A Novel Centralized 'Virtual' Gout Clinic for Chronic Gout Management (NIAMS :CoRT)
Phase: NA
Conditions: Gout
Sponsor: University of Alabama at Birmingham

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Randomized evaluation of an Ambulatory Care Pharmacist-Led 
Intervention to Optimize Urate Lowering Pathways (RAmP-UP) Study 
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NCT02790463

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1 
Contents 
2 
Summary .................................................................................................................................................... 4 
3 
Background ................................................................................................................................................ 4 
4 
Rationale for the Study .............................................................................................................................. 4 
4.1 
Burden of Gout ....................................................................................................................................... 4 
4.2 
Urate Lowering Therapy (ULT) as the Cornerstone of Treating Chronic Gout ....................................... 5 
4.3 
Allopurinol: the Most Commonly Administered ULT in Gout .................................................................. 5 
4.4 
Gout Outcomes with Allopurinol Use ...................................................................................................... 5 
4.5 
Barriers to Optimal Allopurinol Use ........................................................................................................ 6 
5 
Research Strategy ..................................................................................................................................... 7 
5.1 
Study Design .......................................................................................................................................... 7 
5.2 
Study Setting .......................................................................................................................................... 7 
6 
Outcomes ................................................................................................................................................... 7 
6.1 
Primary Outcome ................................................................................................................................... 7 
6.2 
Secondary Outcomes ............................................................................................................................. 9 
7 
Patient Population ...................................................................................................................................... 9 
7.1 
Inclusion Criteria ..................................................................................................................................... 9 
7.2 
Exclusion Criteria ................................................................................................................................... 9 
8 
Study Procedures, Intervention, and Assessments ................................................................................... 9 
8.1 
Study technology .................................................................................................................................... 9 
8.2 
Gout care algorithm and IVRS messages ............................................................................................ 10 
8.3 
Provider interactions ............................................................................................................................. 10 
8.4 
Patient interactions ............................................................................................................................... 11 
9 
Informed Consent (IC) Procedures ............................................................................................................ 9 
10 
Data Management and Statistical Analyses ............................................................................................ 11 
10.1 
Sample Size Justification ..................................................................................................................... 12 
10.2 
Randomization ..................................................................................................................................... 12 
10.3 
Study Analyses ..................................................................................................................................... 12 
11 
Adverse Events (AE) ................................................................................................................................ 12 
11.1 
Capture of Adverse Events (AE) and Serious AE (SAE) ...................................................................... 12 
11.2 
Adverse Event (AE) Classifications ...................................................................................................... 15 
11.2.1 
Expected AE ................................................................................................................................. 15 
11.2.2 
Unexpected AE ............................................................................................................................. 15 
11.2.3 
Related to the research ................................................................................................................. 15 
11.2.4 
Unrelated to the research .............................................................................................................. 15 
11.2.5 
Unanticipated Problems Involving Risks to Participants or Others (Unanticipated Problems) ...... 15 

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11.3 
Relationship to allopurinol .................................................................................................................... 15 
11.3.1 
Probably Related to Allopurinol ..................................................................................................... 15 
11.3.2 
Possibly Related to Allopurinol ...................................................................................................... 15 
11.3.3 
Unlikely Related to Allopurinol ...................................................................................................... 15 
12 
Investigational Study Sites ....................................................................................................................... 16 
13 
Institutional Review Board (IRB) .............................................................................................................. 16 
14 
Administrative Procedures ....................................................................................................................... 16 
14.1 
Protocol Amendments .......................................................................................................................... 16 
14.2 
Compliance with Law, Audit, and Debarment ...................................................................................... 16 
14.3 
Compliance with Financial Disclosure Requirements .......................................................................... 16 
14.4 
Confidentiality and Privacy ................................................................................................................... 17 
14.5 
Study Reports ....................................................................................................................................... 17 
14.6 
Publication of results ............................................................................................................................ 17 
14.7 
Changes in study personnel ................................................................................................................. 17 
 
 
 
 

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2 
Summary  
Title: Randomized evaluation of an Ambulatory Care Pharmacist-Led Intervention to Optimize Urate Lowering 
Pathways (RAmP-UP) Study 
Study Site(s): Kaiser Permanente Southern California Medical Centers  (14 medical centers; 116 ambulatory 
offices) 
Approximate number of participants: 1400 
Investigators: Jeff Curtis, MD, MPH (University of Alabama at Birmingham, UAB); David Redden, PhD 
(UAB),Kenneth G. Saag MD, MSc (UAB); Brian Coburn, MD, PhD (University of Nebraska Medical Center, 
UNMC);  Ted Mikuls, MD (UNMC) Craig Cheetham, PharmD (KPSC); Naz Rashid, PharmD (KPSC); Gerald 
Levy, MD (KPSC) 
Methodology: Open-label two-year cluster-randomized, parallel group, protocol-driven large pragmatic 
multicenter usual care-controlled trial designed to assess a highly automated, scalable, pharmacist-led 
intervention to optimize allopurinol treatment in gout.   
 
3 
Background  
Gout is the most common form of inflammatory arthritis, affecting up to 8 million individuals in the US 1. 
Characterized by painful episodes of arthritis, gout results in substantial morbidity, physical disability, and 
reduced survival 2-5.  Contrary to other forms of arthritis, gout pathogenesis is well understood, with signs and 
symptoms resulting from inflammatory responses triggered by monosodium urate crystal deposition in joints or 
surrounding soft tissues. Under normal physiologic conditions, this occurs when serum urate (SU) concentrations 
exceed 6.8 mg/dl 6. 
 
