Conditions: Pre-hypertension JNC 7 Stage I Hypertension
Keywords: Pre-hypertension JNC 7 stage I hypertension
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 99
Healthy volunteers: yes

Brief summary:
We propose a novel intervention for reducing BP that could have a preferential impact in patients with hyperuricemia and gout. There is a great need for new anti-hypertensives, particularly among those with gout. The proposed study is novel in its plans to investigate the physiologic mechanisms through which urate contributes to vascular disease and by which ULT may contribute to BP reduction. Also innovative, we will: 1) determine to what extent the described benefit of lowering serum urate extends beyond the adolescent population previously studied into young adults, 2) test whether a urate-lowering approach will benefit individuals that do not yet meet the current definition of hyperuricemia and do not have gout, and 3) begin to explore potential mechanisms for the higher prevalence of hypertension among African-Americans. If successful, this work could translate to the standard of clinical care and to health care recommendations for the population as a whole.

Detailed description:

Arms:
arm 1: Participants will be asked to take 4 weeks of allopurinol (300 mg oral per day), then will crossover (after 2-4 week washout period) and take placebo for an additional 4 weeks. arm 2: Participants will be asked to take 4 weeks of placebo, then will crossover (after 2-4 week washout period) and take allopurinol (300 mg oral per day) for an additional 4 weeks.

Interventions: intervention 1: Allopurinol intervention 2: Placebo
Intervention descriptions: intervention 1: Participants who received allopurinol as urate lowering therapy, at a daily dose of 300 mg once daily by mouth for a 4 week duration. intervention 2: Participants who received placebo tablet (matching Allopurinol 300 mg) daily by mouth for a 4 week duration.

Protocol document:
Prot_SAP_ICF_000.pdf: 
Project 2: The Effects of Urate Lowering Therapy on Inflammation, Endothelial 
Function, and Blood Pressure (NIAMS: CORT) 
 
National Clinical Trial (NCT) Identified Number:  NCT02038179 
Principal Investigator: Kenneth G. Saag, MD, MSc 
IND/IDE Sponsor: University of Alabama at Birmingham 
Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases  
Version Number:  9 
 
Summary of Changes from Previous Version: 
Protocol 
Version 
Affected 
Section(s) 
Summary of Revisions Made
Rationale
9
Appendix 1
Informed Consent Approval Updated 
with Annual Review (April 2018) 
Informed consent was updated 
with Annual Review 
8
1aE, G
Plasma oxypurinol and allopurinol 
levels measurement and increased 
compensation for ambulatory blood 
pressure monitoring (September, 
2017) 
Determine participant compliance
and promote 
recruitment/retention 
7
1aF
Urine urate and urine creatinine 
quantification with banked samples 
(May, 2017) 
Measure fractional excretion of 
urate in urine samples 
6
1aF
Reduction of Washout between 
phases from 4 to 2 weeks (August, 
2016) 
Promote recruitment and increase 
retention 
5
1aG, 7a/b
Removal of stable/low dose calcium 
channel blockers as exclusion criteria 
(October, 2015) 
Expand inclusion criteria and 
promote recruitment 
4
1D, 1aI4,7, 
5, 7a 
Age of recruitment lower limit 
decreased from 19 to 18 (July, 2015) 
Expand inclusion criteria and 
promote recruitment 
3
1D, 5
Title of the study changed to Serum 
Uric acid Reduction to Prevent 
HypERtension Study (SURPHER) 
(April, 2014) 
Promote the recruitment of 
younger study subjects with a 
shorter, more recognizable title.  
2
1D, 1aI4,7, 
5, 7a 
Age of recruitment upper limit 
increased from 35 to 40 (September 
2014) 
Expand inclusion criteria and 
promote recruitment 


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Contents 
TITLE ......................................................................................................................................... Error! Bookmark not defined. 
1. Study Overview ................................................................................................................................................................... 5 
1a. Study Protocol ............................................................................................................................................................... 5 
A. Background ................................................................................................................................................................. 5 
B. SPECIFIC AIMS ............................................................................................................................................................. 8 
C. RESEARCH STRATEGY .................................................................................................................................................. 9 
D. Subject Selection ........................................................................................................................................................ 9 
E. Participant Retention ................................................................................................................................................ 10 
F. Study Procedures ...................................................................................................................................................... 11 
G. Study Drug ................................................................................................................................................................ 22 
H. Data collection and Statistical Analyses (see also Data Analysis plan) ..................................................................... 22 
I. Risks and discomforts ................................................................................................................................................. 25 
J. Potential Benefits....................................................................................................................................................... 27 
K. Withdrawal of Participant Consent and Discontinuation of Study Drug .................................................................. 27 
L. QUALITY and Safety ASSURANCE  ............................................................................................................................. 28 
1b. Schedule of visits and evaluations (see Protocol, Table 3. Schedule of visits and evaluations, page 13) .................. 32 
1c. Figure 3-Study Flow ..................................................................................................................................................... 33 
2. Study Organization and Responsibilities ........................................................................................................................... 34 
2a: Table 5 Study Roster ................................................................................................................................................... 34 
2b. Study Center ............................................................................................................................................................... 34 
2c. UAB CORT Executive Committee ................................................................................................................................. 34 
2d. UAB Pharmacy ............................................................................................................................................................ 35 
3. Training Plan...................................................................................................................................................................... 35 
4. Communications plan ....................................................................................................................................................... 35 
5. Recruitment and Retention Plan ....................................................................................................................................... 36 
5a. Recruitment Plan ......................................................................................................................................................... 36 
5b. Participant Retention .................................................................................................................................................. 37 
6. Study Design Diagram .......................................................................................................... Error! Bookmark not defined. 


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7. Criteria ............................................................................................................................................................................... 39 
7a. Eligibility criteria .......................................................................................................................................................... 39 
7b. Exclusion criteria ......................................................................................................................................................... 39 
8. Informed Consent and HIPAA ........................................................................................................................................... 40 
8a. Overview of the informed consent process ................................................................................................................ 40 
8b. Overview of the Informed consent document ........................................................................................................... 41 
9. UAB Pharmacy ................................................................................................................................................................... 42 
11. Blinding and unblinding .................................................................................................................................................. 43 
12. Study Intervention .......................................................................................................................................................... 43 
13. Participant Evaluations- Study timeline, visits, and procedures ( See Protocol, Section F, for details on the study 
timeline, visit schedules, and procedures) ........................................................................................................................... 43 
14. Data Collection, Study Forms, and Logs .......................................................................................................................... 44 
14a. Table 6. Study Participant Forms- Data will be collected by the study staff at each visit on study forms as 
described and presented below: ...................................................................................................................................... 44 
14b. Table 7. Study Specific Administrative Forms, Logs, and Data Tables ...................................................................... 46 
14c. General Instructions for Completing Forms in REDCap ............................................................................................ 49 
14d. Missing or Incomplete data ...................................................................................................................................... 50 
14e. Retention of Study Documentation .......................................................................................................................... 50 
15. Data Management .......................................................................................................................................................... 50 
15a. External Data ............................................................................................................................................................. 51 
15b. Data Entry ................................................................................................................................................................. 51 
16. Safety Monitoring and Reporting ................................................................................................................................... 51 
17. Study compliance ............................................................................................................................................................ 55 
18. Quality Control and Standard Operating Procedures ..................................................................................................... 55 
18a. Standard Operating Procedures ................................................................................................................................ 55 
18b. Data and Form Control ............................................................................................................................................. 55 
18c. Clinical Monitoring .................................................................................................................................................... 56 
18d. Reports ...................................................................................................................................................................... 57 
19. Study Closeout ................................................................................................................................................................ 57 


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20. Policies ............................................................................................................................................................................ 57 
21. Publications ..................................................................................................................................................................... 58 
22. PROTOCOL Maintenance ................................................................................................................................................ 59 
23. References ...................................................................................................................................................................... 60 
 
 
 


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1. Study Overview 
1a. Study Protocol 
A. Background 
The association between elevated serum urate and increased blood pressure is well established from 
epidemiologic data.1-13 Providing further support for the causal nature of this association, rat models describe 
new onset hypertension soon after serum urate increases following the administration of the uricase inhibitor 
oxonic acid.14 Reduction of nitric oxide levels in endothelial cells and the concurrent activation of the renin-
angiotensin system are mechanisms postulated to mediate this effect.15-17 In humans, endothelial dysfunction 
and increased plasma renin activity have been associated with greater serum urate.16-18 Despite these 
compelling data from physiologic and animal studies, there is a paucity of studies that evaluated the blood 
pressure lowering effects of urate-lowering therapy (ULT) in humans.19 In one early study, significant 
reductions in blood pressure were demonstrated in adolescents with hyperuricemia and hypertension after 
treatment with allopurinol. Similar blood pressure reductions after ULT with the uricosuric drug probenecid 
favors the hypothesis that urate reduction leads to blood pressure lowering independent of xanthine-oxidase 
inhibition.20 The trials, however, were small (n=30 and n=60),19 did not investigate the mechanisms underlying 
the blood pressure reduction, and did not evaluate differential responses to ULT by race/ethnicity. This latter 
point is particularly relevant, since racial/ethnic differences in the pathophysiology of hypertension are 
known.21-24 Translational research studies to define the mechanisms through which urate lowering might 
contribute to hypertension control in humans are scarce. Given the high burden of hyperuricemia and 
hypertension among US adults, particularly among those with gout, understanding the blood pressure 
lowering effects of ULT and its underlying mechanisms has important public health implications. 
 
A.1. Hypertension is a common disorder that impacts patients with hyperuricemia and gout 
Persons with gout and hyperuricemia suffer from hypertension and other cardiovascular outcomes at 
disproportionately greater rates compared with the general population and independently of other 
demographic considerations and traditional cardiovascular risk factors.25-29 Since hyperuricemia is a necessary 
precondition for the development of gout, the demonstration that lowering serum urate confers the 
additional benefit of lowering blood pressure (BP) has special relevance for patients with gout. Hypertension 
affects about 37% of US adults.30 Its health care impact is considerable and is one of the most important risk 
factors for chronic kidney disease, stroke, and myocardial infarction.31-33 In 2003, direct costs associated with 
hypertension exceeded $37 billion.34 Several mechanisms contribute to the etiology of hypertension, including 
the renin-angiotensin-aldosterone hormonal system (RAAS), the sympathetic nervous system, and the 
endothelin-nitric oxide system.35 Approaches to hypertension management are based on pharmacological 
therapy to target these systems: angiotensin-converting enzyme blockers and blockers of the angiotensin 
receptor or the mineralocorticoid receptor for the RAAS, alpha and beta adrenergic blockade for the 
sympathetic nervous system, calcium channel blockers for calcium stimulated peripheral vasoconstriction, and 
diuretics for volume expansion.36 Even after combining these approaches, a large proportion of treated 


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hypertensive patients who are adherent with therapy fail to achieve BP goals.37 There is a clear need to 
develop novel approaches to hypertension control, particularly among persons with gout, and to better 
understand the pathophysiology of hypertension in the setting of hyperuricemia. 
 
