad 
 
N (%) 
Concomitant Medications 
Angiotensin 
Converting  Enzyme 
(ACE) Inhibitor 
N (%) 
Concomitant Medications 
Alpha Blocker 
N (%) 
Concomitant Medications 
Angiotensin Receptor 
Blocker (ARB) 
N (%) 
Concomitant Medications 
Losartan 
N (%) 
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 37 of 48 
 
 Table C1. Study Primary Outcome Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outcome Event Type 
Sample  
(N= ) 
Element Code 
Primary Outcome 
 
 
# Subjects with more 
than one gout flare Phase 
3 
N(%) 
Gout flare Questionnaire and 
diary 
Secondary outcome 1 
 
 
# Subjects with CKD3 
in Phase 3 
N(%) 
Clinical Biochem Lab 
# Subjects with more 
than one gout flare in 
Phase 3 
N(%) 
Gout flare Questionnaire and 
diary 
Secondary outcome 2 
and 3 
 
 
# Subjects with mean 
sUA < 6.0 at the end of 
Phase 2 
N(%) 
Clinical Biochem Lab 
# Subjects with mean 
sUA < 6.8 at the end of 
Phase 2 
N(%) 
Clinical Biochem Lab 
Secondary outcome 4 
 
 
EQ-5D-3L 
 
 
Mean ± SD 
Mean ± SD 
 
EQ5D-3L 
 
Range 
(range) 
 
EQ5D-3L 
 
VR-12 
 
 
Mean ± SD 
Mean ± SD 
 
VR-12 
 
Range 
(range) 
 
VR-12 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 38 of 48 
 
Table C2. Study Secondary Outcome Events – Part I 
 
 
 
Outcome Event Type 
Sample  
(N= ) 
Element Code 
Secondary outcome 1 
 
 
# Subjects with CKD3 
in Phase 3 
N(%) 
Clinical Biochem Lab 
# Subjects with more 
than one gout flare in 
Phase 3 
N(%) 
Gout flare Questionnaire and 
diary 
Secondary outcome 2 
and 3 
 
 
# Subjects with mean 
sUA < 6.0 at the end of 
Phase 2 
N(%) 
Clinical Biochem Lab 
# Subjects with mean 
sUA < 6.8 at the end of 
Phase 2 
N(%) 
Clinical Biochem Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 39 of 48 
 
Table C3. Study Secondary Outcome Events – Part II 
 
 
 
Outcome Event Type 
Sample  
(N= ) 
Element Code 
Secondary outcome 4 
 
 
EQ-5D-3L Baseline 
 
 
Mean ± SD 
Mean ± SD 
 
EQ5D-3L 
 
Range 
(range) 
 
EQ5D-3L 
 
VR-12 Baseline 
 
 
Mean ± SD 
Mean ± SD 
 
VR-12 
 
Range 
(range) 
 
VR-12 
 
EQ-5D-3L Week 24 
 
 
Mean ± SD 
Mean ± SD 
 
EQ5D-3L 
 
Range 
(range) 
 
EQ5D-3L 
 
VR-12 Week 24 
 
 
Mean ± SD 
Mean ± SD 
 
VR-12 
 
Range 
(range) 
 
VR-12 
 
EQ-5D-3L Week 48 
 
 
Mean ± SD 
Mean ± SD 
 
EQ5D-3L 
 
Range 
(range) 
 
EQ5D-3L 
 
VR-12 Week 48 
 
 
Mean ± SD 
Mean ± SD 
 
VR-12 
 
Range 
(range) 
 
VR-12 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 40 of 48 
 
Table C4. Study Secondary Outcome Events – Part III  
 
 
 
Outcome Event Type 
Sample  
(N= ) 
Element Code 
Secondary outcome5 
 
 
Tophus Baseline 
 
 
Mean ± SD 
Mean ± SD 
 
Index Tophus Location and Area 
 
Range 
(range) 
 
Index Tophus Location and Area 
 
Tophus Week 24 
 
 
Mean ± SD 
Mean ± SD 
 
Index Tophus Location and Area 
Range 
(range) 
 
Index Tophus Location and Area 
Tophus Week 48 
 
 
Mean ± SD 
Mean ± SD 
 
Index Tophus Location and Area 
Range 
(range) 
 
Index Tophus Location and Area 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 41 of 48 
 
Table C5. Study Secondary Outcome Events – Part IV  
 
 
 
 
Phase 
Gout Flare 
Count 
Sample 
(n= ) 
Form Location 
1 
0 
N (%) 
Gout Attack 
Diary and 
Questionnaire 
1-2 
N (%) 
3+ 
N (%) 
2 
0 
N (%) 
Gout Attack 
Diary and 
Questionnaire 
1-2 
N (%) 
3+ 
N (%) 
3 
0 
N (%) 
Gout Attack 
Diary and 
Questionnaire 
1-2 
N (%) 
3+ 
N (%) 
Overall 
0 
N (%) 
Gout Attack 
Diary and 
Questionnaire 
1-2 
N (%) 
3+ 
N (%) 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 42 of 48 
 
Table C6. Study Secondary Outcome Events – Part V  
 
 
 
 
Phase 
Toxicity Events 
Sample 
(n= ) 
Form Location 
Rise in sUA levels 
1 
Mean ± SD 
N (%) 
Clinical Biochem 
Lab 
 
2 
Mean ± SD 
N (%) 
Clinical Biochem 
Lab 
 
3 
Mean ± SD 
N (%) 
Clinical Biochem 
Lab 
 
Overall 
Mean ± SD 
N (%) 
Clinical Biochem 
Lab 
 
Skin Rashes 
1 
0 
N (%) 
Rash Adverse 
Event 
1-2 
N (%) 
3+ 
N (%) 
2 
0 
N (%) 
Rash Adverse 
Event 
1-2 
N (%) 
3+ 
N (%) 
3 
0 
N (%) 
Rash Adverse 
Event 
1-2 
N (%) 
3+ 
N (%) 
Overall 
0 
N (%) 
Rash Adverse 
Event 
1-2 
N (%) 
3+ 
N (%) 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 43 of 48 
 
Table D1. Rates of Non-Serious Adverse Events (NAEs) and Serious Adverse Events (SAEs), by Site   
 
 
*Rate per year computed as [# events /(sum of (data close date - randomization date))],  if events are rare, 
then present as rate per 100 years.
Site# 
# NAEs 
#Unique 
Subjects 
Rate per 
Year* 
 
# SAEs 
#Unique 
Subjects 
Rate per 
Year* 
101 
N (%) 
N (%) 
 
 
N (%) 
N (%) 
 
102 
N (%) 
N (%) 
 
 
N (%) 
N (%) 
 
.. 
.. 
.. 
 
 
.. 
.. 
 
.. 
.. 
.. 
 
 
.. 
.. 
 
125 
N (%) 
N (%) 
 
 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
TOTAL 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 44 of 48 
 
Table D2. Summary of Non-Serious Adverse Events 
 
 
 
Sample  
(N= Events) 
Form Location 
Element Codes 
#Weeks since Randomization 
Mean+SD 
Randomization 
and AE 
 
    Phase 1 
N(%) 
Randomization 
and AE 
 
Phase 2 
N(%) 
Randomization 
and AE 
 
Phase 3 
N(%) 
Randomization 
and AE 
 
Severity of NAE 
 
 
 
     Mild AEs 
N(%) 
AE 
AESEV=1 
Moderate AEs 
N(%) 
AE 
AESEV =2 
Severe AEs 
N(%) 
AE 
AESEV=3 
Relatedness 
 
 
 
Possibly or Definitely Related 
to Study Treatment 
N(%) 
AE 
AEIVREL=yes, possibly 
# Unique Subjects with at least 1 
NAE that is possibly or definitely 
related to Study Treatment 
N*(%) of N 
subjects 
AE 
) 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 45 of 48 
 
Table D3. Summary of Serious Adverse Events   
Characteristic 
Sample  
(N= Events) 
Form Location 
Element Codes 
#Weeks since Randomization 
Mean+SD 
Randomization and SAE 
 
    Phase 1 
N(%) 
Randomization and SAE 
 
Phase 2 
N(%) 
Randomization and SAE 
 
Phase 3 
N(%) 
Randomization andS AE 
 
SAE category (can be multiple) 
 
 
 
Death 
N(%) 
SAE 
AESDTH=1 
Initial or prolonged 
hospitalization 
N(%) 
SAE 
AESHOSP=1 
Life threatening experience 
N(%) 
SAE 
AESLIFE=1 
Required medical or surgical 
treatment 
N(%) 
SAE 
AESMIE=1 
Persistent or significant 
disability or incapacity 
N(%) 
SAE 
AESDISAB=1 
Congenital anomaly/birth 
defect 
N(%) 
SAE 
AESCONG=1 
Relatedness  
(Possibly or Definitely) 
 
 
 
To Study Treatment 
N(%) 
SAE 
 
# Unique Subjects with at least 1 
SAE that is possibly or definitely 
related to Study Treatment 
N*(%) of N 
subjects 
SAE 
 
# Unique Subjects with at least 1 
SAE that is possibly or definitely 
related to Study Drug Capsule 
N*(%) of N 
subjects 
SAE 
 
Outcome 
 
 
 
Recovered/resolved  
N(%) 
SAE 
AESOUT =1 
Recovered/resolved with 
sequelae  
N(%) 
SAE 
AESOUT =2 
Recovering/resolving 
N(%) 
SAE 
AESOUT =3 
Not recovered/not 
resolved  
N(%) 
SAE 
AESOUT =3 
Fatal 5  
N(%) 
SAE 
AESOUT =5 
Data not available  
N(%) 
SAE 
AESOUT =6 
 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 46 of 48 
 
 
Table D4. Non-Serious Adverse Events by System Organ Class and Preferred Term   
 
 
 
 
 
 
System Organ Class 
Prefered Term 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 47 of 48 
 
Table D5. Serious Adverse Events by System Organ Class and Preferred Term  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 
Prefered Term 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CSP #594 Statistical Analysis Plan v3.0 
DATE: 07AUGUST2019 
 
Page 48 of 48 
 
8. References 
 
[1] Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College 
of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic 
and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 
(Hoboken). 2012; 64(10):1431-46. 
 
[2] Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American College 
of Rheumatology guidelines for management of gout. Part 2: therapy and anti-
inflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 
2012;64(10):1447-61. 
[3] Little RJA, Rubin DB. Statistical analysis with missing data. 2nd ed. New York: John Wiley 
and Sons; 2002. 
 
[4] Daniels MJ, Hogan JW. Missing data in longitudinal studies: strategies for Bayesian 
modeling and sensitivity analysis. Boca Raton: Chapman and Hall; 2008. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
CSP594 Comparative Effectiveness in Gout: Allopurinol 
vs. Febuxostat 
 
NCT02579096 
06.23.2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CSP#594 Protocol V6.2 
 
Page 1 of 71 
DATE:23JUN2020 
                                            
            
 
 
                                              
CSP #594 
Comparative Effectiveness in Gout: 
Allopurinol vs. Febuxostat 
 
 
VA Cooperative Studies Program (CSP) 
A Department of Veterans Affairs Cooperative Study 
 
 
 
STUDY CHAIR: James R. O’Dell, MD 
STUDY DIRECTOR: Mary Brophy, MD, MPH 
BIOSTATISTICIAN: Hongsheng Wu, PhD 
STUDY PHARMACIST: Annie Davis-Karim, PharmD 
 
 
 
 
 


O’Dell, JR. CSP#594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat 
CSP#594 Protocol v6.2 
 
Page 2 of 71  
Date: 23JUN2020 
                                                                                                                       
Table of Contents 
Table of Contents .......................................................................................................................................... 2 
I. Executive Summary .................................................................................................................................... 3 
II. Abbreviations ............................................................................................................................................ 4 
III. Background and Rationale ....................................................................................................................... 4 
IV. Significance of Proposed Research to the VA .......................................................................................... 9 
V. Study Objectives ....................................................................................................................................... 9 
VI. Experimental Design .............................................................................................................................. 11 
VII. Outcome Measures .............................................................................................................................. 12 
VIII. Bio statistical Considerations ............................................................................................................... 17 
IX. Study Population and Patient Recruitment ........................................................................................... 25 
X. Treatment Regimens ............................................................................................................................... 33 
XI. Baseline and Follow-up Assessment ...................................................................................................... 40 
XII. Potential Pitfalls of the Proposed Study Design and Strategies to Address Them ............................... 44 
XIII. Feasibility of Recruitment .................................................................................................................... 45 
XIV. Anticipated barriers to recruitment and strategies to address potential under-enrollment ............. 47 
XV. Human Rights and Informed Consent .................................................................................................. 49 
XVI. Monitoring Adverse Events ................................................................................................................. 50 
XVII. Data Management and Data Security Plans ....................................................................................... 54 
XVIII. Quality Control Procedures ............................................................................................................... 57 
XIX. Good Clinical Practice (GCP) ................................................................................................................ 60 
XX. Study Organization and Administration................................................................................................ 61 
XXI. Publications .......................................................................................................................................... 63 
XXII. References .......................................................................................................................................... 64 
APPENDIX A. Biobank Substudy 
 
 
 
 
 
 


O’Dell, JR. CSP#594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat 
CSP#594 Protocol v6.2 
 
Page 3 of 71  
Date: 23JUN2020 
                                                                                                                       
I. Executive Summary 
Gout is the most common form of inflammatory arthritis affecting adults (1), with a disease 
prevalence that continues to increase relentlessly (2).  Gout is associated with substantial morbidity and 
mortality, particularly in older men and in patients with chronic kidney disease (CKD) (3-6), demographics 
common to the Veterans Affairs (VA) Health System.  Effective gout therapies are readily available and are 
centered primarily on the use of approved urate lowering therapy (ULT).  Despite having excellent ULT 
options available to patients (7), gout is extremely poorly managed, especially in patients with CKD (8-10).   
The two most widely used ULTs in clinical practice, allopurinol and febuxostat, have recently been 
endorsed by the American College of Rheumatology as the two acceptable treatment strategies in chronic 
gout (7). Although both agents appear to be efficacious, allopurinol and febuxostat have significantly 
different costs, safety profiles, and have never been compared to each other across their full dose ranges.  
In particular, randomized controlled trials completed to date comparing allopurinol with febuxostat in gout 
have used ‘fixed’ and, in many cases, insufficient doses of allopurinol (11-13), an approach that is contrary 
to current guideline recommendations (7).  Furthermore, these studies have included only very small 
proportions of gout patients with CKD, even though CKD is present in approximately 1 of every 2 gout 
sufferers (14). 
To test the hypothesis that allopurinol is non-inferior to febuxostat in the treatment of gout, we 
propose a randomized double-blind non-inferiority trial, which for the first time compares allopurinol with 
febuxostat using appropriately titrated doses and a “treat-to-target” approach. Further, we will assess the 
comparative effectiveness of these agents in a significant number of gout patients with co-morbid CKD.   
We plan to enroll 950 participants with a diagnosis of gout, including participants with stage 3 CKD, 
who are hyperuricemic defined as a serum uric acid* concentration (sUA) above 6.8 mg/dl.  Participants will 
be recruited from 20 Veteran Affairs and 5 Rheumatology and Arthritis Investigational Network (RAIN) sites. 
The total duration of the trial will be 4 years. Recruitment will occur over 24 months. Participants will be 
followed for 72 weeks.  The trial will include a 24 week Dose Titration Phase (Phase 1), followed by a 24 
week Maintenance and Optimization Phase (Phase 2) and then a 24 week Steady State Flare Observation 
Phase (Phase 3).  We will use a “treat-to-target” approach with specified titration of ULT dosing to obtain 
goal sUA.  Maximal daily drug doses will be the FDA approved doses of 800 mg/day for allopurinol or 80 
mg/day for febuxostat.  
The primary outcome will be the proportion of participants who have at least one gout flare in the 
allopurinol group compared to the febuxostat group during Phase 3. This primary outcome was endorsed 
by patient and VA provider groups whom we surveyed (see below). All participants will be followed during 
Phase 3 regardless of achievement of sUA goal. The primary hypothesis will test the non-inferiority of 
allopurinol with regards to proportions of flares. We anticipate that approximately 15 to 20% of patients 
will flare during Phase 3. 
*For CSP 594 study purposes we will consider serum and plasma sUA levels interchangeable. 


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**Due to COVID-19, for CSP 594 study purposes we will consider any reference to “in person” or “clinic” 
visits as in person visits and/or telephone visits. 
II. Abbreviations 
ACR = American College of Rheumatology
AHS = allopurinol hypersensitivity syndrome
BRDP = Bio statistical and Research Data Processing
CKD = chronic kidney disease
CKD- EPI = Chronic Kidney Disease Epidemiology Collaboration
CRF = Case Report Forms
CSP = Cooperative Studies Program
CVA = Cerebrovascular Incident
DIR = Drug Information Report
ED = emergency department
EDC = Electronic Data Capture
eGFR = estimated glomerular filtration rate
EULAR = European League Against Rheumatism
GFR = glomerular filtration rate
MDRD= Modification of Diet in Renal Disease 
NHANES = National Health and Nutrition Examination Survey
NSAID = non-steroidal anti-inflammatory drug
OMERACT = Outcome Measures in Rheumatology
RAIN = Rheumatology and Arthritis Investigational Network
RCT = Randomized Control Trial
sUA = serum uric acid
ULT =  Urate Lowering Therapy
ULT = urate lowering therapy
US = United States
VA = Veterans Affairs
III. Background and Rationale 
Gout and hyperuricemia are common in the general population and both have increased recently 
to near epidemic proportions. The reasons for the increased frequency of gout at a national level are multi-
factorial and include an aging population, a significant increase in obesity prevalence and a marked increase 
in the incidence of chronic kidney disease (CKD), risk factors for hyperuricemia that are particularly 
common among U.S. veterans (15).  The increase in gout frequency is most prominent among older men, 
the largest patient demographic encountered in the Veterans Affairs (VA) Health System.  Over the last 
decade alone, gout prevalence in the U.S. has increased by more than 50% in men, 25% in women, and 
more than 100% among individuals over the age of 80 years (1).  Gout is now estimated to affect 4% of the 
U.S. population, surpassing rheumatoid arthritis as the most common form of inflammatory arthritis.  The 
impact of this growing epidemic in the VA is underscored by the robust associations of hyperuricemia and 
uncontrolled gout with cardiovascular disease (16-28), a leading cause of morbidity and mortality among 
U.S. veterans (15). 