Recognizing the role of hyperuricemia as the primary pathophysiologic culprit urate-lowering therapy (ULT) 
represents a cornerstone in gout management 6.  Allopurinol the most frequently prescribed first-line ULT is 
both efficacious and well tolerated in most patients.  Despite this, allopurinol use is frequently accompanied by 
suboptimal patient outcomes that stem, in part, from inadequate prescribing practices and poor adherence 7-13.  
For gout patients initiating allopurinol, management guidelines endorse gradual dose escalation to achieve a 
target SU goal 14,15. These recommendations are based on evidence that achieving and maintaining SU 
concentrations below 6.0 mg/dl greatly reduces the long-term risk of gout flares 14,16.  Contrary to best practices 
promoted by these guidelines, the vast majority of patients initiating allopurinol in “real world” healthcare 
settings fail to undergo requisite SU assessment following initiation and only a small minority ever receive dose 
increases 10,17,18. In previous reports, only one in three gout patients initiating allopurinol ever received a dose 
increase and only a small fraction of these (~10%) ever received a daily dose exceeding 300 mg, dosing 
typically required to achieve desired SU concentrations and control of gout symptoms 10,19.   
 
To address and potentially overcome barriers in achieving outcomes with allopurinol treatment, we completed 
the Randomized Evaluation of an Ambulatory Care Pharmacist-Led Intervention to Optimize Urate Lowering 
Pathways (RAmP-UP) study. RAmP-UP is a large pragmatic site-randomized trial designed to assess a highly 
automated, scalable, pharmacist-led intervention to optimize allopurinol treatment in gout.   
 
4 
Rationale for the Study  
This project fits the UAB CORT in Gout and Hyperuricemia theme of “from bench to bedside, bedside into the 
community, and back again,”  by proposing a novel Type 2 translational research project that addresses a 
currently unanswered question in gout, namely, how to effectively implement evidence into clinical populations. 
 
4.1 
Burden of Gout 
Gout is a chronic and progressive form of arthritis occurring as a result of monosodium urate deposition in the 
joints and surrounding tissues.  Chronic hyperuricemia is a necessary, although not sufficient, precursor of 
gout.  It is estimated that gouty arthritis affects > 8 million people in the US alone,20 now recognized as the 
most common form of inflammatory arthritis.  Accompanying increased rates of disease risk factors including 
hypertension, renal insufficiency, and increased use of predisposing medications, gout incidence has risen 
two-fold in recent decades.21,22  Approximately two-thirds of gout patients will experience progressive disease 
and declines in physical function over time if left untreated.23,24  Recent studies show that gout is associated 
with work absenteeism and losses in work productivity.4  With an aging population, the burden posed by gout 

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will only continue to grow.  Despite its extremely well known pathogenesis and the availability of highly 
efficacious therapies, gout continues to lead to considerable morbidity and mortality due to poor management 
and limited therapeutic adherence.  Our translational research study will address this deficit in evidence 
implementation. 
 
4.2 
Urate Lowering Therapy (ULT) as the Cornerstone of Treating Chronic Gout 
The treatment of chronic gout is based primarily on the use of ULT to reduce the frequency of, and eventually 
eliminate, acute flares in addition to reducing the risk of progressive joint destruction.23  There are currently 
four ULT agents approved for the treatment of gout in the US including probenecid (a uricosuric), pegloticase 
(a biologic therapy approved for treatment-refractory gout), allopurinol, and febuxostat. Allopurinol and 
febuxostat work through the inhibition of xanthine oxidase, the rate limiting enzyme in endogenous urate 
production.  A well-accepted goal of ULT administration in gout is to lower and maintain serum urate 
concentrations below 6.0 mg/dl, a concentration at which urate is more soluble and far less likely to form 
monosodium urate crystals that serve as a nidus for gouty inflammation. Achieving a serum urate of < 6.0 
mg/dl with ULT leads to several clinical benefits in gout including decreased flare rates and dissolution of 
tophi.25-27  The target serum urate threshold of < 6.0 mg/dl has been adopted as a primary outcome in recent 
randomized controlled trials comparing febuxostat with allopurinol25,27,28 and has been endorsed as a goal of 
ULT administration in recently published international gout treatment guidelines.29 
 
4.3 
Allopurinol: the Most Commonly Administered ULT in Gout 
Available for more than 40 years, allopurinol remains the most frequently prescribed ULT, accounting for ~99% 
of all ULT prescriptions (Section C.1.1)).  In contrast to probenecid, allopurinol can be dosed once daily (vs. 
twice to three times daily for probenecid), is effective in patients who overproduce and in patients who under-
excrete uric acid (whereas probenecid is effective only in under-excretors), and may be effective in the context 
of significant renal insufficiency (whereas probenecid is not).30-32  Febuxostat, a novel non-purine inhibitor of 
xanthine oxidase, also appears to have potent urate lowering effects at approved doses and may represent an 
important alternative in patients intolerant to allopurinol.25,27,28  While adverse events occur with allopurinol 
administration, these events appear to be uncommon with less than 5% of patients intolerant to the drug.33  At 
present, febuxostat prescriptions represent only a small proportion of total ULT prescriptions in gout.  With 
daily drug costs 20- to 40-fold higher than allopurinol (www.drugstore.com, accessed June 16, 2011), the 
precise role that febuxostat will play in cost-effective gout management remains unknown.   
 