A.2. Elevated serum urate is independently linked to hypertension 
The association between levels of serum urate and BP has been described for many decades.1,2,4,6-10,25,26,38-48 
This association has been reported even with serum urate levels within the “normal” range. 49 Animal models 
provided additional support for a causal hypothesis by demonstrating that serum urate increases, induced 
artificially in rats through administration of oxonic acid, lead to glomerular hypertension.14,50-52 These changes 
were fully reversible after the administration of ULT.53-55 Administration of 200 mg of twice daily allopurinol as 
ULT for one month resulted in a significant reduction in casual and ambulatory BP among 30 adolescents with 
hypertension and hyperuricemia when compared with placebo in a crossover trial.19 Although this study had a 
very strong design and good medication compliance, it suffered from small sample size, lack of translational 
outcomes related to the mechanisms mediating the BP lowering, generalizability issues (large proportion of 
obese patients), and inability to explore outcomes by race and ethnicity. Another study evaluated the effect of 
urate lowering with 300 mg of allopurinol daily for 3 months on BP among 48 hyperuricemic adult patients in 
Turkey compared to 21 normouricemic age and sex-matched controls that received no treatment. Decreases 
in systolic BP (SBP), diastolic BP (DBP), C-reactive protein (CRP) levels, and serum urate were noted in the 
hyperuricemic patients but not in the control group.56 Significant study limitations include the lack of an 
adequate placebo-controlled group, BP outcome based on casual measurements, and a limited sample-size. 
An additional study demonstrated that the uricosuric drug probenecid is also effective in reducing BP in 
children and adolescents, supporting the notion that BP reduction is associated with urate-lowering by 
mechanisms other than xanthine-oxidase inhibition.20  We will make further progress in addressing these 
questions by including a larger sample size of mixed race/ethnicity, mechanistic and translational studies of 
the effect of ULT on BP, a careful methodology with a crossover design, and a placebo-control group.  
 
A.3. Serum urate lowering is an innovative approach to BP lowering 
 
A.3.1. Serum urate effects on inflammatory markers and hypertension 
Serum urate concentrations have been associated with levels of inflammatory markers in individuals without 
gout.57,58 Improvements in hypertension control have been associated with a decrease in levels of CRP and 
high sensitivity C-reactive protein (hsCRP).59,60 Given their importance in the pathophysiology of endothelial 
dysfunction and cardiovascular disease, changes in inflammatory markers are important candidate 
mechanisms to better understand the action of urate-lowering on endothelial function and BP. A study done 
in a small number (n=30) of hyperuricemic adults (mean age 54 years) showed a reduction in hsCRP after 
treatment with allopurinol but no correlation with BP change.61 The association between levels of 
inflammatory markers, such as hsCRP, and BP could be tested more directly in a younger population with less 
chronic vascular remodeling.62,63    


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A.3.2. Serum urate effects on endothelial function and hypertension 
Endothelial dysfunction is an independent risk factor for cardiovascular events and a well-described 
predecessor and comorbid factor with hypertension, thus increasing cardiovascular risk.64-66 Rat models have 
shown that hyperuricemia can induce endothelial dysfunction,67 and human studies have described 
improvement in endothelial function after treatment of hyperuricemia with allopurinol.16,18,61 Although prior 
studies suggested that improvements in endothelial function achieved with allopurinol were secondary to 
xanthine oxidase inhibition and not to urate lowering 68, data from our group have found that urate lowering 
by mechanisms other than xanthine-oxidase inhibition was effective at reducing BP in adolescents. 20 A study 
done in a small number of hyperuricemic older adults (n=30) reported that ULT with allopurinol improved 
endothelial function.61 Estimation of endothelial function through ultrasound FMD is the most widely used 
method in children and adults, and is reflective of the integrity of the nitric oxide (NO)-mediated vasodilation 
mechanisms. This tool will allow our group to test whether there is an association between serum urate 
lowering, NO-dependent endothelial function, and BP lowering in young adults.  
 
A.3.3. Decreases in serum urate reduce blood pressure 
 This hypothesis has been tested only in small groups of patients.19,56,61 In all cases, reducing urate levels led to 
statistically significant decreases in BP. Given that hypertension is associated with anatomical changes leading 
to an increase in the wall/lumen ratio of the resistance arteries62,63, we expect that our innovative approach 
will show its maximum effect in a population of young adults in whom chronic vascular remodeling induced by 
hypertension is less likely to have occurred. In addition, we expect our proposed translational study to be 
beneficial even in individuals that do not meet the formal biochemical definition of hyperuricemia (greater or 
equal than 6.8 mg/dL).69 This is supported in part by epidemiological data reporting an increase in the risk of 
developing cardiovascular events associated with increases in serum urate even at serum urate concentrations 
below the threshold of hyperuricemia. 25,26 Our own findings showed an increased risk for incident 
hypertension over 20 years of follow-up for women with serum urate concentrations greater or equal to 4.0 
mg/dL and men with serum urate concentrations greater or equal to 5.0 mg/dL. 49  The results of the proposed 
study could lead to more ambitious goals for ULT in individuals with gout and cardiovascular comorbidities.  
 
A.4. Serum urate levels increase more rapidly over time and the prevalence of hypertension is higher among 
African Americans 
Prior studies examining the BP response to ULT have not examined the question of racial/ethnic differences. It 
is well established that hypertension disproportionately affects African Americans70 and that African 
Americans have differential responses to hypertension therapies.21-24 Our group has reported that young 
African Americans have lower serum urate concentrations than Caucasians after adjustment for clinical and 
demographic factors. 71 However, the risk of developing hyperuricemia over 20 years of follow-up increased 
more rapidly in African American women than in men. Other investigators have reported higher 
concentrations of serum urate in African Americans later in life.72 We hypothesize that BP in African Americans 


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is more sensitive to serum urate and that this may be a mechanism to partially explain the higher prevalence 
of hypertension among African Americans. Given these reported differences, we will investigate differences in 
hsCRP, FMD, and BP in response to ULT. 
 
B. SPECIFIC AIMS 
In the context of a prospective, randomized study with crossover, our specific aims are to:  
 
1. Determine in young adults with pre- or stage I hypertension whether ULT with 300 mg of allopurinol once 
daily over 4 weeks will: 
 
1a. Lower blood pressure 
Hypothesis 1: Four weeks of ULT therapy will induce a greater reduction in ambulatory blood pressure levels 
when compared to four weeks on placebo 
Hypothesis 2: ULT will induce a greater reduction in ambulatory blood pressure levels in African Americans 
when compared with other races/ethnicities. 
 
1b. Induce a change in endothelial function  
Hypothesis 3: Four weeks of ULT will induce an improvement in endothelial function as indexed by flow-
mediated arterial vasodilation (FMD) compared to placebo. 
Hypothesis 4: ULT will induce a greater increase in FMD in African Americans when compared with other 
races/ethnicities. 
 
1c. Induce a change in serum levels of high sensitivity C-reactive protein  
Hypothesis 5: Four weeks of ULT will induce a greater reduction in serum levels of high sensitivity C-reactive 
protein (hsCRP) than placebo. 
Hypothesis 6: ULT will induce a greater reduction in hsCRP in African Americans when compared with other 
races/ethnicities. 
 
 
2. Determine if the impact of ULT on hsCRP, FMD, and blood pressure is associated with the change in 
serum urate achieved  
Hypothesis 7: Changes in hsCRP, FMD, and blood pressure will be associated with the serum urate change 
observed after four weeks of ULT with allopurinol compared to placebo. 
 
We initially aimed to recruit 112 young adults (ages 18-40 years) with pre-hypertension or JNC 7 stage I 
hypertension37 not taking antihypertensive medication. Recruitment includes men, women, African 
Americans, and other races/ethnicities in equal numbers. To increase generalizability and add novelty to the 
research question, participants will not be required to be hyperuricemic, but to have serum urate levels > 5.0 


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mg/dL for men and 4.0 mg/dL for women. Participants will be randomized to receive allopurinol or placebo in 
a four-week study with crossover. This novel translational study will generate knowledge about the 
mechanism by which ULT lowers blood pressure and provide evidence that can be translated into clinical 
practice for patients with gout or high-normal urate levels and other cardiovascular risk factors, including 
hypertension. 
 
C. RESEARCH STRATEGY 
We propose a novel intervention for reducing BP that could have a preferential impact in patients with 
hyperuricemia and gout. There is a great need for new anti-hypertensives, particularly among those with gout. 
The proposed study is novel in its plans to investigate the physiologic mechanisms through which urate 
contributes to vascular disease and by which ULT may contribute to BP reduction. Also innovative, we will: 1) 
determine to what extent the described benefit of lowering serum urate extends beyond the adolescent 
population previously studied into young adults, 2) test whether a urate-lowering approach will benefit 
individuals that do not yet meet the current definition of hyperuricemia and do not have gout, and 3) begin to 
explore potential mechanisms for the higher prevalence of hypertension among African Americans. If 
successful, this work could translate to the standard of clinical care and to health care recommendations for 
the population as a whole.  
 
D. Subject Selection 
Similar to past successful recruitment for hypertension studies at our institution, announcements will be 
placed in the web page www.researchmatch.org , Birmingham metro area local newspapers, UAB publications 
(e.g. UAB reporter, distributed to all UAB campus), websites, and flyers that will be posted on UAB campus. 
Given the inclusion age range with this trial, participants will be also be recruited utilizing social media ads 
(e.g., Spotify, Facebook, and Instagram). The flyers and ads will request adults, ages 18-40, that are interested 
in participating in a clinical study for hypertension, to call the recruitment coordinating center. Additionally, 
participants will also be recruited directly from the UAB 700 physician outpatient care facility, The Kirklin 
Clinic, through brochures distributed to physicians and from the Hypertension clinic. UAB is a national leader 
in recruitment of African American study participants for clinical trials and large cohort studies.  
 
We expect a screen fail rate of ≥66%, thus we anticipate screening roughly 3 or more persons by BP 
measurements and focused history to find one eligible participant for laboratory screening. From our previous 
epidemiological work with a population of similar age, we estimate that 30% of adults, 18-40 years of age, will 
have hyperuricemia as defined by a level of > 6.8 mg/dL.73 Since this information was obtained in 1986, and 
the trends for obesity and other conditions known to elevate serum urate have increased, it is likely that over 
50% of the population of men and women will have serum urate levels > 5.0 and > 4.0 mg/dL, respectively. 
Also, based on NHANES 1999-2006 data, 53% of men and women age 20 to 35 years with pre-hypertension or 
stage 1 hypertension have serum urate ≥ 5.0 mg/dL (≥4.0 mg/dL for women). When considering this and the 
past experience of the UAB Hypertension group in screening, we anticipate that about 50% of the laboratory-


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screened subjects will be ineligible. In conclusion, we will need to perform screening laboratory assessments 
in 236 individuals. We have carefully accounted for these recruitment challenges in our study design and 
budget and anticipate enrolling 30 individuals per year. 
 
*Study was amended on  10/2014 and 07/2015 to allow inclusion of individuals ages 36-40 and 18, respectively. 
**Study was amended on 10/2015 to allow of inclusion of individuals on stable doses of calcium channel blockers. 
 