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The treatment of chronic gout is based primarily on the use of urate lowering therapy (ULT).  
Available for more than 50 years, allopurinol is the most commonly prescribed ULT and represents one of 
the most frequent prescriptions dispensed in the VA.  In 2009, a new drug to lower uric acid, febuxostat, 
was approved for the treatment of gout with drug costs that are 25 to 50-fold higher than allopurinol. Some 
of the recently published data leading to its approval attempted to make the case that febuxostat is more 
effective than the much older and much less expensive allopurinol(11-13). This is despite the fact that these 
studies compared febuxostat to inappropriately low doses of allopurinol.  Although allopurinol is approved 
for the treatment of gout in doses as high as 800 mg daily in the United States and 900 in Europe, there 
have been no studies to date that have compared febuxostat to allopurinol in daily doses exceeding 300 
mg.  Importantly, despite a paucity of supporting data (29) and contrary to recently published management 
guidelines (7), older reports have recommended markedly reduced dosing of maintenance allopurinol in 
patients with renal impairment (30), a recommendation that is still frequently followed by clinicians.  When 
this recommendation for renal dosing is strictly followed, the majority of patients with gout and CKD 
experience inadequate control of their hyperuricemia and continue to suffer from severe gouty arthritis 
(31).  While the morbidity and expense of painful gout flares is substantial, the morbidity and costs 
associated with attempts to treat rather than prevent flares may be even greater. Moreover, the purported 
superior efficacy is perhaps not without risks, as the use of febuxostat was associated with a small but 
significant increase in risk of cardiovascular death and all-cause mortality compared to allopurinol. As of 
February 2019, the FDA-approved indication of febuxostat is limited to those patient’s who have failed or 
cannot tolerate maximally titrated allopurinol doses (108). 
The economic impact of gout and hyperuricemia are considerable both to the U.S. and the VA. Not 
only is gout extremely common among veterans but it is a common cause of clinic visits in addition to 
admissions to both the emergency department (ED) and inpatient setting.  In preliminary analyses using the 
Nationwide Emergency Department Sample from 2008, gout was the primary diagnosis for more than 
170,000 ED visits in the U.S. with corresponding total estimated charges of more than $160 million annually 
(32).  Among younger gout populations, gout is independently associated with work absenteeism and losses 
in work productivity (33).  Compared to employees without the diagnosis, employees with gout take nearly 
twice as much sick leave and twice as much short-term disability leave, translating into an estimated total 
loss of more than 3 million days annually across the U.S. civilian workforce (33).  Consistent with these data, 
gout is also associated with substantially higher overall healthcare costs (34, 35) and accounts for 6% of all 
healthcare costs among elderly patients with gout (36).   
For patients with gout, serum urate (sUA) levels serve as an independent predictor of both gout 
flare risk and total gout-related healthcare costs (37), suggesting that effective ULT can mitigate gout-
related morbidity and expense.  Indeed, allopurinol treatment among veterans with hyperuricemia has 
been associated with a significant reduction in all-cause mortality (38).  The costs of recurrent, and 
therefore potentially preventable, gout flares make up the vast majority of the economic burden posed by 
gout.  The cost of colchicine, among the most common agents used to treat acute gout flares, has recently 
increased from just cents per pill to approximately $5 per pill (39).  Most gout experts believe that 
recurrent gout flares are almost entirely preventable if gout and hyperuricemia are appropriately managed.  
Unfortunately, gout is one of the most mismanaged conditions in “modern” medicine. Part of the problem 
with gout mismanagement occurs because ULT agents are not titrated (40) in concordance with recent gout 


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management guidelines (7).  In addition, the adverse impacts of inadequately treated chronic gout may not 
be appreciated by many clinicians. 
As part of recent efforts characterizing gout treatment in a large U.S. health care organization, it 
was shown that among more than 13,000 gout patients initiated on allopurinol only 10% ever received dose 
escalation over an average follow-up period of three years (Rashid & Mikuls, unpublished data).  
Furthermore, of those initiated on allopurinol only 3% ever received a dose of more than 300 mg/day over 
the same observation period.  The vast majority of prescriptions for management of gout are for allopurinol 
doses of 300 mg or less, and the majority of patients remain on their initial dose prescribed (40-43).  Fewer 
than 50% and 25% of participants receiving these doses of allopurinol achieved sUA <6mg/dL after 6 and 12 
months, respectively (11, 12).  This practice directly contradicts best practices in gout management that 
involve the use of maintenance doses of allopurinol gradually titrated upward in order to achieve a target 
sUA threshold (7).  As a partial result of low adherence to these recommendations, a majority of gouty 
patients never reach sUA target levels below 6.0 mg/dl.  Achieving and maintaining sUA levels below 6.0 
mg/dl are critical goals in gout care and are strongly associated with decreased disease burden (including 
decreased total body urate stores, resolution of tophi, and decreased acute disease flares). Excellent 
observational data demonstrate that standard allopurinol dosing schemes lead to target sUA 
concentrations in only a small subset of gout patients (44). Further, the 2012 ACR guidelines for the 
management of gout recommend this as the treatment target.(7) Therefore, as part of this protocol, we will 
use a protocolized ULT dosing algorithm based on sUA levels and a treat-to-target approach geared to 
mimic current best-practice strategies in gout management (7). 
While the management of gout in patients with normal renal function can be challenging, hurdles 
posed in gout management may be even greater in patients with CKD.  The prevalence of gout increases 
with progressive degrees of severity of CKD (45).  In an analysis of data from the most recent National 
Health and Nutrition Examination Surveys, the crude prevalence of gout was 2 to 3% among individuals 
without CKD, as compared to 11 to 13% among individuals with stage 3 CKD (eGFR 30-59 mL/min/1.73 m2) 
and over 30% in individuals with stage 4 CKD (eGFR 15-29 mL/min/1.73 m2), an approximate five-fold 
higher prevalence in individuals with stage 3 CKD and a more than 10-fold higher prevalence in patients 
with stage 4 CKD as compared to individuals with normal kidney function (45).  Less than 0.5% of individuals 
with an eGFR >90 mL/min/1.73 m2 were taking allopurinol as compared to ~5% of individuals with stage 3 
CKD.  Despite the high prevalence of ULT use, the mean sUA concentration in patients with stage 3 CKD was 
6.5 mg/dL with 46% of individuals manifesting hyperuricemia (45). Notably, the prevalence of CKD in the US 
population has been increasing over time with an increase in patients with stage 3 CKD from approximately 
5.4% of the US population during the period from 1988 to 1994 to approximately 7.6% during the interval 
from 1999 to 2010 (46).   The burden of CKD in the VA population is even higher than in the general US 
population with 10.3% of VA populations having stage 3 CKD in 2011 (46).  Thus, there is a strong rationale 
for inclusion of patients with CKD in our study, given the markedly increased prevalence of hyperuricemia 
and gout in this population.   
It is important to note that despite common misconceptions, allopurinol administration in 
approved doses has never been associated with deterioration in renal function in patients with gout and 
renal impairment (29).  Results from small studies have shown that the pharmacodynamics and 


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pharmacokinetics of febuxostat are unaltered in the context of CKD, suggesting that this agent does not 
require renal dose adjustments and ultimately leading many to favor use of this agent over allopurinol in 
patients with renal impairment (47, 48).  Contrary to reports suggesting that allopurinol may lead directly to 
‘renal toxicity’, small studies have shown that allopurinol (as well as febuxostat) may retard the progression 
of CKD (49-52).  
In addition to unfounded concerns over potential deleterious effects on kidney function, results 
from a single case series of 78 patients reported by Hande et al suggested that ‘higher dose’ allopurinol 
may increase the risk of allopurinol hypersensitivity syndrome (AHS) (30), an uncommon (up to1%) but 
serious drug related adverse event that appeared in this study to be heightened in the context of CKD.  
These results led directly to the generation and widespread promulgation of non-evidence based dosing 
guidelines that were founded on the relationship of renal function with observed oxypurinol concentrations 
(an allopurinol metabolite) (30).  It is important to note that the 'effectiveness' of these guidelines in 
preventing AHS has never been demonstrated (29).  Indeed, many patients with CKD have developed AHS 
even with ‘appropriately’ dosed allopurinol (53, 54). In a recent review of 120 gout patients receiving 
allopurinol, more than half (57%) of patients required daily doses above the ‘renal threshold’ 
recommended by Hande to achieve target urate goals.  In this study, only 1 patient developed AHS, a 
patient with normal renal function receiving 300 mg per day (55).  In a more recent study of 90 gout 
patients, Stamp and colleagues found that increasing the dose of allopurinol above the thresholds proposed 
by Hande (30) led to significant reductions in sUA without increased toxicity (31).  In a cohort of more than 
1,200 gout patients treated with allopurinol, investigators observed no association of allopurinol dose with 
the occurrence of adverse drug reactions (56).  Indeed, the risk of adverse drug reactions was related to the 
rate of the allopurinol dose increment and not the final dose in participants with CKD.  Recent regulatory 
studies comparing allopurinol with febuxostat in gout have demonstrated low frequencies of rash leading 
to treatment withdrawal, rates that have generally well below 5% and similar across treatment groups (12).  
Independent guidelines from the European League Against Rheumatism (EULAR) (57), the British 
Society for Rheumatology (58), and now the American College of Rheumatology (ACR) (7) have all 
recommended that allopurinol dosing should be gradually increased to doses as high as 800 (US) or 900 
(Europe) mg/day with a goal of achieving and maintaining sUA concentrations below 6.0 mg/dl, recognizing 
the need for initial dose adjustments in the context of renal insufficiency (59). Indeed the ACR guidelines 
specifically suggest that allopurinol doses may be raised above 300 mg daily, even with renal impairment, 
as long as it is accompanied by adequate patient education and monitoring of drug toxicity (7). Thus, 
current day-to-day practice that adheres strictly to the Hande dosing guidelines (30) contrasts starkly with 
evidence-based recommendations of judicious dose escalation accompanied by appropriate surveillance to 
achieve a target sUA goal of < 6.0 mg/dl (29). 
 
 
 


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To optimally inform our revised application and address feedback from CSSEC, the planning 
committee sent out two surveys: a questionnaire to 179 VA providers from across the US responsible for 
gout management and a survey to 40 gout patients enrolled in the National Data Bank.  A majority (71%) of 
the provider respondents were primary care physicians, highly relevant because the vast majority of gout 
care occurs in the primary care setting.  Forty respondents (22%) were VA rheumatologists.  Both provider 
groups and patients prioritized a reduction in acute gout flare rate as the most important outcome to 
investigate in a comparative effectiveness study of ULT with tolerability and sUA reduction prioritized as 
second and third priorities, respectively.  When presented an established gout patient with comorbid CKD 
(stage III), there was substantially divided opinion among primary care respondents about the comparative 
efficacy, tolerance and likelihood of adverse events for allopurinol and febuxostat even though little data 
exists to support such a difference. Given the same patient, a vast majority of primary care providers 
invoked a maximum daily dose of allopurinol of 300 mg, despite available evidence suggesting that 
judicious titration above this threshold is both safe and tolerated even in patients with CKD.  Together, 
these results support our primary and secondary endpoints and identify potential gaps in care that will be 
addressed and overcome with our rigorous study design. 
As part of this VA Cooperative Studies Program (CSP) trial, we will for the first time compare 
allopurinol with febuxostat in the treatment of gout using appropriately titrated doses and a “treat-to-
target” approach.  Gout patients and VA providers were surveyed and both groups endorsed a reduction in 
gout flares as the most meaningful outcome (see below).  Therefore, our primary outcome will be the 
percentage of patients who flare during maintenance phase (weeks 49-72) after ULT has been 
appropriately titrated (weeks 0-48). This large simple randomized study will include not only US veterans 
with gout, but also gout patients recruited from the Rheumatology and Arthritis Investigational Network 
(RAIN) including sites across the Midwest and Western US.  RAIN has been led by the PI since 1989 and 
recently participated in CSP #551 (60), successfully enrolling 141% of its original target goal.  In addition to 
capitalizing on the substantial track record of RAIN in patient recruitment, the inclusion of these select non-
VA sites will be central in extending the generalizability of findings from this precedent setting effort. 
 
 
 
 
 
 
 
 


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IV. Significance of Proposed Research to the VA 
Gout is common and increasing, accounts for significant morbidity, mortality and work disability, 
and is frequently miss-managed resulting in preventable morbidity and expense.  Compared to veterans 
without gout, US veterans with gout report significantly more bodily pain in addition to having higher rates 
of comorbidity, more annual primary care visits, and admissions to the hospital (6). In a recent study of US 
veterans, only 24% of gout patients initiated on ULT underwent repeat sUA testing within 6 months, 
suggesting that rates of appropriate ULT titration and the achievement of urate goals are exceedingly low in 
the VA (10).  Since gout is much more common in men and increases with age, gout related issues are 
significantly magnified in US veterans.  Approved for the treatment of gout in 2009, febuxostat is much 
more expensive than allopurinol with direct drug costs that are approximately 25 to 50-fold higher.  While 
marketing materials suggest that febuxostat may be more effective than allopurinol these comparisons 
have been done at inappropriately low fixed-doses of allopurinol.  The misconception regarding superior 
ULT efficacy of febuxostat over allopurinol is evident in a substantial proportion of VA healthcare providers. 
In an effort led by our team in preparation for this application, we conducted a national survey that 
included 179 VA providers with approximately 1 in 5 responders reporting that febuxostat demonstrated 
superior efficacy compared to allopurinol in gout treatment (unpublished). Of note, a similar proportion of 
VA providers suggested that febuxostat also demonstrated superior tolerability to allopurinol, a difference 
that has never been reported in any of the head-to-head trials completed to date.  The VA’s annual 
expenditures for febuxostat have increased significantly over the last few years.  Allopurinol is inexpensive 
and effective if used at appropriate doses and we believe will provide similar results to febuxostat in both 
patients with and without CKD. If allopurinol is shown in this trial to be non-inferior to febuxostat the cost 
implications for the VA and US health care in general are substantial. Further, if gout and hyperuricemia can 
be appropriately managed in more than 80% of participants as we predict, this will conclusively 
demonstrate that the incidence and expense associated with gout flares and their consequences can be 
dramatically reduced.  
V. Study Objectives 
Primary Objective: 
To compare the efficacy of appropriately titrated doses of two ULTs, allopurinol and febuxostat, in 
reducing gout flares (during Phase 3, weeks 49-72) in participants with gout who are hyperuricemic prior to 
study entry. 
Secondary Objectives: 
1) To compare the efficacy and tolerability of allopurinol and febuxostat in reducing gout flares among 
participants with gout who have stage 3 chronic kidney disease (CKD 3) and are hyperuricemic at 
baseline. 
2) To compare the efficacy of the two ULT dosing regimens in achieving sUA <6 mg/dL  between 
weeks 36 and 48 (i.e., during Phases 1 and 2: the dose titration phase, and the dose maintenance 
and optimization phase). 
3) To determine if the number of gout flares in participants who achieve a sUA < 6.0 mg/dl by 48 
weeks differ compared with those who do not, regardless of treatment assignment. 


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4) To determine whether health-related quality of life measures differ between participants 
randomized to allopurinol compared to febuxostat, and differ by achievement of sUA < 6.0 mg/dL, 
regardless of treatment assignment. 
5) To determine whether change in tophi area differ by location between participants randomized to 
allopurinol compared to febuxostat, and between participants who achieve or do not achieve sUA < 
6.0 mg/dL, regardless of treatment assignment. 
6) To determine whether the number of gout flares during each of the trial’s 3 phases differ between 
participants randomized to allopurinol compared with febuxostat.  
7) To explore the tolerability/toxicity of the two ULT dosing regimens, we will determine how adverse 
events, gout flares, CKD levels, and titration schedules influence the number of side effects during 
the study.  
8) To describe the effects of baseline covariates and time-dependent covariates on the primary 
results.  
Other Objectives: 
Consent will be sought for continued access to participant electronic health records for ten years 
following completion of study participation in order to examine long-term outcomes. Important outcomes 
will include comorbidities associated with gout over the long-term, including CKD and marked excess 
cardiovascular mortality as outlined in the Background.  Therefore, records will be specifically evaluated for 
the development of cardiovascular complications (MIs, coronary artery bypass graft surgery or stent 
placement, CVAs and hypertension), progression of CKD, and mortality.  This will not require the sites to 
remain open for these ten years, this will also not require sites to create repositories of data, consent will 
be sought simply for access to participants electronic health records for up to 10 years following the last 
participant completing phase 3 of the study. 
There will be a biobank Substudy for identification of genetic factors and biomarkers that may 
predict disease progression, development of comorbidities, treatment response and toxicity. Consent will 
be sought for collecting specimens for the serum bank. Participation in the substudy will be optional.  
 
 
 
 
 
 
 
 


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VI. Experimental Design 
*COVID-19: 
Due to COVID-19, in-person visits may be conducted via telephone if an in-person visit is not 
feasible.  Safety for all subjects, health care staff and others should be considered prior to every study visit.  
The Local Site Investigator has the discretion to determine what type of visit (in-person or telephone) is 
most appropriate.  Sites are to adhere to the strictest safety policies and procedures in place.  If local 
policies and procedures allow for in-person research visits to occur, this is the preferred method of sample 
and data collection.  However, if an in-person visit is not feasible and a telephone visit is conducted instead 
this would not be considered a protocol deviation. Sites are to collect the protocol specified lab values for 
weeks 48, 60 and 72 even if the visit is conducted via telephone. Sites are permitted to utilize a CBOC for 
lab draws.  If subjects are unable to have labs drawn due to COVID-19, lab values within the CPRS system 
that are drawn during the visit window can be used to supplement the study specified labs at a given visit.  
If no lab values are obtained for weeks 48, 60 and 72, this will be considered a protocol deviation. 
Proposed Design: 
Participants will be recruited from 20 Veteran Affairs and 5 RAIN sites.  Individuals with a history of 
gout who continue to be hyperuricemic (sUA ≥ 6.8mg/dl) and fulfill entry criteria will be invited to 
participate.  In this prospective double-blind non-inferiority trial, 950 participants will be randomized in a 
1:1 ratio to receive either allopurinol or febuxostat. Recruitment will occur over 24 months. The total 
duration of the trial will be 4 years.  
Participants will be followed for 72 weeks: a 24-week Dose Titration Phase (Phase 1) followed by a 
24-week Maintenance and Optimization Phase (Phase 2) and then a 24-week Steady State Flare 
Observation Phase (Phase 3).   Patients will undergo active surveillance during Phases 1 and 2 with 
scheduled in-person study visits, while Phase 3 observation will be conducted remotely using telephone 
encounters. There will be one study visit at week 60 to return bottles and diaries and pick up a new three-
month supply of study medication. Specified titration of ULT dosing, adhering to the currently 
recommended initial dosing in gout patients with both normal renal function and CKD stage 3 (7) will be 
used in Phase 1 (see Table 4 for dose titration schedule).  Specified dose titration will occur until: 1) 
achievement of sUA concentrations at target level < 6.0 mg/dl or < 5.0 mg/dl if tophi present; 2)  an adverse 
event occurs mandating drug discontinuation or dose reduction; or 3) maximal daily drug dose has been 
achieved (800 mg/day for allopurinol or 80 mg/day for febuxostat).  During the 24-week ‘Maintenance and 
Optimization Phase’ (Phase 2) ongoing dose titration will be allowed if sUA level remains above 6.0 mg/dl, 
as long as maximal daily drug doses have not been achieved.  Dose escalation will not be allowed during the 
final three study visits of Phase 2 occurring at weeks 36, 42, and 48, to allow for steady-state assessment 
through week 72 (Phase 3).  During Phase 3, participants will be actively followed by monthly phone 
interviews for flare reporting. In order to reduce the frequency of acute gout flares that may complicate 
ULT initiation and titration, anti-inflammatory prophylaxis that conforms to recently published guidelines in 
gout management (61) will be used. 
 