4.4 
Gout Outcomes with Allopurinol Use 
Many early studies confirmed the robust urate lowering effect of allopurinol, a treatment also yielding ample 
improvements in long-term outcomes including a reduction in gouty flares.25-28,31,34-37 A recent 28-week 
randomized trial examining fixed dose daily allopurinol revealed a 34% reduction in serum urate concentrations 
vs. a decrease of 3-4% for those receiving placebo.25,27,28 In a separate study, allopurinol in a fixed daily dose 
of 300mg was associated with a significant 50% reduction in tophus area.25  Recent trials of allopurinol with 
more limited study durations (range of 4 to 12 months) have shown no significant declines in flare rates 
compared to the pre-trial period,25,27 a beneficial effect that appears to require up to 2 years of effective ULT.25 
To date, published studies examining the long-term impact of ULT on health-related quality of life, physical 
functioning, pain, and other patient reported outcomes are scarce, a knowledge deficit that will be addressed in 
Aim 1 of the current proposal.  In addition to decreasing uric acid concentration, reducing tophus size and 
deposition, and reducing or eliminating acute flares, allopurinol use may be associated with other health 
benefits.  Hyperuricemia is independently associated with cardiovascular morbidity and mortality.38-41  In a 
placebo-controlled study of pediatric essential hypertension led by our collaborator (Daniel Feig, MD, PhD,), 
allopurinol use resulted in significant, albeit modest, declines in blood pressure.42  Xanthine oxidase inhibition 
via allopurinol has been shown to improve endothelial function, improving measures of both local and systemic 
blood flow43 and been associated with improvements in renal function, 44,45 physiological effects that will be the 
focus of Project 2 of this CORT application.  In a retrospective study of over 9,000 US veterans with 
hyperuricemia, allopurinol administration was associated with a significant 22% reduction in all-cause mortality, 
that the authors speculated relates to protective cardiovascular effects.46 

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4.5 
Barriers to Optimal Allopurinol Use 
Although approved at daily doses as high as 800 mg, allopurinol is rarely given at daily doses exceeding 300 
mg.  In one study, 97% of gout patients treated with allopurinol 
received doses of 300 mg/d or less (Figure 1).47  It is well 
established that only a minority of patients achieve a target 
serum urate < 6.0 mg/dl with 'standard' dose allopurinol.  Using 
a target serum urate threshold of < 5.0 mg/dl, investigators 
have shown that one-fourth of gout patients achieve this goal 
with 300 mg of daily allopurinol, a proportion that increases to 
78% with a daily dose of 600 mg 48. The limitation of 'standard' 
dose allopurinol has been borne out in recent clinical trials that 
have compared fixed daily doses of 300 mg to febuxostat.  In 
those studies, ~40% of allopurinol treated gout patients 
achieved a final study urate level of < 6.0 mg/dl.25,27 Factors 
contributing to suboptimal allopurinol administration likely 
include, but are not limited to: 1) failure of prescribers to 
appropriately titrate allopurinol dose to achieve optimal serum 
urate target levels; 2) poor long term patient adherence to 
therapy; 3) drug intolerance, recognizing that this affects only a 
small proportion of patients;33 4) limited data regarding the 
effectiveness of doses exceeding 300 mg/day; and 5) concerns 
regarding increased toxicity with higher doses, particularly in the context of chronic kidney disease (CKD).  It is 
important to note that despite common misconceptions, allopurinol administration has never been associated 
with deterioration in renal function in patients with renal impairment.  Indeed, at least one small study has 
shown that allopurinol use may actually retard the progression of CKD.45  In addition to unfounded concerns 
over potential deleterious effects on kidney function, results from a single case series of 78 patients suggested 
that ‘higher dose’ allopurinol may increase the risk of allopurinol hypersensitivity syndrome (AHS), an 
uncommon (0.1% to 0.4%) but serious drug related adverse event that appeared to be heightened in the 
context of CKD. These results led directly to the generation and promulgation of non-evidence based dosing 
guidelines that were founded on the relationship of renal function with observed oxypurinol concentrations (an 
allopurinol metabolite).49 It is important to note that the 'effectiveness' of these guidelines in preventing AHS 
has not been demonstrated.50 Indeed, many patients with CKD have developed AHS even with ‘appropriately’ 
dosed allopurinol.51,52 In their review of 120 gout patients receiving allopurinol, more than half (57%) 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.53  In a recent 
study of 90 gout patients, Stamp and colleagues found that increasing the dose of allopurinol above the 
thresholds proposed by Hande led to significant reductions in serum urate without increased toxicity.54  
Independent guidelines from both the European League Against Rheumatism (EULAR) and the British Society 
for Rheumatology have recommended that allopurinol dosing should be gradually increased to doses as high 
as 800 to 900 mg/day with a goal of achieving and maintaining serum urate concentrations below either 6.0 
mg/dl or 5.0 mg/dl, respectively, recognizing the need for initial dose adjustments in the context of renal 
insufficiency.29,55 Current practice that adheres strictly to the Hande dosing guidelines49 contrasts starkly with 
expert recommendations of judicious dose escalation accompanied by appropriate surveillance to achieve a 
target serum urate goal of < 6.0 mg/dl.50   
 