E. Participant Retention 
Retention of participants is central to the internal validity of the proposed study and will be an extraordinarily 
high priority.  To increase retention, we hire engaging, attentive, and responsive staff and provide participants 
with as much flexibility as we can to complete their study visits.  Other features used to promote high 
retention rates will include tracking systems and collection of information (i.e., names and telephone 
numbers) for two friends/family members who do not live with the study participant but would know where 
to find them. Once enrolled, a proactive plan for retention will be implemented that includes in person visits 
Table 1. Enrollment criteria. 
Inclusion criteria 
Pre-hypertension or stage I hypertension, defined as the following after the mean of two clinic 
measurements: 
-Systolic blood pressure (SBP) ≥ 120 and <160 or; 
-Diastolic blood pressure (DBP) ≥ 80 and < 100 
Serum urate ≥ 5.0 mg/dL for men or ≥ 4.0 mg/dL for women 
Age 18-40* 
Exclusion criteria 
Any current pharmacological treatment for hypertension, including diuretics** 
Estimated glomerular filtration rate < 60 mL/min/1.73m2 
Current use of any urate-lowering therapy or statins 
Prior diagnosis of gout or past use of urate-lowering therapy for gout 
Prior diagnosis of diabetes  
Pregnancy, or recent delivery or last trimester pregnancy loss more recent than 3 months 
Active smokers 
Immune-suppressed individuals including transplant recipients or current use of azathioprine. 
Leucopenia with absolute white cell count < 3000 /mL, anemia with hemoglobin < 12 g/dL, or 
thrombocytopenia with platelet count  < 150,000/mL 
Abnormal liver function tests (AST > 40 Units/L, ALT > 58 Units/L, Alkaline Phosphatase > 117 Units/L)  
Individuals of Han Chinese or Thai descent with HLAB5801 genetic phenotype 
Serious medical condition that at investigator’s judgment precludes utilization of a fixed dose of 
allopurinol 


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every 4 weeks, and phone calls in between each visit. The following major principles and commonly used 
strategies to maximize retention and minimize loss to follow-up will be employed during the trial: 
 Stressing the idea that participants have an active role in the research and are part of the research 
team 
 Enhancing participant’s understanding of the study’s mission and the protocol 
 Stressing that retention efforts begin with recruitment and are an ongoing process 
 Building patient relations and patient satisfaction, with the study staff taking a central role on this 
effort 
 Emphasizing the importance of congeniality, respectfulness and friendliness in interactions with 
participants 
 Actively discuss with patients any questions and concerns pertaining to their condition 
 Identifying potential problems and key retention factors and developing intervention strategies 
regarding retention 
 Assessing each patient’s drop out potential and intervening as needed to keep patients interested in 
continuing to participate 
 
Subjects will be paid $25 for each completed clinic visit and flow mediated dilation procedure. In 
addition, subjects will receive $100 for each complete 24-hour ambulatory blood pressure recording 
session. Payments will be made at the completion of each study visit’s procedures. Should subjects 
withdraw from the study, they will be paid for the completed visits up to the date of withdrawal. 
 
F. Study Procedures 
Recruitment is planned for commencement in month 9 of the first grant year and continue through the middle 
of year 5 of the funding period pending a no cost extension which would augment the proposed timeline. 
Participants will be randomized following confirmation of eligibility.  Enrollment and participant follow-up will 
continue until all participants were enrolled. Data entry and quality control will occur concurrently with 
participant enrollment and follow-up.   
 
 
 


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Table 2. Projected Timeline of Research Tasks 
 
 
 
All study visits and procedures will be performed at the University of Alabama at Birmingham in facilities 
dedicated to clinical research studies. 
 Screening visit (Visit 1) 
The first visit will take about 1-2 hours to complete. Men and women within the first 7 days of the menstrual 
cycle will be re-evaluated for a qualifying BP value, and if within the study range, invited to proceed with 
informed consent and randomization on the same day or as soon as convenient for them. During the first visit, 
the following procedures will be performed, and information will be obtained to determine eligibility to 
continue in this research study: 
• Review inclusion/exclusion criteria  
• Informed consent  
• Focused medical history  
• Medication review  
• Screening Visit Laboratory  
o CBC 
o Hemoglobin 
 
o Liver tests* 
 
o Pregnancy test† 
o Cotinine test  
o Serum creatinine 
 
o Serum urate  
7/12
1/13
7/13
1/14
7/14
1/15
7/15
1/16
7/16
1/17
12/12
6/13
12/13
6/14
12/14
6/15
12/15
6/16
12/16
6/17
Obtain IRB approvals 
Develop patient screening tools
Develop data collection tools 
Testing, screening and 
intervention
  Pilot testing of instruments
  Screening and intervention
Data management
  Database construction
  Data entry
  Data analysis
Report preparation/ 
dissemination
Year 1
Year 2
Year 3
Year 4
Year 5
Tasks (start/stop dates)


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 Administration of single-blind run-in placebo – 2-4 weeks duration (2 week minimum, but longer duration 
for pre-menopausal women).  
Screening visits and study entry criteria assessment. At the screening visit, the study objectives will be 
explained to potential participants and once interest in participating is confirmed, they will be offered an 
initial informed consent for the screening evaluation.  Three BP measurements will be performed following 
the recommendations published in the report of the Joint National Committee on Hypertension 37 participants 
will sit quietly for at least five minutes with feet on the floor and arms supported at heart level, appropriate 
cuff sizes will be used, restrictions on alcohol and caffeine consumption for a specified time period prior to 
obtaining BP measurements will be imposed, and appropriate maintenance of all equipment will be 
performed. We will use automated BP devices for measurement of clinic BP (Omron, Bannockburn, IL, Model 
HEM-705CP).  If the average of the second and third systolic and diastolic BP measurements taken 3 minutes 
apart is found to be within the pre-hypertension or stage I hypertension range (SBP ≥ 120 and <160 mmHg or 
DBP ≥ 80 and < 100 mmHg) the participant will be allowed to continue with the full screening procedures to 
assess for study entry criteria (Table 3). Before randomization, participants will participate in a single blind 
run-in period lasting 2-4 weeks during which they will receive a 21-45 day supply of the daily dose of placebo.   
 
Focused history and physical examination: Information collected will include date of birth, self-reported 
race/ethnicity (defined as in previous studies investigating its role in rheumatic diseases)74, medical conditions 
that might preclude study participation including current or recent infections and gout, medication history 
(including use of aspirin, gout medications, losartan, fenofibrate), duration of hypertension, weight, and 
height. Gynecological history will include last menstrual date. This information will help assess the balanced 
allocation of participants during randomization, estimate glomerular filtration rate, establish phase of 
menstrual cycle for women, and identify exclusion criteria.  
 
Laboratory: Serum urate, transaminases, alkaline phosphatase, serum creatinine, complete blood count, 
bilirubin, cotinine test, and pregnancy test for women. Blood samples will be analyzed at UAB lab facilities in 
the Kirklin clinic. Pregnancy and cotinine tests will be performed by trained personnel at the time of visit using 
urine samples. All lab samples will be discarded if the participant is deemed not eligible for the study. 
Informed Consent 
The process of informed consent will be carried out by one of the study coordinators or research assistants at 
the beginning of the screening in-person study visit. During the screening visit, the consent form will be read 
by the study participant and then each section will be explained by the research study coordinator obtaining 
consent. The participant will be given as much time as they need to read and ask questions about the consent 
form. The individual will be informed that he/she is not obligated to participate in the study and that it is 
strictly voluntary. The informed consent process will ensure that there is no penalty for not participating in a 
clinical trial and that treatment will not be compromised if individuals do not participate or if they cease 
participation at any time. 
 


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By signing the consent form, the participant authorizes the use of their personal health information, that they 
understand the study and its benefits and risks, and agree to all other aspects of the study outlined in the 
form. It allows the participant the opportunity to decide whether they want to participate in a study. During 
this process, individuals will be informed of all aspects of the study so that they can make an informed 
decision. Participants will then confirm their willingness to participate in the research study by signing the 
Informed Consent form.  
 
After the participant has signed the consent form, the study coordinator/research assistant conducting the 
visit must countersign and date the Informed Consent Document, along with a third party witness to the 
consent. A signed version of the consent form will be kept by the study staff in the study binder and an 
additional copy of the consent form will also be given to the participant to keep. 
 
The informed consent document contains the following: 
 Disclosure of relevant information to prospective participants about the research; 
 The participant’s comprehension of the information; 
 The participant’s voluntary agreement to participate in a research study without coercion or undue 
influence. 
 An optional participation in future research by allowing samples to be biobanked. 
 Complete disclosure of any appropriate alternative procedures and their risks and benefits 
 Disclosure of the extent of confidentiality that will be maintained 
 Statement of compensation and/or medical treatment available if injury occurs 
 Name, address, and telephone number of the Principal Investigator 
 
 
If there is a change in any of the study procedures that may affect the participant, the informed consent 
document will be revised and approved by the IRB. Any participants active within the study prior to a change 
in procedures will sign the amended consent form. Per NIH policy, the signed consent forms will be kept as 
part of the study record for at least 7 years after completion of the study. Participants can withdraw their 
consent at any time by informing the study coordinator. Additionally, all participants will be provided with 
descriptions of allopurinol hypersensitivity induced rashes and specific instructions to contact the study staff 
immediately should a rash appear.  
The UAB study staff will: 
 Provide participants with adequate information concerning the study procedures and scope 
 Provide adequate opportunity for the participant to consider all available options 
 Respond to the participant’s questions and concerns 
 Ensure that each participant understands all information provided 
 Confirm acceptable birth control is being used 
 Obtain the participant’s written voluntary consent to participate 


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 Sign the consent form as the person obtaining consent and functioning as a third-party witnesses 
 Provide participants with a copy of the consent form 
 Keep the signed form in the participant’s binder 
 Attempt to  schedule an early end of study assessment in the case of study drug discontinuation 
 
 
 
 
Table 3. Schedule of visits and evaluations  
Treatment Phase
 
Visit description /  
Study Procedures 
 
Screening 
 
Run-in 
period 
 
Phase 1  
 
Washout 
period 
 
Phase 2 (crossover) 
Weeks 
Male participant 
(original) 
0
 
1-2
 
3
 
4
5
6
7-10
11
12
13
14
 
Male participant 
(revised)†† 
0
1-2
3
4
5
6
7-8
9
10
11
12
Female participant 
(original) 
0
1-4
5
6
7
8
9-12
13
14
15
16
Female participant
(revised)†† 
0
1-4
5
6
7
8
9-10
11
12
13
14
Visit 1
Visit 2
Visit 
3 
Visit 
4 
Visit 
5(final) 
Informed consent
X
Pill count
X
X
X
X
X
X
X
X
Adverse events 
reporting 
X
X
X
X
X
X
X
Physical exam
X
X**
X**
X**
X**
BP screening
X
X
X
X
X
Focused  medical 
history 
X
Updated medical 
history 
X
X
X
X
Randomization 
X
24-hr ABPM
X
X
X
X
FMD
X
X
X
X
Blood sample
X
X
X
X
X
 CBC
X
X
X
X
X


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 Liver tests*
X
X
X
X
X
 Pregnancy test†
X
X
X
X
X
 Serum creatinine
X
X
X
X
X
 Serum urate
X
X
X
X
X
 hsCRP
X
X
X
X
 Cotinine
X
X
X
X
X
Serum banking§
X
X
X
X
Contact check in
X
X
2X
X
X
 
Visit 1: 
 
 Informed Consent 
 Blood pressure 
 Physical Exam 
 Focused medical history 
 Blood sample 
 Urine sample 
 CBC 
 Liver tests-Liver tests are alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase 
 Serum creatinine 
 Serum urate 
 Pregnancy test† 
 Cotinine test 
 Dispense placebo run-in if all qualifications are met 
 
Visit 2 will occur 2 weeks following the screening procedures, signing of the consent form, and 2 week long (±3 
days) placebo run-in period in the UAB Hypertension Clinic. For pre-menopausal women, run-in was timed so 
the end of the run-in will coincide with the onset of their menses and no later than day 7 of the next cycle for 
standardized measurements of FMD, thus run-in was typically of a 28-day duration. 75 Compliance with 
placebo run-in will be assessed through pill count. Before and after each intervention phase, the markers for 
PE-physical examination, BP-blood pressure, ABPM-ambulatory blood pressure monitoring, FMD-flow mediated dilation of the 
brachial artery, hsCRP-highly sensitive C-reactive protein 
*Liver tests are alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. At screening only, a bilirubin test 
was performed.  
** Physical exams will be conducted following screening visit only in cases where rash has been reported 
†Only in women 
††Revised timeline corresponded to reduction in washout phase from 4 to 2 weeks for male participants and female participants 
depending on menstrual cycle. 
§Sera and whole blood (for DNA extraction) will be stored. 