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The primary outcome will be the proportion of participants who have at least one gout flare in the 
Allopurinol group compared with the febuxostat group during Phase 3. Flare ascertainment during Phase 3 
has been deliberately chosen (rather than during Phase 1 or 2) with the understanding that gout flares are a 
commonly experienced physiologic consequence of ULT during the first year of therapy, and usually 
indicate successful urate lowering rather than treatment failure. All participants will be followed during 
Phase 3 regardless of the achievement of sUA goal. The primary hypothesis will test the non-inferiority of 
allopurinol based upon the proportion experiencing ≥1 flare in each of the two treatment groups in Phase 
3. 
Randomization: 
Balanced randomization will be used to ensure that equal proportions of participants with the 
following characteristics are in the two treatment arms: 1) CKD Stage 3 (individuals with CKD Stages 4 and 5 
will be excluded); 2) marked hyperuricemia defined as a sUA ≥ 9.0 mg/dl; 3) presence of tophi (focused 
examination involving the hands, elbows, feet, and ears, which are the most common sites for tophaceous 
deposits); and 4) participants with prior receipt of ULT.  All of these factors have been associated with a 
lower likelihood of achieving sUA goals in recent head-to-head trials of these two agents (12, 13).  Further, 
to guarantee enrollment of a sufficient number of gout participants with CKD stage 3 (eGFR ≥30 but <60 
ml/min) to address a key secondary objective (see above), we will randomize at least one participant with 
CKD Stage 3 for every two participants with preserved renal function (eGFR ≥ 60 ml/min). 
VII. Outcome Measures 
Primary Outcome: 
The primary outcome will be the proportion of participants who have at least one gout flare in the 
Allopurinol group compared with the febuxostat group during Phase 3.  
Gout flares: 
Prior randomized trials have used varying definitions of gout flares.  In this study, the occurrence of 
gout flares will be documented according to recently published criteria (63); this approach is consistent 
with the approach used in gout RCTs (64-72).  Subjects will be asked to keep a diary of flares. Information 
about the occurrence of flares will be reviewed at all ULT clinic visits and telephone encounters occurring at 
monthly intervals in Phase 3 with the aid of these diaries to avoid recall bias that could affect this 
measurement if longer intervals were used.  A gout flare questionnaire will be used during each visit (Phase 
1 and 2) and each call (Phase 3) to capture information on: 1) the presence of a ‘warm’ joint; 2) the 
presence of a swollen joint; 3) a corresponding pain at rest score > 3 (0 to 10 scale); 4) patient-reported 
gout flare; and 5) medications used to treat flares, if any.  Participants will be considered to have an acute 
gout flare if 3 of the first 4 criteria are satisfied. This method has been demonstrated to have a sensitivity of 
91% and a specificity of 82% (63).  In addition to examining the proportion of patients with at least one 
flare, we will also examine the number of one-month intervals during Phase 3 with gout flares requiring 
treatment.  Treatment of gout flares will be done at the discretion of the site investigator with guidelines 
provided within the protocol (See Section X. Treatment Regimens below). Because gout patients may treat 
their attack at the first symptoms of attack onset, which can abort the full presentation of an attack, a 
secondary flare definition will be used of patient-reported flare of typical characteristics above plus use of 


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appropriate gout anti-inflammatory medication; this is a standard approach used in gout RCTs in which 
flares are an outcome of interest (64-72). 
Importantly, our focus on the occurrence of acute gout flare as the primary outcome is highly 
consistent with priorities of both healthcare providers and gout patients.  As mentioned above, in preparing 
for this application we conducted separate surveys targeting both gout patients participating in the 
National Data Bank for Rheumatic Diseases (NDB) (n = 40) and a national sample of VA healthcare providers 
actively involved in gout management (n = 179).  Both groups identified a reduction in acute gout flare as 
the top priority and the preferred primary endpoint for any future trial examining the comparative 
effectiveness of ULT (unpublished). 
Secondary End Points 
Key secondary outcomes will include:  
1) Efficacy (occurrence of gout flare in Phase 3) and tolerability in patients with CKD 3. 
 
We plan to enroll approximately 317 participants with Stage 3 CKD; these participants will be 
enrolled in equal proportions in both arms.  To determine whether the efficacy of allopurinol and 
febuxostat differ among those with Stage 3 CKD, a planned secondary endpoint will be the occurrence 
of gout flares during Phase 3 (as defined above) in this patient subset.  Tolerability of the two 
treatments will also be compared in this patient subset and will include comparisons of adverse events, 
serious adverse events, and related study withdrawal.   
 
2) The proportion of patients achieving a sUA threshold < 6.0 mg/dl in Phase 2 across treatment groups. 
The proportion of patients achieving a sUA < 6.0 mg/dl during Phase 2 (mean level assessed at 
weeks 36, 42, and 48) will be examined as a secondary study outcome.  A sUA threshold of < 6.0 mg/dl 
is based primarily on the understanding that hyperuricemia is a necessary, although not always 
sufficient, precursor in gout development and progression.  Indeed, a sUA, 6.0 mg/dl is the 
recommended initial treatment target of the American College of Rheumatology. Hyperuricemia is 
most commonly defined as a sUA concentration exceeding 6.8 mg/dl, the level at which extracellular 
urate super-saturation occurs and promotes the precipitation of monosodium urate crystals in both 
joints and surrounding tissues.   
Lowering and maintaining sUA concentrations below the level of ‘supersaturation’ is absolutely 
essential in reducing the total body urate burden and achieving long-term benefits.  Targeting a slightly 
lower threshold of < 6.0 mg/dl accounts for both the issues of day-to-day variability in sUA and assay 
imprecision (estimated in College of American Pathologists Proficiency Testing [CAP PT] to approach 4 
to 5%).  Although the predominance of literature suggests no significant diurnal variation in sUA (73, 
74), others have suggested a small degree of such variability approaching 0.5 mg/dl (75). In particularly, 
this level of sUA is considered an evidence-based target for treatment, and necessary to achieve 
outcomes pertinent to patients, such as reduction of flare frequency (7, 76). Understanding its essential 
role in gout treatment, we have adopted the biochemical threshold of a sUA concentration below 6.0 
mg/dL as a secondary end-point, and one which regulatory agencies require for approval (11, 13).  


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To facilitate point-of-care ULT dose titration, all sUA measurements will be performed by the 
clinical laboratory at the participating study site.  Importantly, sUA measurement is internationally 
standardized and readily accessible across all participating clinical laboratories.  The prevailing 
technique used for sUA measurement used in the U.S. (including VA centers and RAIN sites) uses the 
Trinder reaction with uricase, an assay that has been shown to be highly reliable with between-
laboratory and between-method coefficients of variation routinely below 5% (77). 
3) Determining if gout flares in Phase 3 differ in those who reach a target sUA of < 6.0 mg/dl compared 
with those who do not by 48 weeks. 
As detailed above, achieving a sUA goal of <6.0 mg/dl is a universally recommended treatment goal 
for ULT in practice as well as regulatory trials.  However, the true relationship of achieving this target 
with reducing gout flares has not been well documented in long-term clinical trials.  The design of this 
trial will allow us to address this important question.  Specifically, we will compare the gout flare rates 
in Phase 3 of those who did and did not achieve a sUA of < 6.0 mg/dl at the end of Phase 2.   
4) The impact of study treatments and sUA levels on health-related quality of life. 
 
Both the five-item EurQol (EQ-5D-3L) and Veterans RAND 12 (VR-12) will be collected from all 
participants at baseline, 24, and 48 weeks.  The EQ-5D-3L is a widely used measure of generic health-
related quality of life, which is relatively brief and provides a single index utility value (78).  This 
measure has been shown to be valid and reliable in assessing health-related quality of life in a number 
of chronic health conditions and will enable future cost-effectiveness analysis. Results from the EQ-5D-
3L will be supplemented with those from the VR-12, an alternative measure of health-related quality of 
life.  Similar to the EQ-5D-3L, the VR-12 survey is relatively brief and demonstrates excellent validity 
and reliability.  Of special note, the VR-12 allows for computation of both Physical and Mental Health 
Scale scores.  Although gout-specific health-related quality of life measures have been proposed, these 
measures have not been consistently demonstrated to have sufficient levels of validity or reliability 
(79). 
 
5) Changes in tophi area by location among those with tophaceous gout across treatment groups and sUA 
levels. 
 
Based on data from a recent clinical trial in chronic gout, we anticipate that ~20% of study 
participants will have tophi at enrollment (12).  Change in tophi area (see below for assessment 
procedure) will be examined as a secondary outcome among this informative subset of patients with 
tophaceous gout.  Providing rationale for their consideration as a secondary outcome, tophi are 
pathognomonic of gout and are problematic for patients as they mediate joint damage, often result in 
troubling cosmetic issues, and frequently obstruct normal joint function. 
 
For this study, a sentinel tophus will be measured at enrollment and the same tophus will then be 
measured in follow-up at weeks 24 and 48 using tape measurement as recently detailed by Dalbeth et 
al. (80).  The sentinel tophus will be defined as the most prominent and/or most readily measured 


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tophus found at the time of the baseline evaluation on the hands, elbows, feet, or ears (i.e., the most 
common sites for tophi).  In addition to having face validity, the tape measurement technique is 
inexpensive, requires minimal training, and a very short time for acquisition (estimated to be < 5 
minutes).  Moreover, this technique yields excellent inter- and intra-observer reliability with interclass 
correlation coefficients exceeding 0.9.  In a 52-week study, patients with tophaceous gout achieving a 
final serum urate < 6.0 mg/dl demonstrated a 75% reduction in tophus size using this technique (11). 
 
6) The impact of treatment on the flare rate over time (comparison of flare rates during each phase). 
 
To determine whether the total number of gout flares differs between the two treatment groups 
the total flare numbers occurring during observation (week 0 to 72) will be compared. Recognizing that 
the duration of a gout flare typically extends from several days to 2-3 weeks, and that it may sometimes 
be difficult for patients to distinguish between two or more back-to-back flares and one persistent but 
fluctuating flare, a maximum of one gout flare will be counted for each one-month observation period. 
Thus, as an example during Phase 3 (24 weeks) patients could experience a number of gout flares 
ranging from 0 to 6 flares. 
 
7) Exploring the tolerability/toxicity of the two ULT. 
 
       Toxicity data will be carefully collected throughout the 72 weeks of the trial (See Section XI, 
Baseline and Follow-up Assessment) and compared across treatment arms. Adverse events will be 
summarized using Medical Dictionary for Regulatory Activities (MedDRA) terminology and reported by 
count and frequency (%) for participants reporting an event for each term. Toxicity data that will be 
systematically collected include rises in sUA levels, serum creatinine, CBC, liver function tests (LFTs), 
blood pressure and reports of skin rashes. The frequency of cardiovascular safety events of interest will 
also be collected and analyzed, with particular emphasis on cardiovascular and all-cause mortality. 
Investigators will report other treatment-related adverse events should they encounter them.  All 
hospitalizations and other adverse events defined as serious per ICH guidelines will be collected and 
analyzed by treatment group.  
 
Serious adverse events which are considered by site staff or the study sponsor to be potentially 
cardiovascular in nature will be reviewed to determine whether the event should be considered a 
major adverse cardiovascular event (MACE) as defined by the CARES trial (CARES appendix s2).  
Adjudication will be performed independently by at least two experienced cardiologists, with a third 
adjudicator used to break ties. Each potential cardiovascular SAE will be assigned to one of the 
following categories. 
 
Arrhythmias not associated with ischemia 
 
Cardiovascular Death 
 
Hospitalization for Heart Failure 
 
Non-fatal Myocardial Infarction 
 
Stroke 
 
Transient Ischemic Attack (TIA) 


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 
Unstable Angina requiring urgent revascularization 
 
Other cardiac event 
 
Not a cardiac event 
 
The decision as to whether participants who experience a cardiovascular event should be continued 
in the protocol is at the discretion of the local site investigator.  The study chair should be consulted for 
any questions or concerns. 
 
Patients reporting skin rash at any time during the study will be evaluated in-person by a study 
investigator, with structured data collection completed in order to precisely characterize the nature 
and severity of the rash.  Data to be collected pertinent to rashes will include the individual 
components of the provisional classification criteria for the definition of allopurinol hypersensitivity 
syndrome (AHS) (81) (see criteria below).   We will modify these criteria slightly to include the use of 
either allopurinol or febuxostat, recognizing that the frequency of rashes for the two drugs has been 
similar in head-to-head trials conducted to date and serious cutaneous reactions have been reported 
for febuxostat during post-marketing surveillance.  Participants satisfying criteria for drug-related 
hypersensitivity will discontinue study medication and will be counted as a treatment failure but will 
continue to be followed.  Participants presenting with rashes that do not satisfy these criteria may be 
continued in the protocol at the discretion of the site investigator and the study chairman.  Such 
participants will have the option of continuing on protocol at stable or reduced doses of study 
medications at the discretion of the site investigator. 
 
Participants will be considered to have drug-related hypersensitivity if they satisfy two of the 
following major classification criteria, or if one major plus at least 1 minor criterion is present in the 
absence of other exposures (e.g. alternative medications) that might explain the clinical picture: 
 
Major Criteria: 
Worsening renal function (drop in eGFR >50% from study baseline) 
Acute hepatocellular injury (ALT >3 times upper limit of normal) 
A rash including features of toxic epidermal necrolysis, erythema multiforme, or a diffuse 
maculopapular or exfoliative dermatitis 
 
Minor Criteria: 
Fever (T≥100.4°F concurrent with the rash) 
Eosinophilia (absolute eosinophil count >2 times upper limit of normal) 
Leukocytosis (WBC >2 times upper limit of normal) 
 
8) To describe the effects of baseline covariates and time-dependent covariates on the primary results.  


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VIII. Bio statistical Considerations 
Overview of the Study Design 
The proposed study is a blinded, intent-to-treat, two-arm intervention trial testing whether 
allopurinol is non-inferior to febuxostat.  The trial will test the primary hypothesis that appropriately 
titrated allopurinol is non-inferior to appropriately titrated febuxostat. 
The trial has three phases: Phase 1 (weeks 0-24) titration, Phase 2 (weeks 25-48) maintenance, and 
Phase 3 (weeks 49-72) steady-state-evaluation. 
The primary outcome measure is the proportion of study participants in each arm who have one or 
more gout flares during Phase 3, weeks 49-72 of the follow-up period. During Phase 1 of the study (first 24 
weeks), participants will have gradual titration of their assigned urate-lowering medication in a protocolized 
fashion to achieve the sUA target of <6mg/dL.  During Phase 2, participants will maintain the achieved dose 
of the assigned treatment during weeks 25-48, with dose titration allowed if the target sUA is not yet 
achieved and if maximal dose of ULT is not yet achieved.  During Phase 3, participants will continue on their 
achieved dose without any titration.  While we will be collecting information on gout flares during both 
Phase 1 and 2, our primary outcome is the proportion of study participants experiencing at least one gout 
flare during Phase 3 because flares during the first two phases are likely reflective of the known increased 
risk of flares during initiation and early maintenance of ULT, whereas participants should be in steady-state 
by Phase 3. Thus, during Phase 3 we will record the occurrence of gout flares for each participant (as will 
also have been done for the first two phases) and record the binary outcome of either no gout flares (event 
absent) or one or more gout flares (event present).    
If the null hypothesis of inferiority is rejected, then the treatment allopurinol will be considered 
‘non-inferior’ (see below for specific parameters).  We wish to reject the one-sided null hypothesis that 
allopurinol is inferior to febuxostat.  This has particular clinical and health economic relevance given the 
substantially higher cost of febuxostat.  
A single analysis of the effect of the study medications will be conducted at the end of the trial. No 
interim analysis is planned. 
The study will enroll and randomize a total of 950 study participants to receive either allopurinol or 
febuxostat.  We expect to enroll, on average, approximately 40 study participants per month for 24 
months.  All participants will be followed for 72 weeks.  
Estimated Incidence of the Primary Endpoint 
The primary outcome is the occurrence of gout flares during Phase 3 (final 24 weeks).   We have 
chosen as the expected rate of outcomes for febuxostat a 20% rate of one or more flares within Phase 3, 
midway between 15% and 25%. Uncertainty arose because relevant studies used different definitions of 
flare, different treatment dosages, and provided little detail about recurrent flares. Also, we cannot 
precisely project the proportion of participants who will have sUA < 6 mg/dl when Phase 2 ends. Hence, we 
believe that in Phase 3, 75%-85% of participants will be flare-free and 15-25% will have one or more flares.  


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This range is based on four studies of gout patients on maintenance doses of one of the study treatments 
(11, 82-84). 
Becker et al (11) tested the non-inferiority of allopurinol to febuxostat using a bound of 10% for the 
binary endpoint of sUA <6 mg/dl and showed monthly rates of gout flares declining over time to 
approximately 10%.  During the final month only 6% of those achieving sUA < 6 mg/dl required treatment 
for a flare compared to 14% of those with sUA ≥ 6 mg/dl. Shoji et al (83) conducted a retrospective study of 
the rate of gout flares with observation periods ranging from 1 to 3 years.  In the medication group, starting 
one year after the first visit, 24% had at least one gout attack and the rate was about 5% per month.  
Rothenbacher et al (82) studied a cohort of over 20,000 gout patients and noted that almost 20% of 
patients had a first flare within the first year of follow-up. Wortman et al (84) reanalyzed data from three 
clinical trials that enrolled 4101 gout patients and showed that rates among treated participants with sUA < 
6 mg/dl declined to 5% per month.   In addition, in a community-based cohort of gout patients, of whom 
less than half were on urate-lowering therapy (45%), the risk of having at least one attack in a year was ~70-
75% (85). 
A strategy of dose titration for each treatment will be employed to bring as many participants as 
possible below the threshold of  sUA < 6.0 mg/dl, established by guidelines and recommendations (7).  The 
Phase 1 titration is intended to bring sUA < 6.0 mg/dl within 24 weeks. All participants will be analyzed 
during Phase 3 regardless of whether their sUA is < 6.0 or ≥ 6.0 mg/dl.  We expect that roughly equal 
numbers of participants in each study arm will reach this threshold.  We expect that 75% - 80% participants 
will have a mean sUA < 6.0 mg/dl across the last 3 study visits occurring during Phase 2 at 36, 42, and 48 
weeks.  For secondary analysis, we define the binary outcome, mean sUA < 6.0 mg/dl as a treatment 
success and mean sUA ≥6.0 mg/dl, as a treatment failure. 
Choice of a Bound, B, for the Non-inferiority Test 
Non-inferiority tests require expert choice of a bound, B, larger than the true difference, D, 
between the treatment proportions of participants with flare events (the proportion for febuxostat minus 
the proportion for allopurinol).  The bound marks where clinicians might begin to doubt that the difference, 
D, is very small and close to zero.  Seven rheumatologists on our Planning Committee, selected for their 
expertise in gouty arthritis and clinical trial design, chose B = 8%. 
The null hypothesis will be rejected if U, the upper limit on the one-sided 95% confidence interval 
on the difference between the two flare-event rates (D), is less than B = 8%. (See Figure 1) If U exceeds B 
then this indicates that the true difference may be large and that allopurinol is inferior to febuxostat. (See 
Figure 2) 
It is important to note that our choice of a bound is more conservative when compared to many 
other recent studies. Previous studies have chosen the true bound to be 10% and a true difference in the 
proportions to be 0% (11). For the non-inferiority test, this more conservative estimate requires CSP 594 to 
enroll a larger sample size.  
 