Without implementation of evidence into practice, the public health benefits of basic and clinical research 
cannot be realized.  Yet, evidence has been notoriously difficult to implement across virtually all medical 
conditions, including gout. Discovering novel methods to implement evidence and conducting scientifically 
rigorous trials to test these methods has become an important area of research featured in this proposal. The 
Institute of Medicine (IOM) defines Type 2 (T2) translational (evidence implementation) research as research 
moving discovery from the bedside to community practice.56 In gout, perhaps more than other musculoskeletal 
conditions, disease pathogenesis (including the central role of hyperuricemia) is well understood and highly 
effective therapies exist.  The IOM has defined deficiencies in medical care as the “quality chasm”,57 and we 
have highlighted that a gout quality chasm also exists.47,58-60  The existence of this quality chasm in gout 
Figure 1:  Daily allopurinol dose use among patients 
with gout prescribed allopurinol; 97% with daily doses of 
≤ 300 mg (Sarawate CA et al. Mayo Clin Proc 2006) 

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management underscores the urgent need for quality T2 translational research in gout.  The proposed study 
represents the largest systematic T2 translational research study to date ever conducted in gout patients, 
examining the use of a highly novel intervention with the goal of improving not only processes of care but also 
patient outcomes.  The implementation of evidence through transportable and innovative data-collection and 
chronic disease-management technologies holds the promise of improving care for a larger number of gout 
patients than is either practical or feasible with more ‘traditional’ approaches. 
 
5 
Research Strategy  
5.1 
Study Design  
RAmP-UP is a cluster-randomized, parallel group, usual care-controlled trial evaluating the impact of a novel 
pharmacist-led, protocol-driven intervention focused on facilitating sUA goal attainment among gout patients 
initiating allopurinol in the Kaiser Permanente Southern California health system(Fig. 1). The intervention uses 
system redesign and direct patient engagement to optimize gout care. The aim of the study is to develop and 
test a pharmacist-led intervention to improve patients' treatment adherence and increase the proportion 
achieving sUA goal b6.0mg/dl, the two primary study outcomes. The intervention has been led by an 
ambulatory care pharmacist and delivered, in part, using an automated calling system to encourage 
appropriate laboratory testing, allopurinol dose titration as needed, and medication adherence. The 
intervention has been designed to supplement usual care in a highly scalable manner that would be 
generalizable to many healthcare systems. Fig. 2 provides an overview of the study timeline including protocol 
development steps, system-level communication efforts, patient enrollment, and outcome assessment. During 
2013, an expert consensus panel meeting, site randomization and 10-week pilot study were completed. 
Additionally, stakeholder involvement began in early 2013 and will continue throughout the study.  
 
5.2 
Study Setting 
Kaiser Permanente Southern California (KPSC), the setting for this study, is an integrated healthcare delivery 
system with over 4 million members. The system is comprised of 14 major medical centers that include over 
200medical offices. Of these offices, we identified 116 ambulatory clinics that prescribed allopurinol during a 
recent one-year period. Few primary care providers or pharmacists practice at multiple clinics and each site 
typically has its own dedicated outpatient pharmacy. KPSC membership reflects the demographics of the 
region, accounting for 15% of the area's population.61. Based on a preliminary study in this population, we 
estimate that 78% of study patients will be men and participants will have a mean ± SD age of 60 ± 14 years 
nd BMI of 31.5 ± 6.6 kg/m2. 62 Further, we estimate that approximately 40% will be white/non-Hispanic, 16% will 
be black/African American, 20% will be Hispanic and 23% will be Asian/Pacific Islander. 61 Finally, we expect 
that approximately 40% will have chronic kidney disease (CKD) stage III/IV while the remainder will have 
kidney function of mild CKD (Stage II) or better. 62 Membership in KPSC can be obtained through individual or 
family plans, Medicaid/Medi-Cal, Medicare or employers.61 
 
6 
Outcomes 
6.1 
Primary Outcome 
Co-primary outcomes are allopurinol adherence during the first year of treatment and achievement of a target 
SU (<6.0 mg/dl) at one year.  Adherence will be assessed using pharmacy dispensing data to calculate the 
proportion of days covered (PDC) with adherence defined as a PDC ≥0.8.  The PDC has been endorsed as the 
preferred method for assessing medication adherence using pharmacy claims data. When multiple sUA values 
are available, we will use the value that is at least 7 days post-index and that is most proximate to one-year of 
follow-up. The proportion achieving sUA <6.0 mg/dl at one year will be examined in an additional subgroup 
analysis limited to adherent patients (PDC ≥0.8).  The effect of treatment assignment on primary outcomes will 
be evaluated in a separate subgroup analysis of “completers”, defined as intervention patients responding to at 
least one IVR-administered survey. 

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Figure 1. Parallel group design for intervention and usual care patients. The RAmP-UP Study is an ongoing two-year cluster-randomized, parallel 
group, usual care-controlled trial evaluating the impact of a novel pharmacist-led, protocol-driven intervention focused on facilitating sUA goal 
attainment among gout patients initiating allopurinol in the Kaiser Permanente Southern California health system; sUA = serum urate; IVRS = 
interactive voice response system. 