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the study primary (serum urate, hsCRP, endothelial function as measured by FMD) and secondary outcomes 
(ambulatory BP monitoring) will be collected. Other data will be collected as needed for safety monitoring.  
 
Women will need to be evaluated between days 1-7 of their menstrual cycles for study visits. This will be done 
to make FMD results comparable among women, and between women and men, since hormone levels have 
been shown to affect FMD results.75 Participants will be entered into the trial and will be randomized to 
receive allopurinol or placebo. Neither the participant nor the Principal Investigator will know the drug 
assignment. This will begin Phase 1 (i.e., the first four weeks of the intervention). Randomization lists, 
stratified by race and gender, will be generated using a random number generator prior to the initiation of the 
study (i.e., in the first six months of study funding).  Randomization will occur in blocks of size 2, 4, or 8 and 
will be stratified on sex and race/ethnicity to ensure order of treatment administration is balanced by sex and 
race. Randomization will occur using a random number generator. The sequence of treatment assignment will 
be determined by the random number generator and held by the pharmacist creating treatment arm study pill 
over-encapsulation. The pharmacist will maintain the master list and securely store the randomization files.  
 
Visit 2: 
 
 Blood pressure 
 Updated medical history 
 Blood sample 
 Urine sample 
 24-hr ABPM 
 FMD 
 CBC 
 Liver tests-Liver tests are alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase 
 Serum creatinine 
 Serum urate 
 hsCRP 
 Serum banking 
 Pregnancy test† 
 Cotinine test 
 Pill count from run-in 
 Potential adverse events 
o Assess any gastrointestinal symptoms, rash, or any other untoward effect 
o If potential untoward effect, study investigator will follow-up with subject 


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 Dispense 4 week course of allopurinol or placebo based on treatment assignment following return of 
the ABPM monitor 
 
Interim visit check-in: 
Between study visits, there will be four contact check-ins to encourage study compliance. These will be made 
by the study coordinator or research assistant. Additionally the study coordinator and/or research associate 
will assess the following during the call.  
 Pill count 
 Potential adverse events 
o Assess any gastrointestinal symptoms, rash, or any other untoward effect 
o If potential untoward effect, study investigator will follow-up with subject 
o If no untoward effects, subject will be encouraged to continue medication 
Visit 3: 
 Blood pressure 
 Physical exam (head/neck/heart/abdomen) 
 Updated medical history 
 24-hr ABPM 
 FMD 
 Blood sample 
 Urine sample 
 CBC 
 Liver tests-Liver tests are alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase 
 Serum creatinine 
 Serum urate 
 hsCRP 
 Serum banking 
 Pregnancy test† 
 Cotinine test 
 Pill count 
 Potential adverse events 
o Assess any gastrointestinal symptoms, rash, or any other untoward effect 
o If potential untoward effect, study investigator will follow-up with subject 
 
Following Visit 3, participants will begin a “wash-out period” before crossing over to the alternate treatment 
assignment. The wash-out period will last one month. Allopurinol has a half-life of 1-2 hours before being 
converted to oxypurinol, which has a half-life of 18 to 30 hours. 2 Thus, thirty days from the last allopurinol 


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dose is an adequate wash-out period and no persistent effects from the drug should be expected at this point. 
In fact, a subsequent amendment to the protocol (approved by IRB on August 2016) allowed the duration of 
washout for male participants and some female participants without a regular menstrual cycle (e.g., 
hysterectomy) to be shortened to 2 weeks. This approach is supported by interventional studies by our co-
Investigator Dr. Daniel Feig and others investigating the effect of allopurinol on cardiovascular disease. 
Additionally during the washout period we will continue our phone check-ins with participants. These phone 
calls will be made by the study coordinator or research assistant, will take about 10-15 minutes each, and will 
assess any potential adverse events the participants may be experiencing.  
 
Visit 4  
 Blood pressure 
 Physical exam (head/neck/heart/abdomen) 
 Updated medical history 
 Blood sample 
 Urine sample 
 24-hr ABPM 
 FMD 
 CBC 
 Liver tests-Liver tests are alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase 
 Serum creatinine 
 Serum urate 
 hsCRP 
 Serum banking 
 Pregnancy test† 
 Cotinine test 
 Potential adverse events 
o Assess any gastrointestinal symptoms, rash, or any other untoward effect 
o If potential untoward effect, study investigator will follow-up with subject 
 Dispense 4 week course of allopurinol or placebo based on treatment assignment following return of 
the ABPM monitor 
 
Interim visit phone call-in : 
Between study visits, there will be four follow-up phone calls to encourage study compliance. These phone 
calls will be made by the study coordinator or research assistant and will take about 10-15 minutes each. 
Additionally the study coordinator and/or research associate will assess the following during the call.  
 Pill count 


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 Potential adverse events 
o Assess any gastrointestinal symptoms, rash, or any other untoward effect 
o If potential untoward effect, study investigator will follow-up with subject 
o If no untoward effects, subject will be encouraged to continue medication 
Visit 5: 
 Blood pressure 
 Updated medical history 
 Blood sample 
 Urine sample 
 24-hr ABPM 
 FMD 
 CBC 
 Liver tests-Liver tests are alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase 
 Serum creatinine 
 Serum urate 
 hsCRP 
 Serum banking 
 Pregnancy test† 
 Cotinine test 
 Pill count 
 Potential adverse events 
o Assess any gastrointestinal symptoms, rash, or any other untoward effect 
o If potential untoward effect, study investigator will follow-up with subject 
 
 
24-hour Ambulatory Blood Pressure Measurements (ABPM) 
 
All patients had 24-hour ABPM evaluations with an automated, noninvasive, oscillometric device (Spacelabs 
Healthcare, Inc., 35301 SE Center Street, Snoqualmie, WA 98065, U.S.A). An appropriate sized cuff is used with 
a cuff bladder encircling at least 80% of the arm, according to guidelines.37 Participants will be receive careful 
instructions at each visit about the appropriate use of the device, including a handout that contains 
information about error codes that may occur and possible ways to resolve them. They will be asked to wear 
the device as much as possible within the 24 hour recording period. Participants will be encouraged to contact 
study staff immediately should they not any abnormalities in cuff or monitor function (e.g., cuff failure to 
inflate fully, repeat error codes). The first measurement will be obtained at the end of the clinic visit to ensure 
proper fit and function.  ABPM monitors will be outfitted with new AA batteries for each participant and will 


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be programmed to obtain blood pressure recordings every 20 minutes for the daytime (awake) and every 30 
minutes for the nighttime (asleep) for a 24-hour period. For the purposes of this study, daytime will be defined 
as 06:00-21:59 and nighttime will be defined as 22:00-05:59. Compliant 24-hour ABPM will be defined as a 
minimum of 14 successful daytime recordings and 5 nighttime readings. Those with less than these minimal 
thresholds will be asked to repeat the test. Should a non-compliant ABPM be unattainable, missing data will 
be handled with multiple imputation analysis.  Normal ABP is defined as mean 24-hour BP <130/80 mmHg 
with a daytime (awake) BP of <135/80 mmHg and a nighttime (asleep) BP of <120/70 mmHg by ABPM 
according to guidelines. 36,37. Average ABPM will be weighted for the proportion of daytime and nighttime 
blood pressure readings. At the time of data analysis, manual readings will be discarded when there is a 
concurrent automated reading within the same 5-minute period. In instances where the ABPM was recorded 
outside of the appropriate time (e.g., the participant did not follow instructions as to the timing of the test), 
each ABPM will be evaluated by two data analysts blinded to condition to determine    
 
Flow-Mediated Dilation analyses (FMD) 
 
At visits 2, 3, 4, and 5, vascular endothelial function is measured by flow-mediated dilation (FMD) of the 
brachial artery performed by a study investigator who is blinded to treatment assignment. In women 
participants, FMD is performed within the first 7 days after onset of menstrual cycle to avoid known cyclic 
variations in FMD. 76,77 after an 8-hour fasting period, FMD is measured by high-resolution ultrasound with an 
11-3 MHz linear-array probe (Philips HP Agilent Technologies, Sonos 5500, Andover, MA, 01810). Prior to 
testing, participants were asked to rest for 10 minutes in the supine position in a quiet room. Ultrasound of 
the brachial artery was taken at approximately 5 cm proximal from the elbow in longitudinal section on the 
right arm. The probe was maintained in a fixed position at a fixed angle, and baseline artery diameter is 
recorded for 1 minute. Blood flow was estimated by pulsed Doppler velocity, and baseline artery diameter was 
assessed with simultaneous ECG recording for baseline assessment at every study visit. Reactive hyperemia 
was induced by inflating a BP cuff around the forearm to 50 mmHg above resting systolic BP. The cuff 
remained inflated for a five-minute period, and then was rapidly deflated. The longitudinal image of the 
brachial artery was recorded continuously from 30 seconds before to 3 minutes after cuff deflation. A mid-
artery pulsed Doppler signal was obtained at an < 60° angle upon immediate cuff release and no later than 15 
seconds after cuff deflation to assess hyperemic velocity parameters. Ultrasound images were recorded 30 
seconds before cuff deflation, and 3 minutes after cuff deflation. The five largest diameters after deflation 
were averaged, and FMD was expressed as the percentage increase in diameter from the baseline average 
measurement to the peak average dilation. Brachial arterial flow-mediated dilation related parameters were 
analyzed with edge detection software and Doppler flow analyzer (Vascular Research Tools 5 Software, 
Medical Imaging Applications, LLC, Coralville, IA). The calculation of FMD as a percentage change utilizes the 
peak diameter in response to reactive hyperemia in relation to the baseline diameter, and was calculated 
utilizing the following equation: Flow mediated dilation (%) = (Peak diameter-Baseline diameter)/Baseline 
diameter, and when multiplied by 100, FMD is expressed as a percent change in vessel caliber. An increase in 


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the % change is considered positive. Mean and standard deviations were calculated at the beginning and end 
of allopurinol and placebo phases for FMD. 
 