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Primary Data Analysis Plan 
The primary hypothesis to be tested is that allopurinol is non-inferior to febuxostat.  The primary 
outcome is the difference (D) in proportion of patients with one or more gout flares during Phase 3.  The 
proposed test is a one-sided non-inferiority test of the null hypothesis that U > B, which the upper limit on 
the 95% confidence interval on the difference between two proportions exceeds 8%.  We posit a true 
difference in proportions of 0%.   
Formal statement of the primary hypothesis 
H0:  Allopurinol is inferior to febuxostat.  The Phase 3 proportion of one or more gout flare events among 
Allopurinol participants is more than the Phase 3 proportion of one or more gout flare events among 
Febuxostat participants by 8% or more (D ≥ 8%). 
Ha:  Allopurinol is non-inferior to febuxostat. The Phase 3 proportion of one or more gout flare events 
among Allopurinol participants is not more than the Phase 3 proportion of one or more gout flare events 
among Febuxostat participants by 8% or more (D < 8%). 
The estimate of D, ܦ෡, is the observed treatment difference.  The difference is defined so that it is 
positive when febuxostat has the higher success rate.  To test the null hypothesis we will compute the 
upper limit of a one-sided 95% confidence interval for ܦ: 
U = ܦ෡ + 1.645*stderr(ܦ෡). 
The graphic below displays the decision process. In Figure 1 the upper limit (U) is less than B, and 
we accept the alternative hypothesis of non-inferiority; allopurinol is non-inferior to febuxostat. In   Figure 
2, U exceeds B indicating that the true difference may be larger than the posited value of D; we cannot 
reject the null hypothesis that allopurinol is inferior to febuxostat. 
Figure 1: One-Sided 95% Confidence Interval for the Non-inferiority Test Depicting ‘Rejection’ of the Null 
Hypothesis 
 
 
 
Figure 2: One-Sided 95% Confidence Interval for the Non-inferiority Test Depicting ‘Acceptance’ of the Null 
Hypothesis 
 
 
 
Figure 2 shows that the estimated difference, D෡, need not exceed B to retain the null hypothesis that 
allopurinol is inferior to febuxostat.   For example, if the observed event rate of gout flares for allopurinol is 
0
ܦ෡
ܷ 
ܤ 
0
ܦ෡
ܷ 
ܤ 


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24% and for febuxostat is 20%, then the difference is 4%, but U = 8.4% which exceeds B = 8%.   In other 
words an observed difference of D෡=4% or more will preserve the null hypothesis and only an observed 
difference, D෡ < 4% will establish non-inferiority.   In effect, an observed difference in proportions of 4% or 
more undercuts the belief in equivalence.  Metaphorically, if the bound B were an electric fence then, for 
safety, the observed difference, D෡, must be more than an arm’s length from B.   
Sample Size and Statistical Power Considerations for the Primary Hypothesis 
The results for the primary hypothesis will be analyzed by means of a one-sided 95% confidence 
interval on the difference in proportion of participants with one or more gout flare events.  The test of the 
difference between proportions will have one-sided type I error of 5%.  Starting with a total of 950 
participants, allowing 5% dropout, and retaining 900 participants, the test has 90% power to reject the null 
hypothesis of inferiority with a total of 900 participants, 450 participants per arm,   
For large samples, regarding the difference between proportions as the difference between means, 
the use of the standard Student’s t distribution closely approximates the non-central t-distribution and 
justifies use of the power formula 3.2.4 (in section 3.2.2) below (Chow, Shao, and Wang (86): 
݊= ݊ଵ= ݊ଶ= ൫ܼఈ+ ܼఉ൯
ଶ2ߪଶ
ሺܦ−ܤሻଶ
 
Note: n = 450 is the number of participants in each of the two study arms, 

Z
= 1.645 is the cut point for a 
one-sided test with a 5%, Type I error,

Z
 = 1.28 provides 90% power, Bound = 8%, D=0% is the true 
difference between the treatment outcome measures, and ߪଶ = 0.16 is the variance associated with the 
distribution of for a single Bernoulli observation.  
As rates are uncertain, we note that if the Phase 3 rate of gout flares is either 15%, 20%, or 25% 
then the respective statistical powers are 96%, 91%, and 87%.   With a rate of 20%, but a higher dropout 
rate of 10%, the power is 90%.  Non-adherence to treatment, inability to attain sUA < 6 mg/dl, or failure to 
appear for clinic visits will not affect dropout, only the explicit decision of the patient to leave the study.  
Participants who experience toxicity that either reduced dosage or other medications reduce to a tolerable 
level can remain on study if they wish to do so.  
The binomial test fails to account for dropout during phase 3.  We suspect that only 1 or 2 of the 
cohort may drop out flare-free, survive, and refuse to allow us to passively follow them until the end of 
phase 3.  Only a few will die before having a flare and they will be counted as treatment failures as if death 
were a flare.  Others will drop out of follow-up protocols, but remain alive and on-study.  With their 
permission we will passively follow them reviewing their charts to see if and when during phase 3 they 
report a gout flare to their physician.  For them dropout entails discontinuing phone contact with study 
staff and declining to complete study forms during clinic visits. Reluctance to adhere to the titration 
regimens and treatment side effects should account for 3% of the annual 5% dropout during phases 1 and 
2.  This leaves 2% who drop out for other reasons.  During phase 3 the adverse events will merely lead to 
adjustments in treatments but not dropout.   Thus, during the half-year of phase 3, only about 1% = (1/2 of 
2%) of participants will drop out. 


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The following speculative but conservative scenario suggests about 1 among the cohort of 900 will 
drop out before having a flare and have a truly censored outcome.  Assuming that dropout is equally likely 
before or after a gout flare, we will have 4.5 = 0.005*900 expected dropouts.  Rounding up to 5 
participants, we suspect 2 will die without a flare (counted as failures) and 2 of the surviving 3 will agree to 
passive follow-up.  The remaining survivor who declines passive follow-up will be counted as a failure. 
A more rigorous survival analysis will be done to confirm the primary result.   It can treat dropout as 
censored data.  However, while we could elicit from physicians a bound B for the proportion of flares, we 
could easily elicit the bound B for the non-inferiority test in terms of beliefs about tolerable deviations from 
a hazard ratio. 
The test of the primary hypothesis compares the treatments without adjustment for any covariates.   
The secondary analyses, particularly secondary analysis will confirm or not confirm the primary hypothesis 
by considering variations on the primary analysis including logistic regression models that adjust for 
covariates.   We note that logistic regression analysis yields a treatment odds ratio rather than the 
difference between proportions.  In this case, to carry out the non-inferiority test, we will estimate the 
difference between treatments by linking the odds ratio to the overall proportion of participants who have 
one or more gout flares. 
In addition to testing the primary hypothesis, extensive descriptive analyses outlined in (BRDP) will 
compare treatments with respect to selected variables among the demographic, medical history, laboratory 
values, anthropomorphic, vital sign, quality-of-life, alternative outcome, and side effect variables.    Simple 
unadjusted comparisons will apply Student’s t-test to continuous variables, the Wilcoxon test to highly 
skewed continuous or ordinal variables and will apply the Chi-square test (or Fisher’s exact test) to 
categorical variables. 
Non-adherence 
Of relevance to this study, observational studies have indicated relatively poor adherence in 
patients with gout (40, 87-90) However, Dalbeth et al. (91) found that higher doses of allopurinol were 
associated with sUA levels at target independent of adherence with treatment. Because all study 
participants will receive active therapies of proven efficacy for lowering sUA levels as well as prophylactic 
treatment of acute gout symptoms, compliance issues are expected to be minimal in this trial.  Other 
studies in rheumatoid arthritis have shown that if patients are doing well, issues of poor treatment 
adherence are minimized (92). 
Participant adherence to protocol-directed study treatment will be assessed via pill counts, 
prescription renewals, and participant interview.  We will use the question and pill count data to determine 
if a participant took 80% or more of treatment medication.  The per-protocol population will be defined as 
participants remaining on the same treatment throughout the entirety of the study with 80% adherence.   
The primary analysis follows the ITT principle that adjusts for, at most, a few covariates and seldom 
directly accounts for non-adherence.  We will compare the primary results with the analogous results for 
the per-protocol participants.  Also, we will model the effects of non-adherence in the secondary analyses. 


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In this case adherence is a time-dependent covariate requiring that the treatment comparison be made 
using a GEE analysis to account for varying periods of follow-up between treatments. 
Secondary Data Analysis 
All secondary analyses are descriptive exploratory analyses and will be done with and without 
covariate adjustment (age, sex, disease severity, comorbidities, etc.).  All secondary analyses deal with 
dropping out in the same way described in the primary analyses 
We describe the proposed analysis for each of the eight secondary objectives: 
1) To compare the efficacy and tolerability of allopurinol and febuxostat in hyperuricemic participants 
with gout and stage 3 chronic kidney disease (CKD 3) in reducing gout flares.  
 
Based on VISN 1 data, over half the participants should have stage 3 CKD.   We will carry out exactly 
the same non-inferiority analysis proposed for the primary objective but restricted to participants with 
stage 3 CKD, using only gout flares observed during Phase 3.  In addition we will carry out logistic 
regression analyses that adjust for covariates as described in the confirmatory analyses in objective 8.  
Also, using the full cohort we will compare gout flare rates of participants with stage 3 CKD to 
participants with an eGFR ≥60 mL/min/1.73m2 within a logistic regression model. Tolerability of the two 
treatments will also be compared in this patient subset and will include comparisons of adverse events, 
serious adverse events, and related study withdrawal.   
 
2) To explore the efficacy of the two ULT dosing regimens in achieving the goal of sUA <6.0 mg/dl 
evaluated at the end of phase 2.   Besides treatment, the primary predictors include the series of sUA 
measures and dose titrations prior to 48 weeks.  This longitudinal analysis will model deviations from 
the titration protocol. 
 
The primary analysis for these longitudinal data will be the mixed effects model with a variance-
covariance structure that assumes auto correlated AR(1) sUA measurements over time.  We will use 
PROC MIXED in SAS.   At each clinical visit a binary factor will indicate if the titration protocol is or is not 
maintained.  Besides baseline factors such as age, sex, and duration of disease, the model will 
incorporate time-dependent factors including side effects.  Missing data methods will address potential 
censoring of events among patients who fail to attend clinic visits.  We will run this same analysis using 
the biological threshold of sUA <6.8 mg/dl after 48 weeks. 
 
3) To determine if gout flares in phase 3 in participants who achieve a sUA < 6.0 mg/dl by 48 weeks differ 
compared to those who do not, regardless of treatment assignment. 
This binary outcome for this logistic regression analysis will be the 48-week status of sUA; namely, 
sUA < 6 mg/dl vs sUA >= 6 mg/dl.  The analysis will model the gout flares in phase 1 and phase 2 as 
time-dependent covariates as in the second secondary analysis above. Models with additional factors 
are described in objective 8.  


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4) To determine whether health-related quality of life measures differ between participants randomized 
to allopurinol compared to febuxostat and differ by achievement of sUA < 6.0 mg/dL, regardless of 
treatment assignment. 
 
EQ-5D-3L & VR-12 instruments will be administered at baseline, 24 and 48 weeks.  At each time we 
will compare the mean scores by treatment groups, using both an unadjusted t-test and linear 
regression with adjustment for baseline covariates.    Also, with outcome change from baseline to 24 
weeks and change from baseline to 48 weeks, we will compare mean changes with and without 
covariates using linear regression.   Finally, we will carry out a repeated measures analysis using all 
three time points.  Missing data methods will address potential censoring of events among patients 
who fail to complete the instrument at a particular time. Analogous analyses will be carried out 
controlling for sUA levels. 
 
5) To determine whether change in tophi area differ by location between participants randomized to 
allopurinol compared to febuxostat and differ by achievement of sUA < 6.0 mg/dL, regardless of 
treatment assignment. 
 
Tophi area will be assessed at baseline, 24 and 48 weeks.  At each time point we will compare the 
mean areas by location by treatment groups, using an unadjusted t-test and linear regression with 
adjustment for baseline covariates.    Also, with area change from baseline to 24 weeks and area 
change from baseline to 48 weeks, we will compare mean changes by location with and without 
covariates using linear regression.   Finally, we will carry out a repeated measures analysis using all 
three times.  Missing data methods will address potential censoring of events among patients who fail 
to complete the instrument at a particular time. Analogous analyses will be carried out controlling for 
sUA levels. 
 
6) To determine whether the number of gout flares during all three phases differ between participants 
randomized to allopurinol compared to febuxostat and then extend this analysis to the entire 72-week 
period.  
 
We will model the number of gout flares, which can have substantial variation, as Poisson random 
variables.   The analyses will compare treatments using a longitudinal repeated measures analysis with 
Poisson counts (PROC GLIMMAX and GENMOD in SAS).   Missing data methods will address potential 
censoring of events among patients who appear to fail to report flares.  Flare counts will be analyzed 
separately during Phases 1, 2, and 3 because dose titration during Phase 1 tends to increase the counts, 
and this effect may still persist in Phase 2, particularly for those still undergoing dose titration; 
participants are expected to be in steady-state by Phase 3.   Also, Phase 2 analysis will consider 
prophylactic treatment after a gout flare and severe side effects of treatment as predictors of 
subsequent counts.   During Phase 3 the same set of factors as well as Phase 2 counts will be used to 
predict gout flare counts. These time-dependent associations will require a mixed effects model using 
an auto correlated variance-covariance to model the series of events.   For these analyses we may treat 


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the counts as continuous measures in order to introduce more subtle variance-covariance structure 
and a variety of random effects. 
 
7) To determine the patterns of tolerability/toxicity for each treatment during Phase 3 and then overall 
from weeks 1-72. 
 
Toxicity events include rises in sUA levels, adverse changes in serum creatinine, CBC, liver function 
tests (LFTs), blood pressure, and the incidence of skin rashes. The incidence of cardiovascular events of 
interest, with particular emphasis on cardiovascular and all-cause mortality, will also be included in this 
analysis.   Within each Phase we will determine if the incidence of such events differs between 
treatments.  In the Phase 3 analysis baseline covariates will include the summary of toxicity events 
during Phases 1 and 2 as well as the 48-week sUA level.  As in the sixth secondary analysis the same 
statistical methods for Poisson counts will be used to express time-dependent events.    
 
At each clinic visit we will assess the count of each type of major side effect episodes between 
visits.  Deviations from the titration protocol will be modeled as a binary factor.  We will model counts 
that have substantial variation as Poisson random variables. These outcome measures include each 
count and the aggregate count.  These counts will be coarsened into binary outcomes of no events 
versus one or more events.  The analyses will compare treatments using a longitudinal repeated 
measures analysis with Poisson count, negative binomial counts, and binary outcomes (PROC GLIMMAX 
and GENMOD in SAS).   Missing data methods will address potential censoring of events among patients 
who fail to attend clinic visits.  We will run this same analysis using the biological threshold of sUA <6.8 
mg/dl after 48 weeks. 
 
8) To describe the effects of baseline covariates and time-dependent covariates on the primary results.  
Baseline data include demographic characteristics (e.g. age, sex), disease history including CKD 
level, presence of tophi at baseline, height, weight, laboratory values, medications, other comorbidities, 
and quality-of-life measures.   Data obtained often after baseline include sUA values, titration levels, 
side effects, and gout flare counts.  Many baseline measurements are repeated at 24 and 48 weeks.   All 
data obtained before Phase 3 may be used as baseline factors for Phase 3 analyses such as the primary 
hypothesis and secondary object #1.   Secondary analyses 2-7 can adjust for covariates obtained at 
baseline and at 24 weeks.  
All major analyses will be repeated on the per-protocol population with adherence and non-
adherence as defined above.   The objective is to either confirm our results or detect that adherence to 
treatment alters the result.  
Missing Data 
Rate of attrition has been estimated as being up to 15% with up to 7.5% data loss, and sample size 
has been adjusted accordingly to maintain 90% statistical power for the primary analysis.  Distribution of 
participants lost to follow-up and missing data on key variables across the treatment groups will be 
monitored throughout the study.  Missing endpoint data will not be imputed.  The intent-to-treat principle 


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will be used to analyze endpoint data. Missing covariate data will be imputed in selected circumstances as 
described in Little and Rubin (93).  We will explore the possibility of non-random dropout on endpoint data 
(94).  
IX. Study Population and Patient Recruitment 
Patient Population: 
Patients with a history of gout who are hyperuricemic defined as a sUA ≥ 6.8 mg/dl will be approached 
for participation in this trial.  Gout will be defined based on satisfaction of American College of 
Rheumatology (ACR) and EULAR gout classification criteria (95) as defined below: 
1) Entry Criterion. Criteria scoring will only be applied to subjects that meet this requirement: At least 
one episode of swelling, pain, or tenderness in a peripheral joint or bursa. 
2) If the entry criterion is met, then the subject should be assessed for the Sufficient Criterion: 
Presence of MSU crystals in a symptomatic joint or bursa (i.e., in synovial fluid) or tophus. If the 
sufficient criterion is met, then the subject is classified as having gout and no further scoring is 
required. 
3) If the entry criterion is met but the subject does not meet the sufficient criterion, then the criteria 
score must be obtained by selecting the highest category within each of the domains in the table 
below. 
4) If a score of ≥8 is achieved, the subject is classified as having gout. 


CSP#594 Protocol V6.2 
 
 
 
 
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DATE:23JUN2020 
Domains 
Categories 
Score 
Total 
CLINICAL 
Pattern of joint/bursa involvement during 
symptomatic* episode(s) ever 
Joint(s) or bursa(e) other than ankle, midfoot or 
1st MTP (or their involvement only as part of a 
polyarticular presentation) 
0 
Ankle OR midfoot (as part of monoarticular or 
oligoarticular episode without MTP1 
involvement) 
1 
MTP1 (as part of monoarticular or oligoarticular 
episode) 
2 
Characteristics of symptomatic episode(s) ever:
i) 
Erythema overlying affected joint 
(patient-reported or physician-observed) 
ii) 
Can’t bear touch or pressure to affected 
joint 
iii) 
Great difficulty with walking or inability to 
use affected joint 
No characteristics
0
One characteristic
1
Two characteristics
2
Three characteristics 
3 
Time-course of episode(s) ever: 
Presence (ever) of ≥2, irrespective of anti-
inflammatory treatment:  
i) 
Time to maximal pain <24 hours  
ii) 
Resolution of symptoms in ≤14 days  
No typical episodes
0
One typical episode
1
Recurrent typical episodes
2


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iii) 
Complete resolution (to baseline 
level) between symptomatic episodes 
Clinical evidence of tophus: Draining or chalk-like 
subcutaneous nodule under transparent skin, often 
with overlying vascularity, located in typical locations: 
joints, ears, olecranon bursae, finger pads, tendons 
(e.g., Achilles). 
Absent 
0
Present 
4 
LAB 
Serum urate: Measured by uricase method. Ideally 
should be scored at a time when the patient was not 
taking urate-lowering treatment and patient was 
beyond 4 weeks of the start of an episode (i.e., during 
intercritical period); if practicable, retest under those 
conditions. The highest value irrespective of timing 
should be scored. 
<4mg/dL         [<0.24mM] † 
 -4 
4-<6mg/dL     [0.24-<0.36mM]
0
6-<8mg/dL     [0.36-<0.48mM] 
2
8-<10mg/dL   [0.48-<0.60mM]
3
≥10mg/dL       [≥0.60mM]
4
Synovial fluid analysis of a symptomatic (ever) joint or 
bursa:** Should be assessed by a trained observer. 
Not done
0
MSU negative
-2
IMAGING‡  
Imaging evidence of urate deposition in 
symptomatic (ever) joint or bursa: Ultrasound 
evidence of double-contour sign¶ or DECT 
demonstrating urate deposition§. 
Absent OR Not done
0
Present (either modality) 
4 


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Imaging evidence of gout-related joint damage: 
Conventional radiography of the hands and/or feet 
demonstrate at least one erosion.‡‡  
Absent OR Not done
0
Present 
4 
Total Score 
* Symptomatic episodes are periods of symptoms that include any of swelling, pain, or tenderness in a peripheral joint or bursa.
† If serum urate <4mg/dL (0.24mmol/L), take away 4 points; if serum urate ≥4-<6mg/dL (≥0.24mmol/L - <0.36mmol/L), score this 
item as 0 
**If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to show MSU crystals, 
take away 2 points. If synovial fluid was not assessed (not done), score this item as 0. 
‡ If imaging not available, score these items 0. 
¶ Hyperechoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation angle of the 
ultrasound beam (note: false positive DCS (artifact) may appear at the cartilage surface that should disappear with a change in the 
insonation angle of the probe).31,32  
§Presence of color-coded urate at articular or peri-articular sites. Images should be acquired using a dual energy computed 
tomography scanner, with data acquired at 80 and 140 kV and analyzed using gout-specific software with a two material 
decomposition algorithm which color-codes urate.33 A positive scan is defined as the presence of color-coded urate at articular or 
peri-articular sites. Nailbed, submillimeter, skin, motion, beam hardening and vascular artefacts should not be interpreted as evidence 
of DECT urate deposition.34 
‡‡Erosion is defined as a cortical break with sclerotic margin and overhanging edge; excluding DIP joints and gull wing appearance. 
 