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6.2 
Secondary Outcomes 
 
sUA goal achievement at year two 
 
Allopurinol adherence during the second year of treatment 
 
Absolute change in sUA over follow-up and the difference in PDC at one year 
 
Gout flares during the second year of observation 
 
Adverse events (Adverse events will be reported as safety outcomes)  
 
Adverse events will be captured through electronic health record review and compiled retrospectively at year 2 
with a special emphasis on diagnostic codes corresponding to severe cutaneous reactions (e.g. drug reaction 
with eosinophilia and systemic symptoms [DRESS], erythema multiform, Stevens-Johnson syndrome, or toxic 
epidermal necrolysis [TEN]). 
 
7 
Patient Population  
 
7.1 
Inclusion Criteria 
 
English-speaking patients 
 
≥18 years of age or older 
 
Minimum of one International Classification of Disease, 9th edition (ICD9) diagnosis code of gout 
(274.xx) and receiving an incident prescription for allopurinol*   
7.2 
Exclusion Criteria 
 
In the absence of consensus surrounding optimal gout management, patients with advanced 
chronic kidney disease (CKD state V) were excluded.   
 
Pre-intervention provider and/or patient opt-out 
*Incident prescription was defined by at least 12 months of previous membership in the absence of such a prescription.  
 
8 
Informed Consent (IC) Procedures 
 
The study has been approved by the University of Alabama at Birmingham Institutional Review Board and will 
be conducted in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice. 
Because the study was deemed to be a quality improvement project, a waiver of written informed consent was 
granted by the IRB allowing for the opt-out study design. 
 
9 
Study Procedures, Intervention, and Assessments 
All study visits and procedures will be performed in facilities in the Kaiser Permanente Southern California 
Network. 
 
Following initial allopurinol receipt (index date), prescribed and dosed at the discretion of the primary provider, 
pharmacist management will be provided to patients from intervention sites.  Following a gout management 
algorithm that was produced through expert consensus 63, we developed the intervention to supplement usual 
care (UC).  The algorithm incorporates a treat-to-target approach with the intervention delivered primarily 
through an interactive voice response system (IVR) 64  IVR messaging will be used to assess whether 
intervention patients continued to take prescribed ULT, alert patients regarding pending SU laboratory orders 
or prescription updates, and to provide encouragement.  IVR messaging will supplemented in select cases with 
telephone calls from the study pharmacist to provide more in-depth assistance (i.e. when patients report that 
they are not taking allopurinol) or respond to patient queries.  Patients at non-intervention sites will receive only 
UC with the exception that patients without an sUA assessment in the previous 3 months (at both intervention 
and UC sites) will receive IVR reminders at baseline and after one- and two-years of follow-up to undergo 
laboratory testing. 
 
9.1 
Study technology 
Pharmacist-patient interactions in this study will be facilitated by an interactive voice response system (IVRS). 
IVRS has been used in health care to facilitate clinical care, aid patient self-management of disease, 
and improve health outcomes. IVRS is a relatively low-cost automated calling system that allows a health 
system to send patient reminders and collect patient-assessed health measures. Using scripted dialogue and a 
keypad response system, IVRS is a consistent and efficient method for tailoring communication to each 

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patient. IVRS allows simultaneous calls, patient identity validation, convenient time-of-day calling and the 
ability for patients to repeat or save messages for a later date. IVRS was used in this study to assess 
medication adherence, alert patients about laboratory appointments or prescription updates, and provide 
encouragement. 
 
9.2 
Gout care algorithm and IVRS messages 
The primary goals of the gout care algorithm are to: 1) promote patient engagement in gout self-management 
especially through medication adherence and 2) overcome clinical inertia related to allopurinol dose titration 
and sUA measurement. We have included IVRS messages in the algorithm to efficiently accomplish certain 
tasks while using live telephone calls by the pharmacist to provide more in-depth assistance or follow-up. 
Importantly, the algorithm is meant as a guide for the pharmacist leading the intervention; the pharmacist is 
allowed to deviate from the algorithms circumstances dictated. A KPSC expert rheumatologist (GL) was 
available to the study pharmacists for ad hoc consultation throughout the trial. IVRS messages used in the 
algorithm are divided into 5 categories: 
1) participation reminder,  
2) allopurinol adherence survey 
3) sUA lab order 
4) allopurinol prescription/dose adjustment 
5) sUA goal achievement  
 
The participation reminder is designed to encourage return mailing of the baseline health survey. The 
allopurinol adherence message is designed to solicit self-reported adherence where a report of ≥5 daily doses 
taken in the past 7 days will be considered adherent. The sUA lab order messages will inform or remind 
patients that they are due for a blood draw. The allopurinol prescription and dose adjustment messages will 
inform patients of changes to their prescriptions as initiated by the study pharmacist. Finally, the sUA goal 
achievement message is designed to celebrate a “good outcome” and remind patients to continue allopurinol 
unless otherwise instructed.  
 