G. Study Drug 
The subjects will be randomized to receive allopurinol as ULT, at a daily dose of 300 mg once daily by mouth. 
Because of the crossover design of this study, all subjects who complete the protocol will be exposed to the 
active compound at some point in the study. Allopurinol will be purchased in bulk quantity through the UAB 
Investigational Drugs Pharmacy, which will also oversee the process of over-encapsulation with cellulose of 
the active medication and placebos, handle medication storage, distribution, and assignment of randomization 
sequence.  The centralized management of the medication will allow maintenance of a double blind trial. A 
research nurse will contact participants approximately a week after the initiation of both intervention phases 
to ask if the participant has any medication concerns and to encourage compliance. Adherence to the 
medication will be recorded by pill counts at the follow-up study visits and consumption of at least 80% will be 
required to consider the participant compliant. A non-compliant participant will continue in the study and 
enter analyses as mandated by the intention-to-treat study design. At the end of the study, biobanked plasma 
samples (1.0-1.5 mL) will be evaluated for levels of allopurinol and the metabolite, oxypurinol, to determine 
an objective measure of study drug adherence. An amendment approved by the UAB IRB in September of  
2017 allowed for testing oxypurinol and allopurinol prospectively on all participants enrolled (previously 
restricted to biobanked samples). 
 
Individuals with transaminases or alkaline phosphatase values more than double the upper limit of normal will 
be excluded. The initial plan was to exclude subjects taking hypertension medications (including diuretics, that 
some participants do not regard as hypertension treatments), as this will have an unpredictable effect on the 
study outcomes. An amendment approved in 10/2015 allowed later for inclusion of individuals in stable doses 
of calcium channel blockers. 
 
As allopurinol is classified as FDA class C during pregnancy pregnant women will not be allowed in the study. 
Women with recent deliveries or third trimester pregnancy losses in the previous 3 months will be excluded 
because of unpredictable effects on FMD. A special question about the use of azathioprine will be included, 
since this can have a severe interaction with allopurinol.78 Participants with serious medical conditions that in 
the investigator’s judgment pose an unacceptable risk for exposure to a fixed dose of allopurinol (e.g. 
advanced heart failure, advanced liver disease or cirrhosis) will also be excluded. 
 
H. Data collection and Statistical Analyses (see also Data Analysis plan) 
Measures of central tendency (sample mean, sample media) and dispersion (sample variance, sample 
standard deviation) will be calculated for all outcome variables  (e.g., hsCRP, endothelial function, and BP on 
ABPM) and covariates (e.g. age, race, etc.). For outcome variables, distributional properties will be evaluated 
using histograms and normal probability plots.  When the assumption of normality is questionable, outcome 


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variable tranformations will be examined to determine if the transformed variables approximate a normal 
distribution.  will be transformed to achieve normality.  Of the main study measures, we anticipate the 
distribution of hsCRP to be highly skewed. Consistent with prior studies, we will log transform hsCRP values for 
analysis.  Possible outlying or inconsistent values will be detected and explored 
 
Aim 1a: ULT and change in BP. The change in the average weighted 24-hour mean SBP and DBP will be 
compared among participants during the active treatment and placebo phases by paired t-test analysis.  
 
Aim 1b: ULT and change in FMD. The change in the FMD will be compared among participants during the 
active treatment and placebo phases by paired t-test analysis.  
 
Aim 1c: ULT and change in hsCRP. For each participant, we will first calculate the change in log transformed 
hsCRP from the beginning to the end of each crossover phase.  The lack of an effect for the treatment 
sequence on the relative treatment responses will be confirmed using a treatment by sequence interaction 
term. Next, the within-participant change in hsCRP will be compared during the allopurinol treatment and 
placebo phases by paired t-test analysis.  
 
Assessing differential treatment effects by race/ethnicity 
Comparison in the mean change achieved in the allopurinol treatment minus placebo phase between African 
Americans and other races/ethnicities will be performed initially using a t-test for independent samples. If 
differences are identified in the distribution of covariates, then the analysis will be completed with analysis of 
variance. 
 
Assessing change in serum urate on change in hsCRP, FMD, and blood pressure 
For this aim, the independent variable is change in serum urate and the outcome is change in hsCRP, FMD, 
and BP.  First, participant factors associated with a significant change in serum urate will be identified using 
unadjusted age, race/ethnicity, and gender adjusted linear regression models. The correlation between 
change in serum urate with change in hsCRP, FMD, and SBP and DBP will be calculated using Spearman 
correlation coefficients. Using linear regression models, the association between changes in serum urate with 
changes in levels of each outcome, separately, will be determined.  Models will include initial adjustment for 
age, gender, and race/ethnicity with subsequent models adjusted for other potential confounders (e.g. 
estimated glomerular filtration rate). In analyzing the association of change in serum urate on change in BP, 
we will additionally adjust for hsCRP and FMD, individually and together. The reduction in the association (i.e. 
beta coefficient) between change in serum urate and change in BP from before to after adjustment for these 
variables will provide insight into the degree that these mechanisms mediate the relation between ULT and BP 
reduction. 
 


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With 56 African Americans and 56 other races/ethnicities, we will be able to detect a difference in the increase 
of FMD of 1.48% for allopurinol versus placebo in African Americans compared to other participants. 
 
The primary analyses will be on an intent-to-treat basis. All statistical analysis will be performed using SAS 
statistical software (SAS, Cary, NC) by analysts masked to randomization assignment. All study related 
information will be entered into a study database.  This database will be maintained on a secure computer 
with access limited to study personnel only.   
 
Research information that identifies subjects will be shared with the UAB Institutional Review Board (IRB) and 
others who are responsible for ensuring compliance with laws and regulations related to research, including 
the U.S. Food and Drug Administration (FDA); and the Office for Humans Research Protections (OHRP). The 
results of this study may be published in scientific journals or presented at medical meetings, but study 
participants identity will remain confidential. 
 
 
 
Calculation of sample size. 
Power and sample size for aim 1c 
In a prior study, a standard deviation of 8.5 mmHg for mean SBP by 24-hour ABPM in young and normotensive 
patients studied over 4 months has been reported.81 Using this standard deviation and similar assumptions as 
outlined above (alpha of 0.05 and a correlation of 10% between pairs of SBP measurements for each subject), 
we will have 90% statistical power to detect a 3.7 mmHg difference in the change in SBP with allopurinol 
treatment versus placebo.  An intra-individual variation (standard deviation) of the difference between two 
values on a same patient in DBP by ABPM of 6.3 mmHg has been reported previously by an international 
consensus conference.82 Using this standard deviation and 90% statistical power, we will be able to detect a 
change in DBP of 2.0 mmHg for treatment with allopurinol versus placebo. For comparing African Americans 
versus participants of other race/ethnicities (assuming 46 participants in each group), we will have 90% 
statistical power to detect a difference in SBP and DBP of 5.8 mmHg and 4.3 mmHg, respectively. 
 
Power and sample size for aim 1b.  
The standard deviation of the difference between two values obtained in the same patient has been reported 
to be 2.5%. 80 With an alpha of 0.05, statistical power of 0.90, assuming a 10% within-period correlation of 
change in FMD and the sample size of 93 individuals calculated for hsCRP, we will be able to detect a change in 
FMD of 1.15% between allopurinol treatment and placebo. With 46 African American s and 46 other 
races/ethnicities, we will be able to detect a difference in the increase of FMD of 1.48% for allopurinol versus 
placebo in African Americans compared to other participants. 
 
Power and sample size for aim 1a. 


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As mentioned above, it is anticipated that the distribution for hsCRP will be skewed, and thus, we will log 
transform hsCRP.  The sample size for the study is based on having 90% statistical power, assuming a two-
tailed alpha error of 5% and a within person correlation of log transformed hsCRP between measurements of 
10%.  The intra-person standard deviation for log transformed hsCRP has been reported to be 0.52 log mg/L 
on serial measurements extending into a one year period.79 To detect a difference in log transformed hsCRP of 
0.25 (log mg/L) will require a sample size of 93 participants with complete hsCRP measurements (i.e., from 
baseline and closeout visits for each of the study phases).  This is equivalent to a net reduction of hsCRP of 
25% (e.g., from 2 mg/L to 1.5 mg/L or from 1 mg/L to 0.75 mg/L).  This difference was chosen as it represents 
approximately half of one standard deviation in log-transformed hsCRP and is a meaningful decline to be 
observed over a four week period.  Although we expect minimal loss to follow-up, we have taken the 
conservative step of increasing the sample size to account for 20% of participants not having complete data.  
Thus, we will recruit and randomize 112 participants for the proposed trial. For comparing differences in the 
net reduction in hsCRP for African Americans in comparison to other races/ethnicities, with 46 African 
Americans and 46 other races/ethnicities, we will have 90% statistical power to detect a differential reduction 
in log transformed hsCRP of 32 log mg/L (e.g., a 10 log mg/L reduction in whites and a 42 log mg/L reduction in 
African Americans).   
 
 
Table 4. Statistical Power for Aim 2 
Proportion of Outcome 
Variance Explained by 
Control Variables 
Incremental increases in R2 due to the addition of change in serum urate in 
the presence of the control variables 
.05 
.075 
.10 
.10 
.64 
.82 
.92 
.20 
.69 
.87 
.95 
.30 
.75 
.91 
.97 
 
 
Power and sample size for aim 2  
Table 4 shows the statistical power to detect various incremental increases in R2 due to the addition of change 
in serum urate in various regression models.  For example, 92 individuals will provide 87% power using a Type 
I error rate of 0.05 to detect an increase of 7.5% in R2 by adding change in serum urate to a regression model 
that already explains 20% of the variability in the change in BP with 5 control variables (age, sex, 
race/ethnicity, body mass-index, glomerular filtration rate).  Due to the nature of multivariable linear 
regression, identical results hold for changes in hsCRP and FMD. 
 
I. Risks and discomforts 
 


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1.Risks associated with phlebotomy  
Subjects may experience pain from the needle used during phlebotomy, as well as possible bruising and 
soreness at the phlebotomy site. 
 
2.Twenty-four hour ambulatory blood pressure monitoring 
The procedure may cause some mild discomfort during cuff inflation, but otherwise has no associated risk. 
 
3.Ultrasonographic measurement of flow-mediated dilation (FMD) of the brachial artery  
The procedure requires the subject to be supine for approximately 20 minutes. The inflation of the blood 
pressure cuff for 5 minutes may cause arm discomfort.  
 
4.Risks associated with allopurinol 
Allopurinol is a competitive xanthine oxidase inhibitor used as a urate-lowering agent in patients with gout 
and for secondary hyperuricemia associated with chemotherapy. The risks of therapy with allopurinol include 
cutaneous reactions, onset of gout, diarrhea, nausea, and elevation of alkaline phosphatase or transaminases.  
Most of these side effects are mild and reversible, but severe cutaneous reaction of the Stevens-Johnson type 
and bone marrow suppression, events that are reported in less than 1% of allopurinol recipients, may not be 
reversible.  
 