 


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Participant ID ______________________ 
 
LSI/Sub I Name: _________________________  LSI/Sub-I Signature ______________________ Date: __________________ 
 


CSP#594 Protocol V6.2 
 
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DATE:23JUN2020 
The study will include gout patients not only receiving first-time ULT but will also allow for the 
inclusion of gout patients who remain hyperuricemic (serum urate ≥ 6.8 mg/dl) despite ongoing therapy 
with uricosurics (e.g. probenecid) or allopurinol at daily doses ≤ 300 mg.  Uricosurics will require a 14-day 
wash-out prior to study enrollment.  Because febuxostat is non-formulary in the VA and considered only for 
patients failing or intolerant to allopurinol, patients with prior use of this agent will be excluded from study 
participation.   
Inclusion Criteria: 
1. 
Age ≥18 years 
2. 
History of gout – crystal proven or historical as defined by ACR criteria listed above 
3. 
Serum urate level ≥ 6.8 mg/dl 
Exclusion Criteria: 
1. 
Stage 4 or 5 Chronic Kidney Disease (CKD) – defined as eGFR of <30 ml/min/1.73 m2 
2. 
Women younger than 50 years of age 
3. 
Patients with a history of prior solid organ / hematopoietic transplantation 
4. 
Previous allergy or intolerance to allopurinol  
5. 
Patients who are not candidates for any of the recommended prophylactic medications 
(colchicine, naproxen or glucocorticoids) 
6. 
Patients who in the opinion of the investigator have a high genetic risk for allopurinol 
hypersensitivity syndrome (AHS*) unless they have been found to be negative for HLA B5801. 
7. 
Previous history of failure to reach target uric acid levels despite therapy with allopurinol at 
dose > 300 mg/day  
8. 
Prior febuxostat use 
9. 
Patients with malignancies that are currently active with exception of non-melanoma skin 
cancer 
10. 
Patients with serum uric acid levels >15 mg/dl 
11. 
Patients with myelodysplasia and hemoglobin of < 8.5 g/dL 
12. 
Patients with chronic liver disease with two or more of the following occurring within the past 
six months: 
a. INR ≥1.7, not on Warfarin therapy 
b. Bilirubin ≥2 mg/dL 
c. Serum albumin <3.5 g/dL 
d. Ascites 
e. Encephalopathy  
13. 
Current use of azathioprine, mercaptopurine, didanosine, cyclophosphamide, probenecid** 
lesinurad or pegloticase*** 
14. 
Enrollment in another randomized interventional clinical trial**** 
15. 
Any severe medical condition that, in the enroller's opinion, is likely to compromise the 
participant's ability to complete the trial (e.g. unable to give informed consent). 
 
 


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*Please see operational manual for further discussion on genetic risk for AHS. 
** Participants on probenecid may be enrolled in the study provided that they undergo a 14-day wash-out 
period before study entry. 
*** Urate-lowering therapies approved after study kickoff are also excluded. 
**** Unless the randomized interventional clinical trial is approved for dual enrollment by VACO 
Defining Chronic Kidney Disease: 
Chronic kidney disease (CKD) is defined on the basis of abnormalities of kidney structure or function 
that are present for >3 months and have implications for health (96). The severity of CKD is stratified based 
on the magnitude of reduction in glomerular filtration rate (GFR) into five categories (Table 3), with the 
presence of decreased GFR (<60 mL/min/1.73 m2) for >3 months defining the presence of CKD independent 
of other markers of kidney damage, such as albuminuria, hematuria or structural abnormalities of the 
kidney.  Inulin, iothalamate or iohexol clearance measurements are the “gold standards” for measurement 
of GFR but are highly cumbersome and are impractical in clinical practice.  While creatinine clearance 
measurements based on 24-hour urine collections have been widely used for estimation of GFR, 24-hour 
urine collections are subject to numerous inaccuracies, including over- and under-collection of the urine 
sample. In addition, creatinine clearance systematically overestimates true GFR by 10% to 40% due to 
tubular secretion of creatinine.  Thus, measured creatinine clearance does not improve the estimate of GFR 
over that provided by estimating equations (96-98). Multiple estimating equations using serum creatinine 
and demographic data have been developed and validated including the Cockroft-Gault equation (99), the 
Modification of Diet in Renal Disease (MDRD) equation (100, 101) and the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equations utilizing creatinine, cystatin C or both (97, 102). In this 
study we will utilize the MDRD equation for estimation of GFR and assessment of kidney function.  
Although the CKD-EPI equation performs modestly better than the MDRD equation, particularly in patients 
with near normal serum creatinine values, this enhanced performance is relatively trivial in comparison to 
the overall precision of the equations (97, 102).  More importantly, the VA utilizes standardized reporting of 
MDRD estimated GFR (eGFR) across all facilities.  
Patients with stage 1 or 2 CKD, based on the presence of persistent albuminuria or known 
structural abnormalities of the kidney (e.g. polycystic kidney disease), but with preserved kidney function 
with an eGFR of ≥60 mL/min/1.73 m2, will be included in the “normal” kidney function cohort for the 
purpose of this study. On the basis of GFR, these patients are indistinguishable from the large numbers of 
healthy elderly who have an eGFR between 60 and 90 mL/min/1.73m2 on the basis of age. Furthermore, 
significant abnormalities in renal urate and drug handling are not seen in patients with eGFR ≥60 
mL/min/1.73 m2. 
 
 
 


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Table 3: Staging of Chronic Kidney Disease based on Glomerular Filtration Rate
 
GFR Stage
GFR (mL/min/1.73 m2)
1
≥90
2
60-89
3
30-59
4
15-29
5
<15
 
Changes in Renal Function during the Protocol 
With a 950 patient study and particular in this gouty population some patients will have renal 
function deterioration during the study. In most cases this will not require any changes in treatment 
regimens with regard to ULT (allopurinol or febuxostat). However, in the case where patients develop stage 
3 CKD (eGFR 30 to <60 mL/min/1.73 m2) investigators will be encouraged to stop naproxen if being used for 
prophylaxis and instead use colchicine 0.6 mg q day or prednisone.  If patients progress to more severe 
stages of CKD (eGFR <30 mL/min/1.73 m2) the colchicine dose should be decreased to 0.6 mg every-other 
day or 0.3 mg daily or prednisone should be substituted for the colchicine.  Colchicine should be avoided in 
patients who develop advanced CKD (eGFR <30 mL/min/1.73 m2) with concomitant hepatic dysfunction.  At 
all times investigators will be encouraged to use their best clinical judgment.  
Participant Recruitment/Enrollment: 
Potential participants will be identified via a number of mechanisms including through primary care 
and rheumatology clinics, self-referrals, and medical record review (through use of HIPAA waiver to screen 
for gout diagnosis, medications used to treat gout, renal function, and uric acid level). 
Several approaches will be used to identify potential participants for the study. The recruitment 
methods we plan on employing are as follows: 
 
Potential participants will also be identified via VA national electronic health record data through 
the VA Informatics and Computing Infrastructure (VINCI) program. We will ask VINCI to provide a 
list of potential participants, including name, address, phone number, upcoming clinic visits, 
primary care panel assignment, and history of clinic attendance who meet our inclusion and 
exclusion criteria.  PIs and Study Staff will use this information to inform primary care providers 
(PCP) of potential eligible patients in their patient panel and provide them with contact information 
to refer interested patients, the primary care providers will refer their interested patients to the 
study team and the study team will follow up with the patient regarding participation in the study. 
If a member of the study team is in the clinic at the time the PCP is seeing an interested patient 
then the PCP will introduce the patient to that study team member.  If there is no member of the 
study team in the clinic the PCP or delegate will use email encryption to contact the study team 
regarding the interested patient. 


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 
Primary care providers or Rheumatologists will also be notified by Study staff about eligible patients 
with pending clinic appointments and will be requested to ask about patients’ interest in 
participation in the study 
 
There will be a standardized letter sent to those patients who do not have appointments coming up 
in the near future.  The letter may be sent by the local site investigator (LSI) and will reference their 
health care provider and make note that the provider is aware they are being contacted regarding 
this study.  The letter will request for them to indicate if they do not want to be contacted in the 
future regarding their interest in participating in the study.  If interested, or no response is received 
within 2 weeks the local site investigator or study staff will contact the patient on the phone to 
discuss their possible participation in the study.  
 
No written documentation will be kept of patient’s interest; however a list of potentially eligible 
patients will be maintained at each site to allow study staff to contact primary care providers or 
Rheumatologists about upcoming patients. 
 
Nurses, primary care providers, or Rheumatologists will be regularly reminded about the study and 
those with eligible patients will be contacted and encouraged to speak with the study staff about 
possible enrollment 
 
Educational materials in the form of posters and brochures may be displayed and distributed 
around the clinics describing the study and giving contact information for those interested. 
 
If patient expresses interest in participation they will be screened by study personnel using the 
Eligibility and Randomization case report form that will be saved in IWRS to confirm eligibility 
criteria is met. 
If participants are eligible after screening, they may be randomized and enrolled in the study. Feasibility 
of recruitment is discussed in Section XIII below. 
RAIN Site Participation: 
When patients are recruited at RAIN sites identical procedures as described above will be followed. 
All RAIN sites will operate under their own IRB guidance, and will be managed by their own investigators. 
This will require no additional VA personnel. Clinical data will be collected at CSP Coordinating Center and 
information will be sent to Albuquerque who will be providing study drug for patients and safety 
monitoring at RAIN sites. The VA will not be using RAIN databases.  The RAIN site will be operating under 
their own IRB and their informed consent/HIPAA form will describe who will have access to PHI and PII and 
what information will be shared with the VA. Veteran PHI will not be disclosed to non-VA site investigators.  
Aggregate study data, such as DMC reports, will be provided to non-VA RAIN investigators as required for 
conduct of the study. 
X. Treatment Regimens 
Dosing of study medications: 
Study medications will be titrated in participants as described below. Participants will be assigned 
to allopurinol active and febuxostat placebo or allopurinol placebo and febuxostat active. Titration of both 
allopurinol and febuxostat will occur simultaneously, as shown below in Table 4.  ULT dosing adheres to the 
currently recommended initial dosing in gout patients with both normal renal function and CKD stage 3 and 


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mandates careful monitoring of patients as the dose is increased (7).  Dose increases will occur until sUA 
concentrations achieve a target level < 6.0 mg/dl, unless the tophi are present then the goal will be < 5.0 
mg/dl, or an adverse event occurs mandating drug discontinuation or dose reduction.   
The 72-week study will be divided into 3 Phases: a 24-week Dose Titration Phase (Phase 1) followed 
by a 24-week Maintenance and Optimization Phase (Phase 2) and then a 24-week Steady State Flare 
Observation Phase (Phase 3).  If sUA level is 6.0 mg/dl (5.0 mg/dl if tophi present) or above at week 30 (the 
first visit occurring during the second phase of the study), dose titration will be allowed as long as maximal 
daily drug doses have not been achieved (800 mg/day for allopurinol or 80 mg/day for febuxostat).  Dose 
escalation will not be allowed during the final three study visits of Phase 2 occurring at weeks 36, 42, and 
48 or during Phase 3. During Phase 3 participants will be actively followed by monthly phone interviews for 
flare reporting; no dose titration will be allowed during this phase to enable capture of flare data while 
participants are in steady-state. 
Table 4*: Phase 1 Dose Titration for CSP 594; Weeks 0 to 24 (maximum ULT dose in mg/day by study week)
Baseline
3 wks.
6 wks.
9 wks.
12 wks.
15 wks.
18 wks.
21 wks.
24 wks.
Allopurinol
100
200
300
400
500
600
700
800
800
Febuxostat
40
40
40
80
80
80
80
80
80
Prophylaxis
All participants required to be on prophylactic medication for a minimum of 6 months (see 
“Prophylaxis” section for details) 
 
For patients not at sUA goal prior to the week 36 visit, including patients who were previously at 
goal, up-titration is required up to the maximal daily dose, with exceptions permitted for patients 
experiencing adverse effects. For patients with an increase in sUA which is believed to be unrelated to 
medication dose (e.g., suspected analytic error or patient non-adherence), up-titration is generally 
encouraged but may be deferred based on clinical judgment until sUA can be retested.  
Gout patients who remain hyperuricemic (sUA ≥ 6.8 mg/dl) despite ongoing allopurinol use in daily 
doses ≤ 300 mg will be allowed to enroll in the study.  These patients will be randomized to receive 
febuxostat or to remain on allopurinol.  For those initiating febuxostat, the starting dose will be 40 mg daily 
irrespective of prior allopurinol dose.  For pre-study allopurinol users randomized to the allopurinol 
treatment arm, patients will continue with their current dose until scheduled for dose escalation based on 
the above schedule.  For example, a patient on allopurinol 300 mg daily randomized to the allopurinol 
treatment arm would remain on 300 mg until week 9 of the study at which time they would be eligible for 
dose escalation.  For a similar patient taking allopurinol 200 mg daily, the first possible titration will occur at 
week 6. We have opted for this approach to minimize the risks of gout flares that may occur as a 
consequence of sUA fluctuations and to ensure the same intensity of follow-up for all participants. 
Recognizing that true equivalency doses have never been established for allopurinol and 
febuxostat, the dose titration schedule has been generated in order to yield a similar ‘velocity’ in sUA 
reduction in the two treatment arms over the first 24 weeks of the study.  We have opted for the proposed 
dosing schedule for febuxostat, recognizing that the drug’s package insert recommends starting all patients 
on 40 mg/day with a dose titration to 80 mg/day after 2 weeks for those with sUA ≥ 6.0 mg/dl (≥5.0 mg/dl if 


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tophi present).  Given the lifelong nature of gout, our study outcomes have focused on longer-term 
reductions in gout flares and sUA rather than the ‘time to achieve goal’.  We believe that the slower dose 
escalation in febuxostat will reduce treatment-related gout flares in this arm, thus increasing participant 
adherence and ensuring a similar follow-up intensity between study arms.  Recognizing that no 
comparative effectiveness trials of these two agents have been conducted using allopurinol doses 
exceeding 300 mg/day, the urate lowering properties of allopurinol 300 mg/day appear to be similar to that 
of febuxostat 40 mg/daily.  In the CONFIRMS trial (12), 45% of patients receiving febuxostat 40 mg daily 
achieved a serum urate < 6.0 mg/dl over the six-month trial compared to 42% of those receiving allopurinol 
300 mg/day. Patients initiated on allopurinol 100 mg daily will be titrated to 200 mg daily at week 3 prior to 
the first follow-up sUA that is planned for week 6.  Although this could lead to ‘overshooting’ the sUA target 
in some patients, we believe this will be quite uncommon based on data from Schumacher et al (13) 
demonstrating that among gout patients with CKD receiving allopurinol 100 mg daily none achieved a sUA < 
6.0 mg/dl. 
In the event that a participant temporarily stops taking the study medication, it is generally not 
necessary to re-titrate. At the discretion of the site investigator, patients who were on a stable dose of 
study drug can be re-started at their prior dose.  Participants who interrupted the study medication during 
the titration phase should be restarted at the dose at which they stopped and titration continued based on 
sUA results. During the titration phases of the study, a participant who stops and restarts the study 
medication should be on the study drug for a minimum of 7 days before SUA is drawn for titration 
purposes. While interruptions in study drug treatment should be avoided as much as possible, short-term 
(≤10 days) discontinuation of study medications during the Dose Titration Phase or a longer period of 
discontinuation during the Maintenance/Observation Phases which may occur due to participant non-
adherence, adverse events, or other reasons is not generally regarded as a protocol deviation. The LSI may 
consult with the study team if clarification is necessary. 
Prophylaxis: 
Prophylactic therapy will be initiated either prior to or concomitant with study medication for all 
randomized participants.  
One or more prophylactic/flare treatments including naproxen, colchicine, or prednisone will be 
dispensed based on prescriber judgment and individual participant need.  While it is important that all 
participants will be on some flare prophylaxis the LSI may use their judgement if adverse events require 
changes or short term (≤10 days) interruption of the prophylactic medication.  In circumstances where the 
LSI has additional questions or concerns the Study Chair should be consulted. 
For patients with normal kidney function or mild renal impairment (defined as an estimated glomerular 
filtration rate [eGFR] ≥ 60 ml/min/1.73 m2), the primary options for anti-inflammatory prophylaxis will be: 
 
Naproxen 250 mg p.o. twice daily with the possibility of dose escalation to 500 mg twice daily for 
patients experiencing breakthrough flares 
 
Colchicine 0.6 mg p.o. once daily with the possibility of dose escalation to 0.6 mg p.o. twice daily for 
patients experiencing breakthrough flares OR a dose decrease (0.6 mg p.o. every other day) for 
patients experiencing gastrointestinal intolerance 


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Based on patient-specific factors about the likelihood of breakthrough flares, intolerance, or other 
factors, it may be appropriate to initiate naproxen and colchicine at higher or lower doses in accordance 
with clinical judgment. 
Precautions or contraindications for the use of low-dose naproxen include: a history of NSAID or aspirin 
allergy, CKD Stage 3 (see below), a history of peptic ulcer disease, ongoing anticoagulation (e.g. warfarin or 
heparin), moderate to severe anemia, poorly controlled hypertension, or cardiovascular disease.    
Precautions or contraindications with the use of colchicine include the use of high-risk medications that 
may heighten the risk for colchicine-related toxicity, including clarithromycin, telithromycin, nefazodone, 
diltiazem, verapamil and certain anti-retrovirals and azole antifungals.  Refer to the Drug Information 
Report (DIR) for more detailed information on drug interactions. 
The choice of which prophylactic agent to use (naproxen vs. colchicine) for gout patients with 
preserved kidney function (eGFR ≥ 60 ml/min/1.73 m2) will be made at the discretion of the site 
investigator.  A study participant may be switched to the alternative prophylactic strategy if the patient is 
intolerant to the first agent selected.  For patients receiving naproxen, proton pump inhibitor (PPI) therapy 
may be considered or other effective suppression therapy for peptic ulcer disease at the discretion of the 
investigator.  For certain patients, including those with contraindications or intolerance to both naproxen 
and colchicine, prednisone may be used as a second-line prophylactic agent with daily doses not to exceed 
10 mg.  For patients receiving prednisone, calcium/vitamin D supplementation in addition to anti-resorptive 
therapy may be considered at the discretion of the investigator.  Prednisone should be used with caution in 
patients with poorly controlled diabetes mellitus. 
For patients with Stage 3 CKD (eGFR of 30 to 59 ml/min), the primary option for acute gout flare 
prophylaxis will be: 
 
Colchicine 0.6 mg p.o. once daily with the possibility of a dose decrease (0.6 mg p.o. every other 
day) for patients experiencing gastrointestinal intolerance; note that colchicine doses exceeding 0.6 
mg daily are not allowed for patients with Stage 3 CKD. 
 
Prophylaxis will stop for all participants at week 48. 
 
Low-dose naproxen will not be allowed for use in gout patients with Stage 3 CKD. 
 
For patients with Stage 3 CKD demonstrating contraindications or intolerance to low-dose oral 
colchicine, prednisone may be used as a second-line prophylactic agent with daily doses not to 
exceed 10 mg. 
During phase 1-2 of the study, consistent with American College of Rheumatology (ACR) Gout 
Management Guidelines (61) the duration of prophylaxis will be the greater of: 
 
Six months’ duration (24 weeks) 
 
Three months (12 weeks) after achieving a target urate goal < 6.0 mg/dl for a patient without tophi 
at enrollment (i.e., continued prophylaxis in patients with unresolved tophi) 
 
Six months (24 weeks) after achieving a target urate goal < 5.0 mg/dL, where there has been 
resolution of tophi that were present at enrollment 


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 
In the event that flares continue after achieving the above criteria in a given patient, prophylaxis 
will be continued for a minimum of three months after the flare (i.e., prophylaxis continued or 
restarted for patients who experience a flare).  
If the above criteria for stopping prophylaxis have been met the investigator is encouraged to do so.  
However, in select cases, prophylaxis may be extended beyond these time frames at the discretion of the 
investigator until the start of phase 3.  
At 48 weeks (start of study phase 3), investigators will discontinue prophylaxis for all participants who 
are still receiving it. Should an acute flare occur, it should be managed as discussed below and the 
investigator may elect to reinstitute prophylactic treatment. 
Management of Acute Gout Flares During the Study: 
Should a patient in the study experience an acute gout flare, the management of the case is left to 
the discretion of the investigating physician and/or his/her local rheumatologic consultants.  For the 
purposes of providing guidance some broad recommendations, based largely on the recent 2012 ACR gout 
treatment guidelines are included below (7). 
The ACR recommends that all patients experiencing acute gout flares be treated with 
pharmacologic intervention, ideally within 24 hours of the onset of attack.  For patients who can take oral 
medication, NSAIDs, glucocorticoids and colchicine may all be efficacious.  If the patient is experiencing a 
monoarticular flare in a single large joint, or the involvement of one or several small joints (e.g., toes) only, 
monotherapy is appropriate.  If the flare is particularly severe (e.g., is polyarticular or oligoarticular 
involving multiple large joints), initial combination therapy with two classes of anti-inflammatory agent may 
be considered. The ACR does not give instructions on adjustment for co-morbidities and/or drug-drug 
interactions but expects that the physician will take these into account.  Some of those issues are discussed 
further below.  A simplified schema for managing routine gout flares is provided in Figure 3. 
 