The number of IVRS calls made and successful contacts will be tracked and documented by the study 
pharmacist and research associate. The algorithm has been tailored to accommodate the slightly differing 
risk profiles of patients with normal kidney function or CKD stage I/II (Fig. 2a) and stage III/IV (Fig. 2b). In 
particular, the initial suggested dose increment of 50 mg/d represents the likelihood for CKD stage III/IV 
patients to start with 50 mg/d of allopurinol and escalate more slowly in order to reduce risks related to 
allopurinol hypersensitivity. For the same reason, the algorithm suggests that all dose escalation 
for CKD III/IV patients be done according to sUA measurements whereas those with stage II or better kidney 
function could be dose escalated to 300 mg/d without sUA measurements. This will allow the study pharmacist 
to reduce patient burden related to blood draws recognizing that at least 50% of patients are likely to need at 
least 300mg/d of allopurinol to achieve sUA < 6.0 mg/d.  
 
The algorithm has a similar design for all levels of kidney function. After receiving an incident allopurinol fill, the 
study packet and IVRS reminders, all patients in the intervention will receive an adherence assessment IVRS 
message. If classified as non-adherent (took allopurinol as indicated on b5 day over the past week), the patient 
will receive a phone call with encouragement from the pharmacist followed by a repeat assessment. If the 
patient is adherent, they will receive an IVRS message notifying them that a blood draw is due. Following sUA 
measurement, patients with a sUA b 6.0 mg/dl will receive the sUA goal achieved IVRS message while 
patients ≥6.0 mg/dl will receive allopurinol dose escalation and the corresponding IVRS dose adjustment 
message. An adherence assessment IVRS message will follow 2–4 weeks later. The sequence of dose 
escalation, adherence assessment and blood draw IVRS messages will continue until the patient achieves a 
sUA < 6.0 mg/dl.  
 
9.3 
Provider interactions 
Two sets of broadcast emails will be sent to providers: a pre-study email and an end-of-study email one year 
after the first patient is enrolled. Providers at usual care sites will be informed that a federally- funded study to 
facilitate gout management is being initiated and their patients may receive questionnaires and a request to 

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have blood drawn for laboratory testing, but that their patients would continue under their care without any 
study intervention. By contrast, providers at intervention sites will be informed that patients newly initiated on 
allopurinol will have a pharmacist assist in patients' care by monitoring sUA levels and escalating the 
allopurinol dose until a sUA b 6.0 mg/dl is met. The email will state that these actions are only intended to 
supplement care while other medications related to gout such as anti-inflammatory medications or colchicine 
would not be impacted by the study and may still be required. Study personnel at KPSC will be available for 
questions and providers will be given the opportunity to opt their patients out of the study.  
 
9.4 
Patient interactions 
Initial allopurinol dosing will be prescribed at the discretion of the primary gout provider. All patients meeting 
eligibility criteria will be randomized into either study arm, and mailed a study packet including an opt-out letter, 
baseline health survey and gout educational material. The opt-out letter will notify patients of the quality 
improvement program, and ask them to return a pre-addressed, postage-paid notification if they wish to opt-out 
of participation. The baseline health survey will record the presence and number of gout attacks in the past 3 
months, patients' gout-specific health as measured on a 21-point visual analog scale and the 12-question 
Short Form Health Survey (SF-12). The same health survey will be sent via mail at the end of years 1 and 2. 
The gout educational material to be included in the mailing is produced by the Arthritis Foundation and covers 
a variety of topics including: gout as a chronic disease, typical treatment options used, and important lifestyle 
changes for self-management. 
 
All patients will be entered into the IVRS system to receive weekly IVRS reminders (maximum of 3) to return 
baseline questionnaires. The usual care patients will receive no further contact after these IVRS messages 
until the blood draw IVRS for the 1 year and 2 year outcomes. Intervention patients, by contrast, will continue 
into the gout care algorithm with the adherence assessment IVRS message. The study pharmacist will 
intervene further if the IVRS proves insufficient at any task for intervention patients. There were three primary 
indications where the IVRS may prove insufficient: 1) if the patient is unresponsive to IVRS calls or fails to 
show up for ordered labs or prescription fill pick-up; 2) a patient self-reports allopurinol non-adherence via 
IVRS; or 3) a patient calls the pharmacist directly. Direct telephone communications will be categorized into 
four broad categories: 1) introduction of IVRS and its purpose with the intent to improve use among 
unresponsive or confused participants, 2) gout education, 3) adherence reassessment and encouragement, 
and 4) dose adjustments. For gout education, a guide to frequently asked questions (FAQ) will be provided 
(Appendix A). Adherence reassessment and encouragement is designed to determine the extent of 
nonadherence, identify reasons for nonadherence and provide encouragement for improved adherence as 
appropriate. Finally, dose adjustments will be facilitated by the study pharmacist using live telephone calls if 
not accomplished by IVRS. 
 
10 Data Management and Statistical Analyses 
 
Dr. David Redden of the UAB School of Public Health will oversee all data management and analysis for the 
proposed study. Dr. Redden and the study team at UAB will ensure that the data collected and analyzed for 
this study are of the highest quality possible, and updated as needed to guarantee high quality data through 
quality control and quality assurance.   Edit checks will be reviewed by the statisticians, program manager, as 
well as other team members on an ongoing basis to evaluate whether any checks need to be added or any 
existing checks need to be modified. All data will be entered into and all analyses will be conducted using 
Statistical Analysis System (SAS; Cary, NC) Version 9.4 or higher. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to UAB by KPSC and stored on secure servers in the UAB Department of Medicine . This will not 
include the participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data will be secured and password 
protected. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 