Allopurinol hypersensitivity syndrome (AHS) is a very rare (occurs in less than 1 in 1000 patients), life 
threatening idiosyncratic reaction that is commonly preceded by rash. published prior report mentions a crude 
incidence rate of .69 per 1000 person years for severe AHS cutaneous reactions. 83 It should be noted that 
during the course of this study we will expose to allopurinol a total 112 (<30 participants/year) ambulatory 
young adults aged 18-40, with normal kidney function. The rate of AHS in younger ambulatory patients with 
normal kidney function has not been established but is possibly lower than in individuals with gout and other 
medical comorbidities. Allopurinol hypersensitivity syndrome has principally been observed in individuals that 
are HLAB5801 positive (primarily individuals of Han Chinese or Thai descent). As recommended in the recently 
released American College of Rheumatology guidelines, we will test for HLAB5801 during initial screening in 
individuals of Han Chinese or Thai descent. 84  
 
5.Hypertension 
Participants might be exposed to elevated blood pressure during a short period of the study. Given that 
adverse outcomes associated with hypertension tend to occur over time-periods measured in years and our 
study extends over a period of only 3-4 months, the risk of short exposure to elevated blood pressure leading 
to an adverse outcome is small. 
To maximize the safety of the participants we have added a safety monitoring rule. When patients are seen at 
visits 2-5, if present with high blood pressure >160/110, first it will be rechecked 24 hrs later, if blood pressure 


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is still elevated, they will excluded from the study, received consultation by PI and/or Co-PI, and referred to 
their primary care provider. 
 
6.Hyperuricemia 
Participants will not be treated for asymptomatic hyperuricemia outside the study protocol, given that they 
are understood not to have been diagnosed with gout for enrollment in the study.  
 
 
7.Pregnancy 
This study will enroll women between the ages of 18-40 years, at which age we expect a greater majority to be 
fertile. If pregnancy occurs during the active treatment study period, there is a theoretical risk for the unborn 
as allopurinol is considered FDA class C during pregnancy. Untreated hypertension during the early pregnancy 
can also carry a small risk. Pregnant women will not be allowed in the study because allopurinol is classified as 
FDA class C during pregnancy, additionally prisoners, and institutionalized individuals will be excluded. Proper 
birth control methods for male and female participants will be confirmed and discussed during the screening 
visit.  
 
8. Psychosocial risks 
There are no obvious psychosocial risks 
 
J. Potential Benefits 
Currently, cardiovascular events caused by hypertension are the leading cause of morbidity and mortality in 
patients with gout and in the general population. If the addition of urate-lowering therapy to the standard 
therapy for hypertension reduces cardiovascular morbidity through improvement in endothelial function and 
inflammation in patients with hyperuricemia and those in the higher percentiles of normal serum urate 
concentration, this knowledge might have a significant impact on the quality of life of a large proportion of the 
general population. 
 
K. Withdrawal of Participant Consent and Discontinuation of Study Drug 
Participants can withdraw their consent at any time by informing the study coordinator. 
This may include but is not limited to the following 
a.  The subject deciding to withdraw consent for study 
b. An intolerable adverse event as judged by study investigator and/or participant  
c. The subject discontinuing acceptable birth control methods or becoming pregnant 
d. The subject enrolling in a conflicting investigational drug trial 
e. The participant  BP>160/110 between visit 2-5 
 


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If the study drug is discontinued, unless the subject withdraws consent, the subject will be followed for the full 
treatment period and all data will be collected as scheduled. Attempt will be made to schedule an early end of 
study assessment in the case of study drug discontinuation 
 
As stated above as the risks to pregnant women or an unborn baby when taking allopurinol are not fully 
known, women must have a pregnancy test before the study starts and again throughout the study.  Women 
must not become pregnant during this study.  Acceptable methods of birth control include hormonal control 
methods, inter-uterine device, a double-barrier method (diaphragm with spermicide, condom with 
spermicide) or abstinence.   
 
If participants suspect that they may have become pregnant during the study, the study coordinator must 
contact the study PI immediately and instruct the participant to stop taking their study medication.  If it is 
confirmed that the participant is pregnant, they will be withdrawn from the study. The study PI may want to 
schedule a follow up visit and may choose to follow the outcome of the pregnancy.  Additionally, taking 
allopurinol may involve unknown risks to a nursing infant.  If it is discovered that participants are 
breastfeeding, they are not eligible to participate in the study and their participation will be discontinued 
immediately.  
 
The rate of AHS is estimated at 1/1000, and may be a particular concern for those with reduced renal function 
or caring the HLA B5801 allele. We will expose 112 young adults with normal renal function to a dose of 300 
mg per day of allopurinol as part of the study protocol, which include checking for the HLAB5801 allele in 
individuals of Han Chinese or Thai descent before exposure to allopurinol. Based on these rates of AHS and the 
procedures we have in place, we believe it is very unlikely, but possible that we could witness one severe 
cutaneous adverse reaction including AHS. Our stopping rule for safety re-evaluation would occur if we 
register more than one of such cutaneous adverse reaction (toxic epidermal necrolysis, Steven-Johnson’s 
syndrome, AHS).  We would then stop the study to comprehensively review safety and allopurinol dosing 
protocols.  Other severe adverse reaction or deaths may or may not be related to the study drug and stopping 
or discontinuation of the study drug will be considered on an individual basis. 
 
L. QUALITY and Safety ASSURANCE  
 
1. Study team monitoring of data 
Goal enrollment is 112 subjects. The history, physical examination and review of laboratory data will be 
conducted by the principal investigator or co-investigator, all of whom are experienced in clinical trials. Case 
report forms will be cross-checked with source documents by study personnel. The research team will meet 
biweekly to review recruitment, enrollment, laboratory tests, source documents, and case report forms.  
 
2. Safety Monitoring  
As this is proposed to be an NIAMS-funded study, NIAMS selected a Safety Officer, Dr. Alan Gelber, to work 
under a subcontract with KAI Research INC to oversee the project. Dr. Allan Gelber, MD, PhD, MPH will serve 


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as the independent Safety Officer for this project. Dr. Gelber will provide independent oversight and act in an 
advisory capacity to the NIAMS to monitor research participant safety and data quality and to alert the 
Institute to potential issues in either of these areas. We will work with Dr. Gelber and provide regular reports 
about blinded clinical outcomes, adverse events, and all laboratory information. In addition, all blinded 
laboratory data will be reviewed by the PI or co-investigator and case report forms. In addition to Dr. Gelber, 
we will submit monthly reports to the CORT Project Advisory Committee detailing the study progress and 
participant status, any adverse events, and any protocol deviations. The safety of the study participants is the 
highest priority for this project. The ability to make appropriate, sound scientific decisions regarding the 
outcome of each participant as early as possible is the top priority and as such, a process for the ongoing 
monitoring of results by independent scientists is important to maintain throughout the duration of the 
project. 
 
In addition to Dr. Gelber, we will convene a Data Safety and Monitoring Board (DSMB) for additional 
monitoring of study procedures. The safety of the study participants is the highest priority for this project. The 
ability to make appropriate, sound scientific decisions regarding the outcome of each patient as early as 
possible is the top priority and as such, a process for the ongoing monitoring of results by independent 
scientists is important to maintain throughout the duration of the project. 
  
The DSMB will be comprised of scientists who are independent of the study, the study investigators, and of 
UAB for this clinical trial.  Sterling West, MD, will chair the DSMB. Dr. West is an internationally known 
rheumatologist at UC Denver.  Additional members include Dr. Annie Howard, a biostatistician with 
cardiovascular expertise and Dr. Paul Palevsky, a nephrologist with gout expertise.   
 
 DSMB Responsibilities 
The DSMB responsibilities are to:  
 review the research protocol, informed consent documents and plans for data safety and monitoring;  
 advise on the readiness of the study staff to initiate recruitment; 
 evaluate the progress of the trial, including periodic assessments of data quality and timeliness, 
recruitment, accrual and retention, participant risk versus benefit, and other factors that can affect study 
outcome; 
 consider factors external to the study when relevant information becomes available, such as scientific or 
therapeutic developments that may have an impact on the safety of the participants or the ethics of the 
trial; 
 review study performance, make recommendations and assist in the resolution of problems reported by 
the Principal Investigator;  
 protect the safety of the study participants; 
 report on the safety and  progress of the trial;  


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 make recommendations to the Principal Investigator, and, if required, to the Food and Drug 
Administration (FDA) concerning continuation, termination or other modifications of the trial based on the 
observed beneficial or adverse effects of the treatment under study; 
 the Principal Investigator will report findings of the DSMB to the FDA in accordance to reporting 
guidelines; 
 if appropriate, review interim analyses in accordance with stopping rules, which are clearly defined in 
advance of data analysis and have the approval of the DSMB; 
 ensure the confidentiality of the study data and the results of monitoring; and,  
 assist in the commenting on any problems with study conduct, enrollment, sample size and/or data 
collection. 
 
The DSMB will discharge itself from its duties when the last participant completes the study. 
 
Membership 
The DSMB will include experts in or representatives of the fields of: 
 rheumatology,  
 cardiovascular disease  
 biostatistics.  
 
The Chair is the contact person for the DSMB. The University of Alabama at Birmingham shall provide the 
logistical management and support of the DSMB.  
 
Board Process  
At the first meeting the DSMB will discuss the protocol, suggest modifications, and establish guidelines to 
study monitoring to be reported.  The DSMB Chairperson (Dr. West) in consultation with the Principal 
Investigator and the study team will prepare the agenda to address the review of study materials, 
modifications to the study protocol and informed consent document, initiation of the trial, reporting of 
adverse events, statistical analysis plan including interim analysis, etc.  
 
Meetings of the DSMB will be held at the call of the Chairperson. The study investigators or designee will 
attend most of the meetings. An emergency meeting of the DSMB may be called at any time by the Chair or by 
the Principal Investigator should participant safety questions or other unanticipated problems arise. 
 
 
Meeting Format 
DSMB meetings will consist of open and closed sessions. Discussion held in both sessions is confidential. The 
Principal Investigator and key members of the study team attend the open sessions. Open session discussion 
will focus on the conduct and progress of the study, including participant accrual, protocol compliance, and 
problems encountered. Unblinded data are not presented in the open session.  


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The closed session will be attended by the DSMB members and the study representative(s). The study 
statistician may be present, at the request of the DSMB. Any data by blinded study group and, as necessary, 
unblinded data, are presented during the closed session.  
 
Each meeting must include a recommendation to continue or to terminate the study and whether the DSMB 
has any concerns about participant safety made by a formal DSMB majority or unanimous vote. Should the 
DSMB decide to issue a termination recommendation, the full vote of the DSMB is required. In the event of a 
split vote, majority vote will rule and a minority report should be appended. The DSMB Chair provides the 
tiebreaking vote in the event of a 50-50 split vote. 
 
A recommendation to terminate the study may be made by the DSMB at any time by majority vote. The Chair 
should provide such a recommendation to the Principal Investigator immediately by telephone and email. 
 