 
 
 
 
 
 
 
 


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Standard agents 
Colchicine—Colchicine is an effective drug for gout flare treatment but ideally should be given 
within the first 36 hours of the flare, as it may be less efficacious after that time.  The standard dose for 
colchicine for this purpose is 1.2 mg, followed by 0.6 mg 1 hour later; no further dose is given on the day 
of the flare, as higher doses cause toxicity without increased efficacy.  This regimen may be used even in 
patients with mild-to-moderate renal insufficiency.  In patients who have no contraindication, colchicine 
may or may not be continued at 0.6 mg once or twice daily until the flare is fully resolved; this follow-up 
dose is at the discretion of the physician.  Patients who are already on daily colchicine prophylaxis may 
also receive this regimen, but only if they have not already been treated with colchicine for an acute 
flare in the last 14 days.  In that case, an alternative therapy should be selected.   
 
Figure 3: Management of routine gout flares 


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Treatment considerations include the potential for increased adverse event rates in patients 
with renal insufficiency and or concurrently taking drugs that affect colchicine metabolism by inhibiting 
the CYP3A4 or p-glycoprotein enzyme systems.  For participants with stage 3 CKD who are on colchicine 
prophylaxis additional colchicine for flares is not recommended.  Drugs that require a dose adjustment 
of colchicine when administered concurrently include clarithromycin and many anti-retroviral agents 
(strong interaction); and diltiazem, verapamil and others (moderate interaction).  For simplicity’s sake 
practitioners may want to consider using alternative flare treatment regimens in these patients, or 
consult the package insert for dose adjustment guidelines. 
Glucocorticoids—the standard oral glucocorticoid therapy for gout is prednisone, typically 
starting at 0.5 mg/kg (i.e., typically about 25-40 mg) daily.  The medication should either be continued at 
this dose until gout resolution, or may be tapered and then discontinued.  The use of a Medrol dose 
pack may provide a simple tapering alternative.  Patients may also receive an IM injection of 
triamcinolone 60 mg, but in this case the ACR recommends follow-up with an oral glucocorticoid.  For 
patients who can’t take oral medication, direct injection of a single joint is a possibility but requires 
expertise that is not presumed for the purposes of this study.  Other alternatives include 
methylprednisolone, 0.5-2.0 mg/kg once IV or IM, and repeated daily as needed. 
Short-term treatment considerations for glucocorticoids include the potential for promoting 
hyperglycemia, hypertension, stomach ulcer (particularly in patients already on an NSAID), agitation and 
avascular necrosis, among others.  Practitioners may want to consider using a different agent in patients 
at higher risk for any of these or other steroid-related complications. 
Non-steroidal anti-inflammatory agents—All NSAIDs are considered to effectively treat acute 
gout, but these agents must be used at their maximal, anti-inflammatory doses (e.g., indomethacin 50 
mg every 6 hours, ibuprofen 800 mg every 8 hours, naproxen 500 mg every 8 to 12 hours, etc.).  The 
selection of a particular NSAID should therefore be based on availability, patient convenience, and 
importantly, the side effect profile of the individual NSAID in the individual patient.  COX-2 selective 
NSAIDs (e.g., celecoxib) are also effective for gout flares at their highest dosages and may be of value in 
selected patients with high GI risk; addition of a concurrent proton pump inhibitor may also be a 
consideration, even for short-term use.   The selected NSAID should be used at the maximal dose until 
the flare is fully resolved, then discontinued.  Short-term treatment considerations for NSAIDs include 
the potential for promoting hypertension, renal insufficiency, gastrointestinal intolerance and peptic 
ulcer disease, bleeding and potentially cardiovascular events; practitioners may consider using an 
alternative therapy if the patient is at high risk for any of these problems, particularly if their co-
morbidities (e.g., hypertension) are presently not adequately managed.  The simultaneous use of an 
NSAID plus daily aspirin may cause more gastrointestinal intolerance than either agent alone; if these 
are used together a PPI is probably warranted. NSAIDs will not be used to treat acute gout flares in 
patients with stage 3 CKD. 
 
 


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Specific situations 
Severe flares—as noted above, combination therapy should be considered in a patient with a 
particularly severe gout flare.  While all three classes of agents described above can theoretically be 
combined, we would recommend that first consideration be given to a glucocorticoid or an NSAID plus 
colchicine. The combination of an NSAID and a glucocorticoid may have synergistic effects in worsening 
hypertension and gastrointestinal events, especially in high risk patients, and should probably be 
reserved for special cases. 
Treatment of a patient with normal renal function already on prophylaxis—Patients who 
experience acute gout flares while already on prophylaxis may be treated by advancing the dose of the 
prophylactic agent from its prophylactic low dose to its acute treatment higher dose (e.g., instituting 
acute colchicine therapy in a patient already on colchicine, raising the NSAID dose temporarily in a 
patient already on a low-dose daily NSAID).  Alternatively, the prophylaxis may continue with a second 
agent added.  In some cases, it may be advisable to hold the prophylactic agent temporarily while 
instituting the acute treatment agent (e.g., consideration of temporarily discontinuing a prophylactic 
NSAID dose while starting an acute gout flare dose of prednisone), to reduce the risk of adverse events. 
Failure to respond—Patients who fail to respond to a single agent should be considered for 
combination therapy.  As noted above, we recommend colchicine plus an NSAID, or colchicine plus a 
glucocorticoid, as a first-line combination, with combinations of NSAID plus a glucocorticoid reserved for 
special circumstances only.  If combination therapy with these agents fails to induce a response, 
consideration may be given to the use of off-label anti-IL-1 therapy (e.g., anakinra 100mg 
subcutaneously daily until flare resolution).  In that case, participation of a rheumatologist is strongly 
advised. 
XI. Baseline and Follow-up Assessment 
After enrollment all patients will be followed in a ‘ULT clinic’, implemented specifically for 
CSP594. 
ULT clinic visits will occur every six weeks throughout Phase 1 and Phase 2 (weeks 0 to 48) of the 
study with patients followed by monthly telephone encounters during Phase 3 (weeks 49 through 72).  A 
gout flare questionnaire will be administered during each of these encounters, as described above in 
Section VII. SUA will be measured at baseline, week 6, and then every three weeks during Phase 1 of the 
study (0 to 24 weeks) until target sUA levels have been reached and then with each ULT clinic visit after 
that.  SUA will be measured at the time of all Phase 2 visits (weeks 30, 36, 42, and 48) (See Table 5 
below).  Additional surveillance laboratory, including serum creatinine, ALT and complete blood count 
(CBC, including platelet count) will be drawn at every ULT clinic visit.   
As outlined above in Section VII, patients reporting the occurrence of a new rash (outside the 
context of the ULT clinic visit), will be asked to present for an in-person evaluation by a study 
investigator.  Structured data will be collected for each rash reported.  


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After each sUA draw, study personnel will contact the patient (in-person for ULT clinic visits; by 
telephone for blood draws not coinciding with visit) and adjust the study medication as described above 
to reach target sUA levels.  Information pertinent to adverse events will be collected every 3 weeks for 
all study participants during Phase 1 (0 to 24 weeks) either at the time of ULT clinic or during telephone 
encounters.  During Phase 2 of the study (24 to 48 weeks), adverse event information will be collected 
every 6 weeks during ULT clinic visits. For additional information about adverse event surveillance, see 
Section XVI.  Increased surveillance frequency scheduled during Phase 1 of the study is predicated on 
data demonstrating that serious adverse events (particularly serious dermatologic adverse events 
related to allopurinol) are most common during this early period of drug initiation.  As part of a recent 
retrospective case-control study, investigators observed that 90% of allopurinol hypersensitivity 
syndrome (AHS) occurs in the first 6-months of treatment (59). 
Post Study Care: 
In this study all patients will return to standard care – in some cases this will be primary care 
providers and in other cases this will be rheumatologists specifically for gout related follow-up. At the 
end of the study (week 72) the participant will return for their final study visit and the LSI and SC will 
inform the participant of the study drug that they have been taking. In addition, the study team will 
send a letter to the treating physician and if applicable, a CPRS note will be completed. Treatment 
decisions after the study will be up to the primary care doctor’s discretion.   For participants who choose 
to withdraw from the study early or have been lost to follow-up (who received drug and have neither 
revoked consent or HIPAA authorization) the study team will unblind them at what would have been 
their expected week 72 visit via a letter to their PCP and a note in CPRS. If at any point during the study 
a subject passes away, the unblinding process listed above is not required.  Since gout is a major part of 
the metabolic syndrome which has a marked increase and morbidity and mortality, particularly from 
cardiovascular events a 10-year passive follow-up will provide extremely valuable insights in how long-
term control of hyperuricemia modifies risks for cardiovascular events, hypertension and renal failure. 
The 10-year passive follow-up is being sought to explore the impact of improved gout management on 
long term effects related to gouty arthritis/disability and progression of renal and cardiovascular disease 
(refer to page 8, section titled “Other Objectives” for a detailed outline).  This follow-up will only be in 
VA patients and will explore meaningful clinical outcomes such as dialysis, MI, stroke and death which 
are resident in the electronic health record.  
Schedule of Events: 
A schedule for all study-related procedures including ULT clinic visits, telephone contacts, and 
laboratory surveillance are shown in the table below: 


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1Study visits will have a window of +/- one week in Phase 1 and +/- two weeks in Phase 2 and 3 with the exception of weeks 48 and 72 which are 
+/- four weeks. 
Table 5:  Study follow-up and procedures1
Phase 1 – Dose Titration
Phase 2 – Optimization and 
Maintenance 
Phase 3 – Steady State Flare 
Observation 
SC2
0
3
6
9
12
15
18
21
24
303
36
423
484
Every 4 
weeks 
Week 
60 
Every 4 
weeks 
724
Informed Consent
X
ULT Clinic visit
X
X
X
X
X
X
X
X
X
X
Telephone contact
X
X
X
X
X
X
X
X
Gout Flare5
X
X
X
X
X
X
X
X
X
X
sUA blood draw
X
X
X
†
X
†
X
†
X
X
X
X
X
X
X
Creatinine
X
X
X
X
X
X
X
X
X
X
CBC, ALT
X
X
X
X
X
X
X
X
X
X
CRP
X
X
X
X
X
Blood pressure
X
X
X
X
X
X
X
X
X
Weight
X
X
Comorbidities6
X
X
Tophi area
X
X
X
Tophi location
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-3L & VR-12
X
X
X
X
Alcohol intake 
questions 
X
X
X
Concomitant 
Medications7 
X
X
X
X
X
X
X
X
X
Patient Reported 
Adherence5 
X
X
X
X
X
X
X
X
X
X
Pill Counts Adherence8
X
X
X
X
X
X
X
X
Provide Participant 
with Diaries5 
X
X
X
X
X
X
X Phase 3 
Diary 
X


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2Tests done at screening do not need to be repeated at baseline if visits occur within 2 weeks of each other 
3During weeks 30 and 42 the patient does not come in for a clinic visit but will need to go to the local lab or CBOC to have a sUA blood draw. 
4 Early terminations: request participant come in to complete week 48 for participants currently in Phase 1 or 2, or week 72 for patients currently 
in Phase 3, if feasible.  
5Patient Diaries (Gout Attack Diary and Medication Adherence Diary): Diaries will be collected from participants at all clinic visits. During phase 1 
& 2 phone visits remind participants to continue to complete their diaries and to bring them to the next scheduled clinic visit.   At week 48 
participants will be given a gout attack diary and a new Phase 3 study drug diary.  Participants should be instructed on how to complete the 
diaries and should have their diary available to review during all visits in phase 3. The patient reported response over the phone and at the clinic 
visits (weeks 60 & 72) will be collected using the phone script, if feasible.  
6 Comorbidities is listed in both the SC and Baseline Visit (0) because it can be started at the SC visit and finished at the baseline visit. 
7 Concomitant Medication:  Use of medications known to impact sUA concentration (e.g. diuretic use, aspirin) will be collected at weeks 0, 24 
and 48; screening for use of medications known to cause drug-drug interactions with study drugs will be completed during all ULT clinic visits 
starting with week 6 
8Participants will bring in their bottles at all clinic visits.  Pill counts will be completed at all ULT clinic visits starting with week 6;  
† sUA drawn at weeks 9, 15, and 21 only if prior sUA level not at target threshold (target threshold is defined as sUA < 6.0 mg/dl or < 5.0 mg/dl 
for tophi);  


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XII. Potential Pitfalls of the Proposed Study Design and Strategies to Address 
Them 
A major concern of the Planning Committee on the initial submission was for the proposed 
open-label design. Randomized, double-blind, placebo-controlled trials are regarded as the “gold 
standard” study design to evaluate efficacy, therefore we have switched to this design.  The 
development of skin rash could “break the blind” if it occurred more commonly in one group, however 
skin rash has been reported with similar frequency with both of our ULT agents in other blinded trials.  
To minimize unnecessary withdrawal for all skin rashes, the protocol requires investigators to evaluate 
all rashes and provides guidelines for study drug discontinuation.  Investigators will receive extensive 
training regarding these guidelines. Specific reporting forms for rash will help document all rashes.  
Although we will include patients with stage 3 CKD (eGFR 30-59 mL/min/1.73 m2), we will 
exclude patients with more severe kidney disease.  While stage 3 CKD comprises 7.6% of the most 
recent NHANES cohort (corresponding to more than 23 million US adults) and more than 10.3% of the 
VA population, patients with stage 4 CKD comprise less than 0.4% of the US population and less than 
0.7% of VA patients (46). Thus, the ability to recruit a sufficient number of patients with advanced CKD 
and gout to provide a meaningful analysis in this subpopulation is doubtful.  In addition, 
pharmacokinetic studies of febuxostat demonstrate increased concentrations of both parent drug and 
active drug in patients with severe renal impairment (creatinine clearance <30 mL/min) and there are 
insufficient data regarding drug dosage and safety in this population (104).  Dose reduction of 
allopurinol is also recommended in patients with severe renal impairment (105), which may necessitate 
an adjusted dose titration if patients with more severe CKD were included in the study. Moreover, both 
NSAID and colchicine prophylaxis are contraindicated in patients with more severe CKD (stages 4 or 5), 
which may skew results in that subset of patients.    For these reasons we will have targeted recruitment 
to include patients with stage 3 CKD but will exclude patients with more severe degrees of renal 
impairment at study enrollment.  
Gout flares are nearly ubiquitous with initiation of effective ULT.  Bias could occur if one 
treatment group has more gout flares than the other leading to a differential change in treatment 
recommendations or adherence. Indeed, these expected flares are one of the major reasons why 
patients and clinicians fail to continue effective therapies or to use them at appropriate doses. In order 
to assure protocol compliance and to avoid early withdrawal, participants will be provided with 
appropriate anti-inflammatory gout prophylaxis. Anti-inflammatory prophylaxis will conform to recently 
published guidelines in gout management (61). 
 
 


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XIII. Feasibility of Recruitment 
We propose to enroll 950 participants from 20 VA sites. Based on national data from 2009 to 
2012, Table 6 below shows the 40 VA sites with the largest estimated number of 12-month prevalent 
gout patients.  The 12-month prevalence is the number of patients on a particular day plus the number 
of new patients expected within 12 months. The national data indicate that the point prevalence pool 
increased by about 20% during the last year.  The mean pool size among the top 40 VA sites is 398.  Data 
from VISN#1 indicate that about 50% of these patients have a sUA level > 6.8 mg/dl, and thus would be 
eligible.  Hence, these sites need to enroll 25% of the eligible patients.   
Table 6: VA sites with largest estimated number of 12-month prevalent gout patients without AKI 
Site
Number of 
Patients 
Site
Number of 
Patients 
Buffalo, NY
786
Denver, CO
344
Kansas City, MO
657
Charleston, SC
341
St. Louis, MO
586
Boston, MA
334
Minneapolis, MN
556
Portland, OR
334
Atlanta, GA
555
Orlando, FL
330
Gainesville, FL
549
Indianapolis, IN
322
Nebraska-Western Iowa, NE
525
Loma Linda, CA
321
Tampa, FL
492
Puget Sound HCS, WA
316
Columbia, SC
490
Philadelphia, PA
311
Cleveland, OH
488
Connecticut HCS, CT
310
Richmond, VA
485
Durham, NC
309
Greater Los Angeles, CA
441
N. California HCS, CA
307
Dallas, TX
426
Albuquerque, NM
304
Milwaukee, WI
397
Washington, DC
304
Bay Pines, FL
393
Chicago HCS, IL
302
Pittsburgh, PA
386
Hines, IL
302
Mid Tennessee HCS, TN
378
Memphis, TN
298
Baltimore, MD
373
Birmingham, AL
295
Southern Arizona HCS, AZ
359
Central Texas HCS, TX
293
Houston, TX
252
Salt Lake City, UT
290
 
From the survey of providers mentioned above we already know they endorse the importance 
of the question we are asking and both the provider and patient survey support the primary end-point. 
This endorsement by both providers and patients will certainly help with recruitment. CSPCC conducted 
a site survey to obtain information on the interest in and feasibility of recruitment for the study. The 26 
sites contacted include the CSP NODES sites, CSP551 VA sites (60), sites involved in a Musculoskeletal 
Mini-Residency education initiative, and sites with a large gout population suggested by the Planning 
Committee. Twenty-three of the 25 sites contacted (92%) expressed interest in participating in this 
study. The vast majority of sites have previously participated in CSP trials and rheumatology studies. 
Only three sites had open studies that would compete for this patient population.  Mechanisms to 


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facilitate recruitment from primary care clinics existed at 87% of sites. The CSP NODES sites were given 
detailed information on the study design, inclusion/exclusion criteria and the visit schedule, and agreed 
that the schedule and recruitment goals were feasible for both participants and coordinators.  
Table 7 below shows site responses to questions regarding gout patients seen at their site over 
the past year.  The sites were queried about: 1) the number of gout outpatients; 2) those receiving a 
prescription for ≤300mg daily allopurinol; 3) those receiving a first-time prescription for allopurinol; 4) 
those who received ≤300mg allopurinol and had a uric acid level measured; and 5) those who had a uric 
acid level <6mg/dl.  
Table 7: Site survey results 
VA Site 
1. Gout 
outpatients* 
2. Allopurinol
scripts 
3. New Allo.
scripts 
4. UA 
available 
5. UA <6 
Boston, MA
100
70
50
70
42
Dallas, TX
3412
3468
955
2215
958
Durham, NC
2128
2037
516
1022
610
Fargo, ND
5-10
>40
>20
vast majority
vast majority
Los Angeles, CA
2245
1659
205
1493
600
Hines, IL
83
216
54
62
30
Loma Linda, CA
approx. 150
approx. 100
approx. 30
>100
approx. 80
Long Beach, CA
1148
906
about 800
612
230
Miami, FL
1400
1229
161
85%
66%
Milwaukee, WI
1954
846
unable to discern
590
354
Minneapolis, MN
2994
726
305
2482
1315
Omaha, NE
3598
1665
187
823
466
Orlando, FL
3253
2724
1463
1495
595
Philadelphia, PA
477
170
96
147
61
Portland, OR
3064
2120
517
1421
658
Salt Lake City, UT
1297
1210
167
630
354
San Diego, CA
1700
1400
220
1000
400
San Francisco, CA
>2000
1033
approx. 100
>400
approx. 30%
St. Louis, MO
1668
1596
426
approx. 80%
approx. 25%
Tampa, FL
3840
2124
927
1494
722
Washington, DC
2200
576
150
220
64
White River Junction, VT
1011
530
110
314
180
* Sites were asked to estimate total patients using ICD 9 codes for gout or the number of allopurinol 
prescriptions given at their site 
 
 
 