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10.1 Sample Size Justification 
Sample size estimates are based on an assumption that 30% of gout patients given allopurinol from usual care 
clinics will achieve a sUA below 6.0 mg/dl [1]. To be conservative, we assumed a worst-case scenario intra-
class correlation coefficient of 0.1 by study site. Based on these assumptions, an alpha of 0.05 and 51 
intervention sites, 11 patients per site (or 561 total patients from intervention sites) will provide 80% power to 
detect a 10% absolute improvement in sUA goal achievement (i.e. ≥40% success rate) [25]. Finally, we  
estimate that after opt-out up to 20% of patients would drop-out or otherwise be nonresponsive to the study. 
We thus inflated the sample size estimate using a standard equation of the estimated sample size divided by 
1minus the estimated drop out proportion. Our target enrollment using this equation was over 702 per study 
arm; 1404 total. 
10.2 Randomization 
Clinic site will serve as the first level of randomization. Coverage at multiple clinics by primary care providers 
and pharmacists is uncommon at KPSC making clinics an ideal unit of randomization to limit cross 
contamination between intervention and usual care sites. However, more than one clinic or pharmacy could 
reside in the same or nearby building. To further minimize the risk of contamination, close proximity clinics will 
be combined into units for randomization. Demographic characteristics (age, gender and race/ethnicity) and 
size of clinic membership will be reviewed prior to randomization to balance these important factors.  
 
10.3 Study Analyses 
Baseline characteristics of patients from intervention sites will be compared with those from UC sites using a 
Chi square test for categorical variables or Student’s t-test for continuous variables.  General estimating 
equations will be used to examine group differences in the primary outcomes (sUA <6.0 mg/dl and PDC ≥0.8) 
in an intent-to-treat analysis, accounting for correlation among patients nested within a clinic site.  Factors that 
are imbalanced by group following randomization (race and calendar year of enrollment) will be included as 
covariates.  Non-responder imputation will be used for models examining sUA goal achievement when follow-
up sUA values are missing.  A mixed effects linear regression will be used to examine the continuous 
outcomes of absolute sUA change, differences in PDC, and change in renal function from baseline at years 
1 and 2 with intervention assignment as a fixed effect and clinic as a random effect. Flare rates will be 
calculated by treatment assignment for each six-month interval of the two-year follow-up period. 
 
11 Adverse Events (AE) 
 
Definitions below incorporate guidelines provided by the Office of Human Research Protections (OHRP) of the  
DHHS and describes FDA reporting requirements. All AEs will be collected. An AE is any untoward event 
whether or not considered related to the use of denosumab or zoledronic acid or alendronate. Any worsening 
(i.e., any clinically significant adverse change in frequency or intensity) of a preexisting condition which is 
temporally associated with the use of allopurinol is also considered an AE. Abnormal laboratory values or test 
results constitute AEs only if they induce documented clinical signs or symptoms or require therapy, and are 
recorded in the electronic health record. Conditions present at time of enrollment will not be considered 
adverse events; however, worsening of a preexisting condition may be considered an AE. We will report all 
AEs according to, the IRB, and the appropriate health authority (e.g., Food and Drug Administration [FDA]).  
 
11.1 Capture of Adverse Events (AE) and Serious AE (SAE) 
General adverse events (AEs) and serious adverse events (SAEs) will be captured by either self-report or 
through electronic health records review and classified in accordance with Good Clinical Practice 
(GCP) guidelines. SAEs and AEs captured in medical records will be ascertained and compiled retrospectively 
at the end of years 1 and 2 of follow-up. SAEs include any event or illness leading to death or hospitalization 
during observation. SAEs of special interest captured and reviewed in the electronic health records as part of 
the patient's normal care include any hypersensitivity or cutaneous drug reactions, Stevens- Johnson 
syndrome, toxic epidermal necrolysis (TEN), acute renal failure, or major acute coronary event (MACE). 
Recognizing that acute gout flares are a common complication of ULT, gout flares occurring during the first 
year of observation will be considered as a potential SAE if leading to hospitalization and an AE if leading to an 
emergency room visit. Less severe AEs will include all other drug-related events captured 
using diagnostic outpatient claims data during observation. 
 

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Figure 2. 
 
 
 
 

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11.2 Adverse Event (AE) Classifications  
 
11.2.1 Expected AE  
 
The expected adverse effects of allopurinol could be found in the drug Investigator’s Brochure. AEs will be 
collected as described in section 10.1. 
11.2.2 Unexpected AE 
 
Any AE, the specificity, frequency, or severity of which is not consistent with either: 
The known or foreseeable risk of AEs associated with the procedures involved in the research that are 
described in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, the current IRB-approved informed consent document, and other relevant sources of 
information, such as product labeling and package inserts; or the expected natural progression of any 
underlying disease or condition of the participant(s) experiencing the AE. 
 
11.2.3 Related to the research 
 
An event is related to the research if, in the opinion of the investigators, it was more likely than not to be the 
result of the interventions and interactions used in the research or the collection of identifiable private 
information in the research (i.e., there is a reasonable possibility that the event may have been caused by 
participation in the research). 
 
11.2.4 Unrelated to the research 
An AE is unrelated to the research if, in the opinion of the investigators, the AE is not related to the research. 
 