Meeting Materials  
DSMB interim report templates will be prepared by the study staff, typically the statistician, to be reviewed by 
the DSMB members at the first meeting.  Interim data reports generally consist of two parts:  
 
 Part 1 - Open Session Report and  
 Part 2 - Closed Session Report  
 
Format and content of the reports for both the open and closed sessions and plans for interim analyses should 
be finalized and approved at the initial DSMB meeting, although changes throughout the trial may be 
requested by the Board. 
 
The reports will list and summarize safety data and describe the status of the study.  All meeting materials 
should be sent to Principal Investigator who will forward the materials to the DSMB at least 7 to 14 days prior 
to the meeting. The reports are numbered and provided in sealed envelopes within an express mailing 
package or by secure email as the DSMB prefers. In select cases, Principal Investigator may approve direct 
mailing of the reports from the study to the DSMB. 
 
1. Part 1 - Open Session Reports: Open session reports generally include administrative reports by 
site that describe participants screened, enrolled, completed, and discontinued, as well as baseline 
characteristics of the study population. Other general information on study status may also be 
presented. Listings of adverse events and serious adverse events as well as any other information 
requested by the DSMB may also be in the open session report, but none of the data should be 
presented in an unblinded manner. The DSMB may direct additions and other modifications to the 
reports on a one-time or continuing basis.  


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2. Part 2 – Closed Session Report:  Closed session reports generally present the same information as 
presented in the open session but by blinded treatment group (e.g., A/B, etc.). The reports may 
also contain data on study outcomes, including safety data, and depending on the study, perhaps 
efficacy data. The Closed Session reports should be destroyed at the conclusion of the meeting. If 
the meetings are held by telephone, printed copies of the closed reports should be destroyed 
immediately following the meeting.  If a study has an interim analysis, it is also discussed in the 
closed session. 
 
Additional Reports 
1.  Mailings to the DSMB: On a scheduled basis (as agreed upon by the DSMB) blinded safety data could be 
communicated to all DSMB members and to the designated Safety Officer (VIA KAI). The study may provide 
these data directly to the DSMB, if such communication procedures are approved by Principal Investigator. 
 
Reports from the DSMB 
A formal report containing the recommendations for continuation or modifications of the study will be 
prepared by the DSMB Chairperson, Principal Investigator or designee. The draft report will be sent to the 
DSMB members for review and approval. It is the responsibility of the Principal Investigator to distribute the 
DSMB recommendation to all co-investigators and to ensure that necessary reports are submitted to the UAB 
IRB. 
 
As previously stated, the formal DSMB report must include a recommendation to continue or to terminate the 
study. This recommendation should be made by formal majority vote. A termination recommendation may be 
made by the DSMB at any time by majority vote. In the event of a split vote in favor of continuation, a 
minority report should be contained within the regular DSMB report. The report should not include unblinded 
data or discussion of the unblinded data.  
 
Confidentiality  
All materials, discussions and proceedings of the DSMB are completely confidential. Members and other 
participants in DSMB meetings are expected to maintain confidentiality.  
1b. Schedule of visits and evaluations (see Protocol, Table 3. Schedule of visits and evaluations, page 13) 
 
 
 


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1c. Figure 1-Study Flow  
Pre-screening 
phone call
Patient Enters 
Clinic
Patient consents
Patient given BP
 screening
Complete blood panel
 and urine tests
Confirm placebo 
adherence, enroll 
participant, 
randomize, and 
conduct Visit 2
Stop- Staff thanks 
patient for time 
and completes 
screening log
Conduct 
Visit 3
Conduct 
Visit 4
Conduct 
Visit 5
Participant 
completes 
visits
END OF STUDY
CONTINUE
ELIGIBLE 
ELIGIBLE
 BEGIN 2 WEEK RUN-IN PERIOD
NOT ELIGIBLE
CONTINUE
Conduct interim visit check-in
CONTINUE
YES
NOT ELIGIBLE
Conduct interim visit check in
 
 
 


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2. Study Organization and Responsibilities 
2a: Table 5 Study Roster  
 
REDACTED 
 
2b. Study Center 
This is a single site study, and the staff listed above will be responsible for all aspects of the trial. This includes 
but is not limited to the following: 
1. Development of the study protocol 
2. Development of the manual of procedures and its maintenance 
3. Participant randomization  
4. Development and implementation of the data flow and data tracking 
5. Development of procedures for data entry, error identification, and error correction 
6. Adverse event monitoring and reporting 
7. Quality control procedures  
8. Submitting for IRB review and approval 
9. Creating reports - enrollment, adverse events, participant status (e.g., withdrawals) 
10. Preparing and sending required reports to the Safety Officer and the IRB 
11. Submitting all required reports to KAI for distribution to the study appointed Safety Officer 
12. Distribution of all changes, updates and policies of above mentioned reports and documents to KAI, 
NIAMS, and the study appointed Safety Officer.  
13. Maintaining the study binder (regulatory and clinical documents) 
14. Preparation of all study materials- data tables, recruitment materials, official reports 
15. Identifying, recruiting, screening and enrolling participants 
16. Obtaining informed consent from each participant 
17. Protecting participants' rights 
18. Collecting study data and following participants through study completion 
19. Compliance and accountability of administration of study intervention, and 
20. Communicating questions, concerns, and/or observations to the Principal Investigators 
All of the above activities will be carried out by the study’s project coordinator, project managers, and 
research assistants on a weekly basis (or more frequently as needed) and monitored by the principal and co-
investigators. All instructions, forms, and documents necessary for these tasks are contained in the PROTOCOL 
and/or study binder.  
 
2c. UAB CORT Executive Committee 
As this project is a part of the UAB CORT of Gout and Hyperuricemia this project is subject to review by the 
UAB CORT Executive Committee. This committee is made up of project principal investigators, co-


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investigators, and senior UAB researchers who meet periodically to discuss all facets of the CORT and its 
projects. Any concerns voiced by study staff members will be brought to the attention of this committee. 
 
 
 
2d. UAB Pharmacy 
The UAB Investigational Drug Service (IDS) is responsible for the storage and preparation of both the study 
drug and placebo for this study. Placebo run-in medication will be picked up for dispensement after a 
participant is deemed eligible. The labeled study drug is picked up by a research assistant to dispense to study 
participants (depending on assigned group) at visits 2 and 4. A drug log will be used to track the study drug 
from pharmacy to study participant. Further questions about pharmacy activities can be directed to: Rebecca 
Quinn, PharmD. IDS Pharmacy, University of Alabama at Birmingham Hospital, 205-934-7191. 
 
3. Training Plan 
Each study staff member will be trained in the protocol by the investigators named above. The investigators 
and all staff involved in the study will have completed their required IRB / human participants training.  New 
study staff members will be trained on the protocol and spend a visit shadowing another trained staff member 
before carrying out visits independently. If necessary, any non-MD study personnel will be trained to take a 
blood pressure reading, height, and weight; those with additional phlebotomy training will be permitted to 
draw blood labs. Any study personnel tasked to enter participant information/data will be certified to enter 
data utilizing the using the REDCap (Research Electronic Data Capture) system. Prior to study start up, the 
project manager and Data Work Group Leader will certify study personnel to enter in study data and they 
have completed REDCap training.  
 
Prior to conducting visits, the investigator will be asked to sign off that the staff member has been 
appropriately trained in the study protocol.  
 
If a staff performance problem arises, several steps will be taken to resolve the problem. First, the project 
manager will communicate the problem to the PIs. At this stage, the PIs will work with study personnel to 
identify causes of the problem and offer solutions. If the problem continues, additional training will be 
considered. In cases of problems of sufficient severity or intractable problems that are not resolved by the 
procedures described above, the under-performing team member may be removed from active participation 
in the study.  
 
4. Communications plan 
As this protocol is currently only being carried out at one site (the University of Alabama at Birmingham-UAB), 
meetings will be held between the entire study staff on a monthly basis to communicate the on-going 
progress of the study. 


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Topics of discussion at each meeting will include: 
 Recruitment progress 
 Adverse events 
 Issues or concerns with the study and possible solutions 
 Any data available at that time 
 Safety reporting 
 Other study updates 
 
Additionally, study personnel will keep investigators informed of the weekly progress of the study with weekly 
study work group meetings and email updates that include the following information: 
 Number of patients screened that week 
 Number of patient visits overall 
 Prospective study participants to speak with the following week 
 A recap of any adverse events (which, if classifies as a severe adverse event or requiring additional 
review, would have already been reported immediately following the event) 
 Other study updates 
 Any recent data collection that is useful for viewing or necessary to see for safety monitoring 
 
Finally, routine progress and safety reports will be provided to NIAMS-KAI within the intervals requested, but 
no less than quarterly.  
 
5. Recruitment and Retention Plan 
 
5a. Recruitment Plan 
The target population to be recruited is patients with Pre-hypertension or stage I hypertension. Similar to past 
successful recruitment for hypertension studies by Drs. Calhoun and Oparil, announcements will be placed in 
the web page www.researchmatch.org , Birmingham metro area local newspapers, UAB publications (e.g. UAB 
reporter, distributed to all UAB campus), and flyers that will be posted on UAB campus requesting adults, ages 
18-40, that are interested in participating in a clinical study for hypertension, to call the recruitment 
coordinating center. Given the inclusion age range with this trial, participants will be also be recruited utilizing 
social media print and radio ads (e.g., Spotify, Facebook, and Instagram). Patients will also be recruited directly 
from the UAB 700 physician outpatient care facility, The Kirklin Clinic, through brochures distributed to 
physicians and from the Hypertension clinic. The inclusion and exclusion criteria will be reviewed during a 
telephone interview (pre screening), and if the participant wishes to proceed, a screening visit will be 
scheduled (section 7). Informed consent will be obtained by the principal investigator, one of the co-
investigators, or a trained member of the study staff. Study procedures will not begin until signed informed 
consent has been obtained (section 8). 


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Informed consent will be obtained by the principal investigator, one of the co-investigators, or a 
trained member of the study staff (ex. Study coordinator). Study procedures will not begin until signed 
informed consent has been obtained (section 8). 
Figure 2. Example patient recruitment flyer 
 
 
5b. Participant Retention 


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Retention of participants is central to the internal validity of the proposed study and will be an extraordinarily 
high priority.  We will aim to have an 80% retention rate. During the screening and enrollment process, 
contact will be made with participants in a variety of ways (letters, staff contact by phone and in person) for 
optimal retention. To increase retention, we hire engaging, attentive, and responsive staff and provide 
participants with a flexible time to complete their study visits.  Other features used to promote high retention 
rates will include tracking systems and collection of information (i.e., names and telephone numbers) for two 
friends/family members who do not live with the study participant but would know where to find them. Once 
enrolled, a proactive plan for retention will be implemented that includes in person visits every 4 weeks, 
phone calls between each visit, and transportation vouchers to encourage participants to come to their visits. 
The following major principals and commonly used strategies to maximize retention and minimize loss to 
follow-up will be employed during the trial: 
 
 Stressing the idea that participants have an active role in the research and are part of the research 
team 
 Enhancing participant’s understanding of the study’s mission and the protocol 
 Stressing that retention efforts begin with recruitment and are an ongoing process 
 Building participant relations and participant satisfaction, with the study staff taking a central role on 
this effort 
 Emphasizing the importance of congeniality, respectfulness and friendliness in interactions with 
participants 
 Actively discuss with participants any questions and concerns pertaining to their condition 
 Identifying potential problems and key retention factors and developing intervention strategies 
regarding retention 
 Assessing each participant’s drop out potential and intervening as needed to keep participant 
interested in continuing to participate 
 
Figure 3. Study Diagram 
Screening
 (wk 0)
No 
Intervention
Run-in
 (wks 1-2)*
Placebo
Crossover
Phase 1
 (wks 3-6)
Allopurinol
Placebo
Washout 
period
(wks 7-8)*
Crossover
Phase 2
(wks 9-12)
Allopurinol
Placebo
 
*Timing within these phases were up to 4 weeks for pre-menopausal women 
 


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7. Screening and eligibility criteria 
 
During the screening phase, potential participants will be determined as described in the Recruitment Plan in 
section 5A. Study personnel following instructions outlined in the study binder will carry out screenings.  
The set of screening questions will be asked prior to starting any study procedures and immediately after 
obtaining consent. These questions will be based on eligibility and exclusion criteria described below (see 
Appendix 2 for REDCap screenshots). Screening logs will be kept in electronic format and saved in a password 
protected file folder in the REDCap system (See Appendix 2 for REDCap screenshots) and updated as needed 
during recruitment. 
 