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To assure complete and timely recruitment, we will engage the RAIN to supplement VA 
recruitment.  RAIN was established in 1989 and is recognized internationally for its innovative 
investigator-initiated research in rheumatic diseases (60, 106, 107).  This group recruited at 141% of 
target for CSP 551 (60).  RAIN participants will provide data from non-veteran patients, thus enhancing 
the generalizability of our findings. Participants recruited from the RAIN network will augment the 
eligible pool of patients.  During 2012, the Omaha RAIN site had 477 gout patients taking ≤300mg of 
allopurinol daily. Data from other RAIN sites shows similar numbers of potentially eligible gout patients.  
If RAIN recruits 100 participants the VA recruitment rate decreases from 25%to 22.5% of eligible 
participants. 
With the above information and with the ability to identify potential patients for the sites using 
the national VA database were are confident that we will be able to recruit the necessary numbers of 
patients for this important study. 
XIV. Anticipated barriers to recruitment and strategies to address potential 
under-enrollment  
To ensure adequate recruitment, it will be critical to have access to patients where clinicians are 
considering starting ULT and to existing gout patients on ULT with sUA levels > 6.8mg/dl. Since most 
gout patients are seen and treated by primary care providers rather than rheumatologists, it is critical to 
engage these clinicians.  The common misconceptions of many clinicians in regards to renal dosing of 
allopurinol must also be dispelled. In our recent national survey of VA providers (n = 179), a majority 
reported routinely using maximum daily allopurinol doses of 300 mg among patients with stage 3 CKD 
(unpublished) despite the substantial aforementioned evidence suggesting that allopurinol is both safe 
and well tolerated in such patients. Education regarding guidelines for gout management, including 
“treat to target” dosing and appropriate use of ULT in CKD, may be needed.  Site investigators may be 
supplied with educational materials to inform, update and engage clinicians and pharmacists.  We will 
leverage materials used by the VA Musculoskeletal Mini-Residency education initiative.  This initiative 
has been used to educate primary care clinicians regarding the diagnosis, work-up, and management of 
common musculoskeletal disorders, including gout.  The site survey affirms that 87% of the surveyed 
sites had mechanisms in place to engage primary care, and suggests that this strategy will be highly 
successful.  
To minimize potential patient-centered barriers to recruitment, this protocol avoids onerous 
study procedures, offers reimbursements for travel to study visits, and provides medications for 
prophylaxis against and treatment of acute gout flares.  Educational materials about gout and its 
treatment may also be provided to all potential participants to enhance enrollment and adherence once 
enrolled.   
Along with the inclusion of the RAIN centers to augment enrollment, an increase in FTE for VA 
sites that meet or exceed recruitment targets will be used as an incentive to enhance timely 
recruitment.  Sites that succeed in recruiting 25 participants within their first 6 months will receive an 


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additional FTE research assistant.  A half time research assistant will be given to sites between 6 and 12 
months once they achieve enrollment of 30 participants.  The additional FTE will enable successful sites 
to continue recruitment while assuring completion of trial procedures, and, if successful, allow for a 
shortened trial recruitment period.  
We will also plan to leverage the program’s investment into Point of Care (POC) Randomization 
and engage the POC team to explore possible use of alerts in the VA electronic medical record system, 
which could provide point of care identification of patients.  Alerts that inform clinicians about the trial 
when they initiate or renew either ULT or colchicine could assist in the identification of potential 
participants. In addition data will be gathered from VA databases to identify eligible participants. 
In addition, we will initiate 6 more sites (i.e., approximately 25% more) than what is needed for 
successful enrollment into the study. In the event that sites fail at recruitment or as the potential patient 
pool decreases at the vanguard sites, enrollment into CSP 594 will be started at these additional sites. 
Should this event occur, the financial support for the failing sites will be transferred to the newly 
initiated sites.


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XV. Human Rights and Informed Consent 
CSP follows the principles of medical research involving human subjects as outlined in the 
Declaration of Helsinki.   
Informed consent will be obtained from all CSP study participants prior to participation in this 
study.  Informed consent requires that the participant understand and agree to the study procedures, 
treatments, and risks.  The participant will be explained the voluntary nature of participation in the 
research study and can withdraw from participation without penalty at any time.  It will be 
communicated that the current treatment, future medical care, and benefits will not be dependent on 
participation in the research.  The participant must have sufficient time to read the informed consent 
document prior to signing.   
Informed consent must occur verbally with the study participant.  In discussion of the consent 
form with the participant, the investigator (or other study personnel identified on the Delegated 
Responsibilities Log to conduct the informed consent process) may provide additional details beyond 
those contained in the consent form.  Additional information may not represent any significant 
additions, deletions or modifications to the information in the informed consent document.  The 
research participant will be provided with a paper copy of the consent form and any supplementary 
materials to read and review prior to consent.   
The informed consent document will contain all elements as outlined in VHA Handbook 1200.05 
as required by the Common Rule.  The consent will be documented on VA Form 10-1086 Research 
Consent Form.  The consent form will be approved by the VA CIRB or other IRB of record for the study 
prior to its use.   
The informed consent must be signed and dated by the study participant and the person 
obtaining the informed consent.  The original signed informed consent document will be placed in the 
investigator’s research file.  Copies of the signed informed consent document will be provided to the 
patient at the time of consent.  
A signed copy of the informed consent (either hard copy or a scanned version within the 
participant’s medical record) will be made available to the VA pharmacist dispensing the investigational 
drug or product under investigation for this research prior to the patient receiving  any study 
medication.  
The informed consent process will be documented in a detailed progress note prior to study 
participation.  The following elements should be included in the progress note: 
1. Name of the study 
2. Name of the person obtaining informed consent 
3. Statement that the participant was capable of understanding the informed consent process 
4. Statement that the study was explained to the participant and the participant was given the 
opportunity to ask questions 


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5. Statement that consent was obtained before participation in the study began 
6. Information on possible drug interactions and/or toxicity of the study medications 
7. A copy of the signed and dated informed consent form and HIPAA authorization 
A separate written HIPAA authorization for the use of individually identifiable health information  
must be signed by the research participant. 
In this research study, a waiver of informed consent and HIPPA authorization will be submitted for 
recruitment purposes in order to access information on potentially eligible patients.  In addition consent 
will be obtained for continued access to participant electronic health records for ten years following 
completion of the study in order to examine long-term outcomes.  Sites will maintain a log of all 
potentially eligible patients, kept in a secure location and not transmitted to CSPCC. CSPCC will only 
collect patient information on those who have provided informed consent. A plan to protect patient 
identities and destroy patient identifiers after use is in place and is described in Section XVII of the 
protocol. 
XVI. Monitoring Adverse Events 
Overview of Adverse Event Reporting 
Timely and complete reporting of safety information assists study management in identifying 
any untoward medical occurrence thereby allowing: 1) protection of study patients’ safety; 2) a greater 
understanding of the overall safety profile of the study interventions and therapeutic modalities; 3) 
appropriate modification of the study protocol; 4) improvements in study design or procedures; and 5) 
compliance with regulatory requirements.  All reporting of protocol related events will include CIRB, 
FDA, CSP as indicated by rules and regulations. 
The local Site Investigator will be responsible for the AE and SAE reporting requirements as 
described in this protocol outlined below:  
 
Closely monitoring research participants during the study for the development of new AEs and 
SAEs. 
 
Reviewing the accuracy and completeness of all AEs and SAEs reported. 
 
Reporting all SAEs to the CSPCRPCC and MAVERIC CSPCC within 3 calendar days of the site 
becoming aware of the event 
 
Complying with VA Central IRB policies for reporting adverse events and other VA policies as 
detailed in VHA Handbook 1058.01 
 
Implementing plans the Study Group and Executive Committee may develop in response to 
safety concerns 
Adverse Events 
Adverse Events (AEs) are defined by the VHA Handbook 1058.01, paragraph 4(b) as “… any 
untoward physical or psychological occurrence in a human subject participating in research.” An AE can 
be any unfavorable and unintended event, including an abnormal laboratory finding, symptom, or 


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disease associated with the research or the use of a medical investigational test article. An AE does not 
necessarily have to have a causal relationship with the research. 
For the purpose of CSP 594, the study interventions are allopurinol/matching placebo (100 mg, 
300 mg and 400 mg capsules) and febuxostat/matching placebo (40 mg and 80 mg tablets). Prophylactic 
medications, including those provided for the study, have well established safety profiles and are not 
the primary topic of interest in this study; therefore, these medications are not considered study 
interventions for purposes of AE reporting.  
Local site investigators, with assistance from their study coordinators, are responsible for 
collecting AE information regarding the participants at their sites. During the study, data on adverse 
events will be collected spontaneously through patient reports, actively elicited during visits through 
open-ended questioning and examination, and gathered at the time of telephone contact and medical 
record reviews during the follow-up period.  
Beginning at informed consent and continuing until the end of participation in the study, all AEs 
identified for a participant must be recorded on a CSP #594 AE Tracking & Evaluation Record provided 
by SMART. Each event must be evaluated by the SI/sub-I to determine if the event is: 
1. Severe 
2. Likely attributable to the Study Intervention 
3. Anticipated or unanticipated (expected or unexpected) 
4. Serious 
After completing the evaluation, the SI/sub-I must initial and date the event on the record, which 
then serves as a source document for safety evaluation and oversight.  
In addition to completing the tracking and evaluation log, AEs which are non-serious but which are 
judged to be severe or likely attributable (possibly related or related) to the study intervention will be 
recorded on an adverse event form and documented in source records (e.g., electronic VA medical 
record and/or the participant’s study record). Determination of attributability involves an assessment by 
the site investigator of the degree of causality between the study interventions (allopurinol or 
febuxostat) and the event. All AEs with a reasonable causal relationship to the investigative treatment 
will be considered “possibly related” or “related.” A definite relationship does not need to be 
established. In this way the site creates a permanent record that provides information on the 
participant’s clinical course while in the study. 
Related adverse event data will be collected from the time of consent until the end of participation 
in the study. If a patient receives care at a non-VA facility for an adverse event they experience, research 
personnel will obtain the requisite release of information form(s) from the patient and once received, 
acquire the pertinent medical records from the facility.  
Adverse events which are or develop into Serious Adverse Events (SAEs), as defined below, will be 
reported as such and followed to the SAE resolution, stabilization, or study discontinuation.  


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Serious Adverse Events (SAEs)  
SAEs are a subset of adverse events. As defined in VHA Handbook 1058.01, a serious adverse 
event (SAE) is an untoward occurrence in human research that results in: 
 
Death 
 
A life-threatening experience 
 
Inpatient hospitalization 
 
Prolongation of hospitalization 
 
Persistent or significant disability or incapacity  
 
Congenital anomaly or birth defect, or 
 
Requires medical, surgical, behavioral, social or other intervention to prevent such an 
outcome 
All SAEs will be collected and reported via DataLabs and to CSPCRPCC and MAVERIC CSPCC 
within 3 calendar days of knowledge, regardless of whether or not they are considered related to the 
study interventions. SAEs with a reasonable causal relationship to the study interventions and 
associated medications will be reported as “possibly related” or “related.” A definite causal relationship 
does not need to be established.  
While additional evidence about febuxostat’s cardiovascular risks continues to accumulate, side 
effect profiles for both study medications (allopurinol and febuxostat) and all the supplemental 
medications (prednisone, colchicine and naproxen) are generally well established and will be used as the 
basis to determine what are expected and unexpected events.    Local site investigators will determine 
the relatedness to the study medications for any reported event. These local site investigators, with 
assistance from their study coordinators, are responsible for collecting SAE information regarding the 
participants at their sites. SAEs will be collected from the time of consent until 30 days after the end of 
participation in the study. During the study, data on SAEs will be collected spontaneously through 
patient reports, actively elicited during visits through open-ended questioning and examination, and 
gathered at the time of telephone contact and medical record reviews during the follow-up period. If a 
patient receives care at a non-VA facility for a SAE they experience, research personnel will obtain the 
requisite release of information form(s) from the patient and once received, acquire the pertinent 
medical records from the facility.  
SAEs are a subset of AEs; thus they will be recorded on the AE tracking and evaluation log as 
described in the previous section. SAEs that are reported to research personnel will be documented in 
source records (e.g., the electronic VA medical record and/or the participant’s study record). In this way, 
the site creates a permanent record that provides information on the participant’s clinical course while 
in the study. Research personnel at the site will ask follow-up questions to determine the exact nature 
of the SAE and obtain appropriate medical records, if needed. All unresolved SAEs must be followed up 
at least every 30 days until resolved or when no further change is expected. All SAEs are followed until 
no changes are expected or the study is discontinued. The follow up reports will be entered into the EDC 
system by the site coordinators in a timely manner. 


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CSP Global SOP 3.6 sets forth situations in which safety events must be reported by individuals 
within CSP (primarily the PCC clinical research pharmacist) to various parties, including the FDA and VA 
Central Office. This study will adhere to the most current approved version of this SOP.  
SAE reporting will start at the time of patient consent and continue until 30 days after the 
patient’s involvement in the study. All SAEs must be entered in to the EDC system by site personnel 
within 3 calendar days of the local site staff becoming aware of the event. The site should notify 
MAVERIC CSPCC, Chair’s Office, and CSPCRPCC of the event by encrypted email upon entering the SAE 
into the EDC system. All unresolved SAEs will be followed up at least every 30 days until resolved or 
when no further change is expected (i.e. event is ongoing recovering/resolving or not recovered/not 
resolved. No changes to the event will occur in the future). All SAEs are followed until no changes are 
expected or the study is discontinued. When the participant’s study involvement ends, the investigator 
will be responsible to arrange for continued follow up.  
Site Investigators will review all SAEs to determine their relatedness to participation in VA CSP 
#594 and whether they are expected in the study population. SAEs that meet VA Central IRB expedited 
reporting requirements will be reported as detailed on the CIRB website 
(http://www.research.va.gov/vacentralirb/). All SAEs that are considered related and unanticipated 
must be reported in writing to CIRB within 5 business days of the site becoming aware of the event. Any 
participant death that is considered related and unanticipated must be immediately reported orally to 
CIRB and followed with a written notification within 5 business days of the site becoming aware of the 
event. All SAEs that are not considered related and unanticipated must be reported to CIRB at the time 
of continuing review. In addition, all AEs must be reported to CIRB at the time of continuing review.  
Emergency Breaking of the Blind 
The CSPCRPCC will not provide Emergency Code Envelopes to the Research Pharmacy for CSP 
#594. Emergency unblinding will be managed through the 24-hour emergency call service (505-248-
3203). This number is also listed on the participant ID cards given to each patient participating in CSP 
#594. The system managed by the CSPCRPCC will electronically capture up-to-date study drug 
assignment information gathered from the CSP #594 IWRS. 
Authorization to Break the Blind: 
Under unusual circumstances, chiefly related to participant safety, unblinding may be necessary. 
This is usually done after consultation with the Study Chair (James O’Dell, MD). If Dr. O’Dell is 
unavailable, the PCC Clinical Research Pharmacist (Annie Davis-Karim or another Clinical 
Research Pharmacist), the Study Biostatistician (Hongsheng Wu, Ph.D.), or the medical project 
director (Mary Brophy, M.D.) should be contacted.  
In life-threatening emergencies, the PCC is available through the 24-hour emergency call service. 
If the PCC receives a request for unblinding information from anyone other than the LSI or SC, 
the PCC will refer the requester to the LSI or SC, or, in his or her absence, the PCC will attempt to 
contact the parties above. If unblinding is required in an emergency, the treating physician may 
contact the PCC through the 24-hour emergency call service to obtain study drug assignment 
information. The PCC will notify the Study Chair’s Office and the Boston CSPCC by telephone as 
soon as possible after an unblinding has occurred.  


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If the toxicity is severe enough to require removal of the patient from the study and the blind is 
broken, the participant and physician will be informed of the drug they were receiving.  
XVII. Data Management and Data Security Plans 
The Boston CSPCC will manage the trial data using a web-based Electronic Data Capture (EDC) 
system. The EDC system allows direct entry of case report forms (CRF) into a web-based study database 
and thus allows site coordinators to manage their participants, handle data clarifications, and correct 
data online. This system makes patient data management easier, timelier, and more efficient.  The 
electronic system will be used to create, modify, maintain and retrieve clinical data for CSP#594 during 
each step of the data collection process. The EDC system will be validated by the Boston CSPCC Quality 
Assurance department to ensure the integrity of the data capture software. 
Paper CRFs for all data including Quality of Life measures will be provided to site coordinators as 
a primary means of collecting data. Data entered on paper CRFs will be used as source documentation 
for EDC entries. All paper-based study records will be kept under lock and key.  
The Study Chair and Study Director will prepare an Operations Manual. A training session at the 
study kick-off meeting for all site investigators and site coordinators will be conducted to assure 
uniformity in patient management, data collection, and study procedures. At this training, site 
coordinators will be provided with reference materials on the software tool and tasks. Formal training 
on the use of the EDC system for clinical study management will also be conducted at investigator 
meetings and on an as-needed basis for new study personnel. 
For CSP#594, EDC designers will create a specific database that includes case report forms, the 
interview schedule, and data queries. The purpose of data clarifications (DCFs) or data queries is to draw 
attention to data that are inconsistent or potentially erroneous. DCFs will be managed in two ways. 
Certain queries will be programmed into the forms that are designed to activate upon data entry if data 
is missing or discrepant with study parameters. Additional DCFs will be programmed using other data 
analysis tools such as SAS and will be uploaded into the system for study coordinators to address. 
Furthermore, the system will allow manual DCFs to be entered into the forms by the coordinating center 
as needed. Updates to the electronic forms and database can be generated during the study without 
impacting collected data. Study reports can be generated from exported data in order to track the study 
progress and to monitor adverse events, particularly Serious Adverse Events. Study reports will be 
circulated to appropriate individuals, including the Site Investigators, the Study Chair, the Study Director, 
and the DMC. 
 
 
 
 


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Study data is housed on secure VA servers, encrypted and protected in accordance with VA 
policies compliant with FDA requirements, Federal Information Security Management Act and the HIPAA 
Privacy and Security rules.  Boston CSPCC personnel manage the data access request process to ensure 
that data access is appropriate for each individual and the level of the individual access.  VA’s Office of 
Information & Technology (OI&T) is responsible for ensuring the security and integrity of VA information 
systems, including the databases and servers housing study data.  In accordance with VA Handbooks and 
Directives, OI&T is responsible for ensuring that appropriate firewalls and data security is implemented 
and maintained, that data backups are performed and that data may be restored in the event of a 
system malfunction. 
Hard copy data will be sent via a traceable mail system (i.e., UPS), via a courier, or via secure fax. 
Faxes are electronically routed on in-house VA servers located in Boston. DataLabs resides on a VA 
server in Martinsburg, WV. Access to these secure fax servers is restricted to the Coordinating Center 
personnel with approved access to the system. All data security incidents will be reported in accordance 
with VA policy within one hour of discovering the incident to: 
1. The District (local) Information Security Officer (ISO) 
2. The Boston CSPCC Quality Assurance department 
3. The VA Central IRB 
Study data will be coded and stored using a unique study identifier for each participant. 
Identifiable information will be collected for patient tracking and safety purposes, and kept on an 
encrypted, password protected server to which a small number of people will have access. Access to the 
cross-walk file linking the participant's identifiers and their study data will be restricted to the clinical 
site and to the approved personnel at the coordinating center. This file will be destroyed according to 
CSP policy. 
Access to the study data is restricted to individuals with CSP approval. Individuals must be 
properly credentialed research staff and must be compliant with VA security trainings (e.g. HIPAA, Rules 
of Behavior, and Good Clinical Practices). Once formal training is completed, user accounts utilizing a 
URL specific to the study to access and use the system and enter patient data will be activated. Accounts 
will be password protected and unique to the each user. The account permissions will correspond with 
the users' functional study group (i.e., those for a site coordinator would differ from those of the 
coordinating center or site monitors).  Furthermore, the permissions of the electronic systems are 
structured such that individual sites can only see the data for their study participants. They cannot see 
or access the data for another clinical site or for another participant. Research data will be stored on VA 
secure servers with restricted permissions for copying and exporting data. Only properly approved 
Coordinating Center personnel will have the ability to copy and export data. These individuals have 
received training on the local SOP governing their permissions. Access to protected health information 
(PHI) will be restricted to individuals approved by CSP to have access to the data. 
 