11.2.5 Unanticipated Problems Involving Risks to Participants or Others (Unanticipated Problems)  
Problems that are (1) unexpected (in terms of nature, severity or frequency) given the research procedures 
and the participant population being studied; and (2) suggest that the research places participants or others at 
a greater risk of harm or discomfort related to the research than was previously known or recognized including 
physical, psychological, economic or social harm.  
 
11.3 Relationship to allopurinol 
The determination of the likelihood that allopurinol caused the AE will be assessed by the study team and 
reported as follows 
 
11.3.1 Probably Related to Allopurinol 
 
There is evidence of exposure to the allopurinol 
 
The temporal sequence of the AE onset relative to administration of the allopurinol is reasonable 
 
The AE is more likely explained by the allopurinol than by another cause 
 
11.3.2 Possibly Related to Allopurinol 
 
There is evidence of exposure to allopurinol 
 
The temporal sequence of the AE onset relative to administration of the allopurinol is reasonable 
 
The AE could have been due to another equally likely cause 
 
11.3.3 Unlikely Related to Allopurinol 
 
There is evidence of exposure to the allopurinol 
 
There is another more likely cause of the AE 
 
There is no temporal relationship to allopurinol 
 
 

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12 Investigational Study Sites 
 
Kaiser Permanente Southern California (KPSC), the setting for this study, is an integrated healthcare delivery 
system with over 4 million members. The system is comprised of 14 major medical centers that include over 
200medical offices. Of these offices, we identified 116 ambulatory clinics that prescribed allopurinol during a 
recent one-year period. Few primary care providers or pharmacists practice at multiple clinics and each site 
typically has its own dedicated outpatient pharmacy. 
 
13 Institutional Review Board (IRB)  
 
The study will be conducted under the auspices of the IRB at University of Alabama at Birmingham. Prior to 
initiation of the study, the investigator will forward copies of the protocol, Investigator's curriculum vitae (if 
applicable), study advertisements (if applicable), and all other subject-related documents to be used for the 
study to the IRB for its review and approval. Before initiating a study, the PI will have written and dated full 
approval from the responsible IRB for the protocol. The investigators will also promptly report to the IRB all 
changes in the study, all unanticipated problems involving risks to human subjects or others, and any protocol 
deviations, to eliminate immediate hazards to subjects. 
 
The study site PI and/or staff will not make any changes in the study or study conduct without IRB approval, 
except where necessary to eliminate apparent immediate hazards to the subjects. For minor changes to a 
previously approved protocol during the period covered by the original approval, it may be possible for the PI to 
obtain an expedited review by the IRB as allowed. As part of the IRB requirements for continuing review of 
approved studies, the Investigators will be responsible for submitting periodic progress reports to the IRB 
(based on the Committee's requirements), at intervals appropriate to the degree of subject risk involved but no 
less than once per year. The study PI will provide a final report to the IRB following study completion. 
 
14 Administrative Procedures  
 
14.1 Protocol Amendments 
 
Any change that affects the conduct of the study or significantly alters the protocol will be made in the form of 
an amendment. Any change or addition to this protocol requires a written protocol amendment that must be 
approved by the UAB before implementation. Amendments significantly affecting the safety of participants, the 
scope of the investigation, or the scientific quality of the study require additional approval by the IRB. Examples 
of amendments requiring such approval are: 
 
An increase in drug dosage or duration of participant exposure  
 
A significant change in the study design (e.g. addition of a new immunosuppressive) 
 
An increase in the number of study visits and procedures to which participants are exposed 
 
14.2 Compliance with Law, Audit, and Debarment 
 
The study PI will prepare and maintain complete and accurate study documentation in compliance with GCP 
standards and applicable federal, state, and local laws, rules and regulations. Study documentation will be 
promptly and fully disclosed by the study PI upon request for inspection, copying, review, and audit at 
reasonable times by any regulatory agencies. The study site PI agrees to promptly take any reasonable steps 
that are requested by designated representatives as a result of an audit to cure deficiencies in the study 
documentation. Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will NOT be allowed to conduct or work on this studies.  
 
14.3 Compliance with Financial Disclosure Requirements  
 
The study PI will provide accurate financial information to allow submission of complete and accurate 
certification and disclosure statements as required by US FDA regulations (21 CFR Part 54). This requirement 
also extends to Sub-Investigators. 

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14.4 Confidentiality and Privacy 
 
Participant confidentiality and privacy will be strictly held in trust by the participating investigators, their staff, 
and their interventions. This confidentiality is extended to cover testing of biological samples in addition to the 
clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. All research activities will be conducted in as private a 
setting as possible. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by the reviewing IRB. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored in secure servers at the University of Alabama at Birmingham. This will not include 
the participant’s contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management systems used 
by research staff will be secured and password protected. At the end of the study, all study databases will be 
archived at UAB. 
 
14.5 Study Reports 
 
Annually, the study team will provide to NIAMS copies of all reports related to the study. These include annual 
safety reports filed with the IRB.  
 
14.6 Publication of results 
 
It is mandatory that the first publication will be based on data that has been analyzed as stipulated in the 
protocol. Participating investigators agree not to present data before the full publication, unless formally agreed 
to by all other investigators. 
 
14.7 Changes in study personnel 
 
If there is a change of any personnel listed on human subjects protocol, a new form reflecting the change will 
be completed and forwarded to the IRB along with the new staff member’s signed curriculum vitae, medical 
license (if relevant), and signed financial disclosure statement. 
 
 
 

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