 


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At the Study Sites, three FTE staff positions will have access to PHI. Individuals in these positions will be 
able to access all forms of PHI: 
1. Site Investigator 
2. Site Physician 
3. Site Coordinator 
At the Boston CSPCC nine staff positions will have access to all forms of PHI: 
1. Center Director 
2. Study Director 
3. Project Manager/Project Coordinator 
4. Data Manager 
5. Biostatistician 
6. Junior Biostatistician 
7. Quality Assurance Specialist 
8. Data Programmer 
9. Research Assistant 
At the CSPCRPCC four staff positions will have access to PHI. Individuals in these positions will be able to 
access de-identified forms of PHI: 
1. Clinical Monitors 
2. Study Pharmacist 
3. Adverse Event Specialist (Regulatory Affairs and Safety Officer) 
4. Pharmacy Project Manager 
Quality control checks and clinical monitoring will enable the Coordinating Center to survey the 
study database and the clinical sites to ensure that the data have not been improperly used or accessed. 
21 CFR part 11 compliant audit trails and access logs will be checked routinely. In addition, the clinical 
monitors (SMART) will provide continuing education on good clinical practices and will check clinical site 
operations for compliance with data security policies and best practices.  
At the end of the study, the data for CSP#594 will remain property of the Cooperative Studies 
Program, and be stored and shared according to VA CSP policies on data transfer and data security.  The 
Boston CSPCC Quality Assurance team will work closely with the local CSPCC research compliance 
officer, the information security officer, and the VA privacy officer as needed to ensure that data 
security and data transfers are handled appropriately. 
Retention and destruction of data will be conducted according to CSP operating procedures and 
federal and local VA regulations. This will include paper and electronic data stored at the study sites, the 
Boston CSPCC, and at the VA facility housing our servers. Identifiable data will be kept according to CSP 
policy as outlined in the "CSP Guidelines for the Planning and Conduct of Cooperative Studies”.  


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Specifically, identifiers will be kept on site at the MAVERIC CSPCC for a minimum of five years or as 
dictated by the FDA or other regulatory agency with specific written procedures (i.e., two years after last 
approval of a marketing application, etc.). At the end of the record retention period, the Boston CSPCC 
will conduct a review to determine if it is appropriate to archive study data. If it is determined that the 
study data must be kept active, the Boston CSPCC will retain the database in its entirety until the 
primary and secondary analyses are completed. At the completion of analyses, study data will be de-
identified and stored indefinitely. If, however, the study is archived, the study data will be de-identified 
and stored indefinitely. Study records maintained at the local sites cannot be destroyed without written 
permission from Boston CSPCC.  
Data Management and Access Plan (DMAP)  
Upon final analyses of the stated objectives in this proposal, the study plans to submit results for 
publication in scientific peer- reviewed journals and provide summary results on ClinicalTrials.gov. After 
acceptance of the primary and other stated analyses by a journal, CSP will make these publication(s) 
available via the National Library of Medicine’s PubMed Central within a year of the date of publication.  
Digital data underlying primary scientific publications from this study will be held as part of data 
sharing resource maintained by the Cooperative Studies Program (CSP). Study data held for this purpose 
may include data, data content, format, and organization. The data may contain but are not limited to 
individually identifiable information, other protected health information, and study codes. The data may 
be available to the public and other VA and non- VA researchers under certain conditions and consistent 
with the informed consent and CSP policy which prioritize protecting subject’s privacy and 
confidentiality to the fullest extent possible. A detailed plan for data sharing will be developed in 
accordance with current technology, infrastructure, best practices, and policies and procedures in place 
at the time of oversight committee reviews (e.g., Privacy Board, IRB, Information Security, and IT 
standards). The plan will include how data will be discovered, retrieved, and analyzed, managed and will 
note the materials that are available in machine readable formats. This plan may be revised to ensure 
consistency with VA, including CSP, policies and standards for overall data management and sharing.  
XVIII. Quality Control Procedures 
 
Training on Study Measures 
Prior to the initiation of the study, all site investigators and site coordinators will meet to review 
the governance and management of the study, study procedures and receive training on collecting data 
for the study.  Much of this will take place during the study kickoff meeting.  The protocol and case 
report forms will be sent to site investigators and coordinators to review prior to the meeting.  During 
the meeting, study personnel will receive training on obtaining and maintaining source documents, and 
completing study assessments and case report forms. Verbal feedback and discussion will follow to 
ensure that each coordinator comprehends the proper methodology for assessment. The meeting will 
also cover an in-depth review of the study operations manual. Such a review will serve to reinforce the 
training described above and will orient the study personnel to the reference guides for the study. 


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Protocol deviations 
Strict adherence to the protocol will be expected of every participating center and monitored by 
the DMC, the Executive Committee, and the Study Group. Any protocol violations will be fully 
documented on the Protocol Deviation form developed by the Boston CSPCC. Any protocol deviation 
that affects the rights, safety, or welfare of the research participant, the participant’s willingness to 
continue participation; or the integrity of the research data, including VA information security 
requirements will be reported within 5 business days of the site being made aware of the occurrence to 
CIRB. Protocol deviations will be summarized for review at each DMC meeting. Any medical center or 
participant with repeated protocol violations, and after remedial action, may be recommended for 
termination to the Director of the Cooperative Studies Program after discussion with the CSPCC 
Director, Study Chair, Executive Committee, and DMC. If any member of the DMC or of the monitoring 
bodies for CSP#594 feels that adherence to the protocol will be detrimental to a participant's health or 
well-being, the interest of the participant will take precedence and the participant withdrawn after 
consultation with the Executive Committee. Site coordinators will be responsible for reporting protocol 
deviations to the IRB of record as required.  
Participant non-compliance (e.g. forgetting to take study medication, losing it, or choosing not 
to take it) with study drug is not considered a protocol deviation. However, if study drug was incorrectly 
administered, prescribed, or there was a significant misunderstanding of dosing instructions that would 
constitute a deviation. 
Enrollment or Termination issues 
I. Guidelines for Early Termination of a Study Site 
During the course of a study, it may be necessary to drop one or more participating medical 
centers from the study. Such action must have the prior approval of the CSPCC Director and the CSP 
Director. Early termination is usually based on recommendations from the Executive Committee and the 
Data Monitoring Committee and most often reflects inadequate patient intake or serious 
noncompliance with Good Clinical Practices. This action should always be based on the best interests of 
the study and study participants and does not necessarily imply poor performance on the part of the site 
investigator or the medical center. Termination will be conducted per CSP guidelines.  
II. Enrollment Issues 
The Study Chair and the study biostatistician will monitor the intake rate and operational 
aspects of the study. Participating medical centers will continue in the study only if adequate participant 
intake is maintained. The Executive Committee may take action leading to the discontinuation of 
enrollment at a center with the concurrence of the CSPCC Director. If recruitment is not proceeding at 
an appropriate rate, the Study Chair and study biostatistician will scrutinize the reasons for participant 
exclusions and other barriers to recruitment.  Based on this information, the Executive Committee may 
choose, with the approval of the DMC and the Director, VA CSR&D, to drop centers, add additional 
centers, make minor modifications to the inclusion/exclusion criteria, or extend the recruitment period.  


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The following performance measures will be used to determine whether sites are at risk of being placed 
on probation or should be placed on probation:  
1. Noncompliance with the protocol, ICH, or applicable federal regulations. 
2. Recruitment rate: Recruitment rate will be calculated by dividing the number of randomized 
patients by the number of expected patients (each site is expected to recruit approximately 3 
patients per month). This measure will be continuously monitored and sites between 75% and 
90% of expected recruitment will be subject to remediation such as action plans or mentoring. 
Sites under 75% cumulative recruitment after a 3-month ramp-up period will be recommended 
for probation. Assessment for probation will occur on a monthly basis. 
3. Follow-up rate:  Follow-up rate will be calculated by dividing the number of patients with follow-
up forms completed by the expected number of patients with visits due.  Both the numerator 
and denominator will be subject to a 4-week delay in order to allow for scheduling of visits and 
completion of forms. Sites with cumulative follow-up rates below 90% will be recommended for 
probation. Assessment for probation will occur on a monthly basis. 
4. Forms completion rate: Forms completion rate will be calculated by dividing the number of 
completed forms by the number of expected forms, excluding forms marked “not collected”. 
Forms completion rates will be calculated both by patient and by form. Sites with cumulative 
forms completion rates under 90% will be recommended for probation.  Assessment for 
probation will occur on a monthly basis. 
If a medical center is placed on probation, the Study Chair will confer with the site personnel and 
may visit the site, if necessary, to help improve the rate of recruitment. Once a site is placed on 
probation, failure to meet the requirements specified by the end of the probation period will result in a 
recommendation for termination.  Additionally, sites that fail to meet two or more of the above 
performance measures, and sites that habitually under-perform by any of these measures, will be at risk 
of termination. 
To plan for the possible termination of a site(s) and the addition of a new site(s), back-up sites with 
IRB approval will be identified prior to study initiation to minimize the delay in adding a new site. The 
Executive Committee will take actions leading to discontinuation of a site only with the concurrence of 
the CSPCC Director. If a site is terminated from the trial, resources will be reallocated to other medical 
centers or used to start up a back-up site. 
III. Premature Termination of the Study 
The Director, CSP, can terminate a cooperative study before completion. The DMC makes 
recommendations as to whether the study should continue or be terminated. The decision to terminate 
a study prematurely is a complex one involving many factors. The DMC may consider the following 
circumstances as grounds for early termination: 
1. 
If patient accrual falls far below that which is predicted (e.g., 75% of expected accrual), it 
will be necessary to reassess the study design and the potential value of its continuation. 
2. 
If patient accrual far exceeds the predicted, this study could be completed at an earlier date. 
3. 
If serious adverse events or mortality are noted to be excessive in either treatment group.  


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Termination by recommendation of the DMC will be carried out as outlined in CSP Guidelines. 
Quality Control through the Boston CSPCC Quality Management System  
The quality management system (QMS) in place at the CSPCC will ensure further quality control 
for CSP 594. The Quality Assurance Department of the CSPCC will subject the data to risk based audits 
and monitoring that will verify and validate data elements according to internal SOPs.  In brief, a sample 
of the data will be verified at routine intervals. If errors are identified they will be referred to the data 
management team for resolution. If the error level rises to a predefined threshold, then the entire 
record or data element type will be subjected to verification and validation. Further, the CSPCC will 
conduct internal audits to ensure the quality of the clinical trial processes and procedures. If deviations 
or non-conformances are identified they will be remedied through the internal corrective 
action/preventive action system of the QMS.  
Risk based monitoring and auditing will also allow for the early systematic identification of 
problems that require remediation at the clinical site level. If problems are identified, the CSPCC will 
work with the clinical site to create a remediation plan to address the issues. If the problems persist 
after remediation, the site may be recommended for closure to the executive committee. 
XIX. Good Clinical Practice (GCP) 
Role of GCP  
This trial will be conducted in compliance with Good Clinical Practices (GCP) regulations.  The 
intent of these regulations is to safeguard participants’ welfare and assure the validity of data resulting 
from the clinical research. The VA Cooperative Studies Program will assist LSIs in complying with GCP 
requirements through its Site Monitoring, Auditing and Resource Team (SMART) based in Albuquerque, 
NM. SMART serves as the Quality Assurance arm of CSP for GCP compliance. Study site personnel will 
receive a GCP orientation at the study kickoff meeting. SMART will provide training, manuals, and 
materials to assist study personnel in organizing study files and will be available throughout the trial to 
advise and assist LSIs regarding GCP issues. 
Summary of Monitoring and Auditing Plans: 
Monitoring Visits  
 
Initial visits at each site soon after study start-up 
 
Subsequent monitoring will be conducted yearly.  
 
Final monitoring visit to each site during last year of the study 
 
Additional monitoring visits may be conducted as deemed necessary by study leadership or 
SMART. 
Audits  
 
Routine audits –independent site visits to one or more sites per year as determined by SMART  
 
For-Cause audits – independent audits of a site as requested by study leadership or CSP Central 
Office.  


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Note: Audits may be scheduled or unannounced 
XX. Study Organization and Administration 
A. Administration 
The administrative structure of this study is similar to others in CSP and includes: 
 
The Cooperative Studies Program (VA Central Office) establishes overall policies and 
procedures that are applied to all VA cooperative studies through the Study Chair’s office and the 
CSPCC. 
 
The CSPCC and the Study Chair’s office jointly will perform the day-to-day scientific and 
administrative coordination of the study. These include developing and revising the study protocol, 
Operations Manual, and case report forms; ensuring the appropriate support for the participating 
centers; scheduling meetings and conference calls; answering questions about the protocol; conducting 
site visits; publishing newsletters; preparing interim and final progress reports; and archiving study data 
at the end of the study. Study progress reports will be produced every 6 months. Patient accrual, patient 
safety, and data quality will be monitored closely to ensure that the study is progressing satisfactorily. 
 
The CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC) manages the 
pharmaceutical aspects of multicenter pharmaceutical and device clinical trials including patient safety 
monitoring. CSPCRPCC acts as a liaison between the study participants, the FDA, and the manufacturers 
of the study drug(s) or device(s) in all VA Cooperative Studies that involve drugs or devices. The 
CSPCRPCC develops Drug Treatment and Handling Procedures, obtains and distributes the study drug(s), 
prepares a Drug Information Report for the study drug, and provides advice and consultation about 
drug-related matters during the study. CSPCRPCC is responsible for monitoring and reporting the safety 
of trial participants through the review, assessment, and communication of adverse events and serious 
adverse events reported by study personnel with reviewing responsibilities occurring through ongoing 
communication with the Study Chair, Executive Committee, CSPCC, and CSP Central Office. The 
reporting activities include filing regulatory documents involving adverse events with the FDA and 
manufacturers to meet federal regulations and CSP policies. In conjunction with the CSPCC, the 
CSPCRPCC trends and analyzes safety data to prepare reports for various committees including the DMC, 
VA Central IRB (CIRB), Executive Committee(s), and Study Group meetings.  
 
Each participating VA medical center will designate a site investigator (SI) to be responsible 
administratively and scientifically for the conduct of the study at the center. SIs will be expected to 
attend all annual Study Group meetings, as well as to hire and supervise personnel. By agreeing to 
participate in the study, the medical center delegates responsibility for global monitoring of the ongoing 
study to the DMC, the CSPCC Human Rights Committee, and the CSSEC.   
 
The Clinical Sciences Scientific Evaluation Committee (CSSEC) reviews the scientific merit of all 
new cooperative study proposals and all ongoing cooperative studies every 3 years. The committee is 
composed of both VA and non-VA clinical research scientists, most of whom have had experience in 
managing their own cooperative studies. 
 
The Study Group will be composed of the SIs from each participating center, the Study Chair, 
Study Director, and CSP staff (biostatistician, project manager, clinical research pharmacist, and others). 


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The Study Chair will head the group, which will meet once a year to discuss the progress of the study, 
any problems that the investigators have encountered, and any suggestions for improving the study. 
 
B. Monitoring 
The following groups monitor the various aspects of the study.  These committees will meet 
according to current Cooperative Studies Program guidelines. In addition, the CSP SMART will monitor 
the trial for GCP compliance as indicated above.   
 
The Executive Committee is responsible for the operations of the study, including protocol 
amendments, and overall management of the study. It will be headed by the Study Chair and Study 
Director and consist of the study biostatistician, study project manager, clinical research pharmacist, 
selected participating investigators, and outside consultants as needed. This committee will meet 
regularly to review blinded data (not broken down by treatment group), decide upon changes in the 
study, determine the fate of hospitals whose performance is substandard, initiate any sub protocols, 
and discuss publication of the study results.  This Committee must grant permission before any study 
data may be used for presentation or publication. 
 
The Data Monitoring Committee (DMC) will review the progress of the study and will monitor 
patient intake, outcomes, adverse events, and other issues related to patient safety. Interim, 
independent, and unbiased reviews of the study's ongoing progress will be provided. The DMC will 
consist of experts in the study’s subject matter field(s), clinical trials, biostatistics, and ethics. These 
individuals will not be participants in the trial and will not have participated in the planning of the 
protocol. The DMC will consider safety or other circumstances as grounds for early termination, 
including either compelling internal or external evidence of treatment differences or the unfeasibility of 
addressing the study hypothesis (e.g., poor patient intake, poor adherence to the protocol).  
 
At each of its meetings during the study period, the DMC will review the randomization rates 
and assess the difference between the actual and the projected rates, as well as the impact of these 
assessments on overall trial size. If the study enrollment is inadequate, the reasons for exclusion may be 
scrutinized and actions may be suggested. An assessment of whether the trial should be continued will 
be made followed by recommendations, as appropriate. All serious adverse events will be reported 
regularly to the DMC for review. Unexpected, related serious adverse events will be reported to the 
DMC as soon as they become known based upon the consensus of the Study Chair, the study 
biostatistician, the Study Director, and the study pharmacist. The study biostatistician will provide the 
appropriate data to the DMC at specified intervals for this purpose. Conditional power estimates will be 
provided to the DMC to assist them in making their decisions and recommendations. To help them make 
their assessment, the Study Chair and study biostatistician will furnish the Data Monitoring Committee 
with appropriate monitoring data before each meeting.  The DMC makes recommendations after each 
meeting to the CSP Director about whether the study should continue or be stopped.  
 
The VA Central IRB will be the IRB of record for all VA sites.  They will monitor the study’s 
serious adverse events and review deviations on a continual basis.  They will conduct annual reviews of 
the study.  All local sites may be required to submit reports to their local Research and Development 
and/or Safety Committee for approval. In addition, some study materials (such as participant 
correspondence and protocol changes) will have to be reviewed by the VA CIRB, and approved prior to 
implementation.  
 


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The CSPCC Human Rights Committee (HRC) is composed primarily of lay people and is 
responsible for ensuring that patients' rights and safety are upheld prior to study initiation and during 
the conduct of the study. The committee reviews all new protocols, periodically makes site visits to 
participating centers to monitor firsthand the progress of the study, and may be asked to review any 
ethical and human rights issues that arise during the conduct of the study.  
   
The CSP Site Monitoring, Auditing and Resource Team (SMART), located at the CSPCRPCC in 
Albuquerque, will monitor the trial for compliance with Good Clinical Practices (GCP).  GCP monitors 
from SMART will visit participating sites shortly after enrollment is initiated and subsequent monitoring 
will be conducted yearly thereafter to ensure investigator regulatory and protocol compliance and to 
evaluate research practices.  SMART will provide an orientation to GCP at the study kick-off meeting and 
provide GCP tools to enhance compliance.  Additionally, SMART will conduct periodic routine audits 
throughout the course of the study and for-cause audits as requested by study leadership or CSP VACO.  
 
XXI. Publications 
Publication policy 
It is the policy of the CSP that outcome data will not be revealed to the participating 
investigators until the data collection phase of the study is completed. This policy safeguards against 
possible biases affecting the data collection. All presentations and publications from this study will be 
done in accordance with current CSP Guidelines, including the Authorship Policy. The most current 
version of the Guidelines should be referenced when planning any study publication.The presentation or 
publication of any or all data collected by participating investigators on patients entered into the VA 
Cooperative Study is under the direct control of the study's Executive Committee. No individual 
participating investigator has any inherent right to perform analyses or interpretations or to make public 
presentations or seek publication of any or all of the data other than under the auspices and approval of 
the Executive Committee. 
The Executive Committee has the authority to establish one or more publication subgroups of   
investigators and members of the Executive Committee for producing scientific presentations and 
publications. Authors with VA appointments must list their VA affiliation first. The VA contributions to 
the research project should be acknowledged in all written and oral presentations of the research 
results, including scientific articles, news releases, news conferences, public lectures, and media 
interviews.   
All study reports and journal manuscripts must be reviewed and approved by the Boston CSPCC 
Director prior to submission for publication.  After approval for submission is granted by the Boston 
CSPCC Director, VA Central Office must be notified upon acceptance of any publications.  This includes 
minor publications such as abstracts and poster presentations. 
 
 


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