7. Criteria 
7a. Eligibility criteria 
A screening visit will occur to confirm study eligibility, explain procedures, and sign an informed consent for 
screening. For men and women in days 1-7 of the menstrual cycle eligible for the study, randomization and the 
baseline visit will occur 2 weeks after the screening procedures and signing of the consent form. Women after 
day 7 of the menstrual cycle will be invited to return after the onset of their menses and no later than day 7 of 
the next cycle for standardized measurements of FMD (4 week placebo run-in ±3 days) in the UAB 
Hypertension Clinic. 85,84 Participants will be randomized following confirmation of eligibility. We anticipate an 
additional 10% that initially fulfill inclusion criteria will fail to randomize because their BP will be outside the 
study range at visit 1. In conclusion, we project the need to perform screening laboratory assessments in 236 
individuals. Enrollment and participant follow-up will continue until 112 participants are enrolled. We 
anticipate recruiting 30 persons per year based on the following inclusion criteria.  
1. Pre-hypertension or stage I hypertension, defined as the following after the mean of two clinic 
measurements: 
o -Systolic blood pressure (SBP) ≥ 120 and <160 or; 
o -Diastolic blood pressure (DBP) ≥ 80 and < 100 
2. Serum urate ≥ 5.0 mg/dL for men or ≥ 4.0 mg/dL for women 
3. Age 18-40 
 
7b. Exclusion criteria 
Individuals below 18 years of age will be excluded given that although hyperuricemia may affect children, it is 
predominately a condition of adults and gout is almost exclusively a problem of adulthood. The science 
proposed and the rationale for our study of this disorder in adults only is clarified in our research strategy and 
significance section. While prior research of this type has examined adolescents, part of the novelty of our 
study is to focus only on adults and given the increased risk to benefit ratio of our proposed study in children, 
children will not be included in this research. Prisoners and institutionalized individuals will be excluded. In 
individuals of Thai or Han Chinese descent that test positive for HLAB5801 will be excluded due to the high risk 
of allopurinol hypersensitivity.  


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The risks to pregnant women or an unborn baby when taking allopurinol is not fully known.  For this reason, 
women must have a pregnancy test before the study starts and again throughout the study.  Women must not 
become pregnant during this study.  All females of childbearing potential must use an effective form of birth 
control during this study.  Acceptable methods of birth control include hormonal control methods, inter-
uterine device, a double-barrier method (diaphragm with spermicide, condom with spermicide) or abstinence.   
 
If participants suspect that they may have become pregnant during the study, the study coordinator must 
contact the study PI immediately and instruct the participant to stop taking their study medication.  If it is 
confirmed that the participant is pregnant, they will be withdrawn from the study. The study PI may want to 
schedule a follow up visit and may choose to follow the outcome of the pregnancy.  Additionally, taking 
allopurinol may involve unknown risks to a nursing infant.  If potential participants are breastfeeding, they are 
not eligible to participate in the study. 
 
If participants suffer from very high BP >160/110 ,first it will be rechecked 24hrs later, if blood pressure is still 
elevated, they will excluded from the study, received consultation by PI and/or Co-PI, and referred to their 
primary care provider. 
 
8. Informed Consent and HIPAA 
 
8a. Overview of the informed consent process 
 
During the screening visit, the form will be read by the study participant and then each section will be 
explained by the research study coordinator obtaining consent. The participant will be given as much time as 
they need to read and ask questions about the consent form. After the participant has signed the consent 
form, the Principal Investigator, and the research assistant conducting the visit must each sign and date the 
Informed Consent Document. A signed version of the consent form will be kept by the study staff in the study 
binder and an additional copy of the consent form will also be given to the participant to keep. 
 
The individual will be informed that he/she is not obligated to participate in the study and that it is strictly 
voluntary. The informed consent process will ensure that there is no penalty for not participating in a clinical 
trial and that treatment will not be compromised if individuals do not participate or if they cease participation 
at any time. 
 
By signing the consent form, the participant authorizes the use of their personal health information, that they 
understand the study and its benefits and risks, and agree to all other aspects of the study outlined in the 
form. Participants can withdraw their consent at any time. 


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8b. Overview of the Informed consent document 
The process of informed consent will be carried out by a study coordinator or the research assistant involved 
in the screening visit after the participant appears to meet the pre-screening criteria. It allows the participant 
the opportunity to decide whether they want to participate in a study. During this process, individuals will be 
informed of all aspects of the study so that they can make an informed decision. Participants will then confirm 
their willingness to participate in the research study by signing the Informed Consent form (see Appendix 1 for 
the complete informed consent). After the participant has signed the consent form, the research coordinator 
conducting the visit must sign and date the Informed Consent Document. 
 
The informed consent document contains the following: 
 Disclosure of relevant information to prospective participants about the research; 
 The participant’s comprehension of the information; 
 The participant’s voluntary agreement to participate in a research study without coercion or 
undue influence. 
 An optional participation in future research by allowing samples to be biobanked. 
 Complete disclosure of any appropriate alternative procedures and their risks and benefits 
 Disclosure of the extent of confidentiality that will be maintained 
 Statement of compensation and/or medical treatment available if injury occurs 
 Name, address, and telephone number of the Principal Investigator 
 
If there is a change in any of the study procedures that may affect the participant, the informed 
consent document will be revised and approved by the IRB. Any participants active in the study 
prior to a change in procedures will sign the amended consent form. Per NIH policy, the signed consent forms 
will be kept as part of the study record for at least 7 years after completion of the study. 
 
Important Steps for the Study Staff: 
 Provide participants with adequate information concerning the study procedures and scope 
 Provide adequate opportunity for the participant to consider all available options 
 Respond to the participant’s questions and concerns 
 Ensure that each participant understands all information provided 
 Obtain the participant’s written voluntary consent to participate 
 Countersign the consent form  
 Obtain a third-party witness signature 
 Provide participants with a copy of the consent form 
 Keep the signed form in the study binder 
 


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8c. HIPAA Authorization 
The privacy requirements, as outlined by The Health Insurance Portability & Accountability Act (HIPAA) to 
protect the participant’s confidentiality, are met by reading through the consent form with the potential study 
participant before obtaining a signature. Additionally, the following HIPAA Specific requirements are met in 
the last section of the consent form:  
 The form contains language that satisfies the HIPAA requirements and outline the 
protection of health information utilized in the study 
 That participants are authorizing investigators, IRBs, research administrators, and others to 
share and disclose their Protected Health Information (PHI) for research purposes. 
 
 
 
9. UAB Pharmacy 
The UAB Investigational Drug Service (IDS) is responsible for the storage and preparation of both the study 
drug and placebo for this study. The labeled study drug is then picked up by a research assistant to dispense to 
study participants (depending on assigned group) at visits 2 and 4. A drug log will be used to track the study 
drug from pharmacy to study participant.  
 
The manual of operations and procedures provides instructions to site personnel on the requirements and 
processes for handling and management of the study drugs and other study medication-related supplies. 
Instructions provided in this document must be followed precisely.  
Conduct of clinical studies and the associated activities outlined in this Manual are subject to various local, 
national, and international regulations.   All policies and procedures must be adhered to. 
 
STUDY SUPPLIES 
Study drugs used in the study are: 
1. Allopurinol 300 mg, oral administration 
2. Placebo, oral administration  
     
Placebo and allopurinol will be over encapsulated at UAB pharmacy by Rebecca Quinn.  
 
The UAB pharmacy will provide storage for non-encapsulated allopurinol and placebo. Dr. Quinn will prepare 
in advance for up to 10 subjects. Encapsulated study supplies should be picked up on the day of study visit 
appointments or stored in a locked drug cabinet in the clinic space until the time of this visit.  The study 
coordinator will be responsible for distribution of study supplies to participants. Upon distribution the study 
coordinator should log the distributed pill bottle.  
 


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Further questions about pharmacy activities can be directed to: Rebecca Quinn, PharmD. IDS Pharmacy, 
University of Alabama at Birmingham Hospital, 205-934-7191. 
 
 
 
10. Randomization 
Randomization will occur using a random number generator. Specifically, permuted block randomization will 
be used allowing for balance between crossover arms throughout the investigation.  Block sizes will be 
variable to prevent research staff from anticipating subsequent crossover arm allocations.  The sequence of 
treatment assignment will be held by the pharmacist creating treatment arm study pill containers. The 
pharmacist will maintain the master list and securely store the randomization files. The study coordinator will 
initiate the randomization procedure after a subject has consented. The coordinator will let the pharmacist 
know that a study pill container is needed according to the randomization scheme.  If any concerns arise 
during the randomization procedures, both the pharmacist and study coordinator will contact the study 
statistician. 
 
 
11. Blinding and unblinding 
All study investigators and participating coordinators will be blinded to treatment assignment. If there is a 
serious adverse event, then unblinding will be discussed and if deemed necessary to unblind the participant, 
then the ID of the unblinded participant, reasons for unblinding, name of the pharmacist and a list of 
whomever becomes unblinded will be kept in the study binder. The pharmacist will contact that participant's 
primary physician about the exposure. If necessary, the participant will be withdrawn from the study. The 
pharmacist will hold the randomization codes securely until the completion of the study.  
 
12. Study Intervention 
This study meets the criteria of a clinical trial but it is not a NIH-Defined Phase III Clinical Trial as defined by 
NIH. The UAB IDS pharmacy is responsible for the preparation and labeling of allopurinol and the placebo. 
Participants will be asked to take 4 weeks of allopurinol or placebo, then will crossover to the other drug (after 
2-4 week washout period) and take either allopurinol or placebo for an additional 4 weeks. Allopurinol will be 
prescribed in 300mg tablets. At visit 2 and 4, participants will be given a 5-week (with an additional 7 days to 
account for variability in appt availability) supply of medication. During visits 3 and 5 study staff will count pills 
(any extra will be discarded) to determine compliance. Allopurinol and placebo prescriptions will be 
administered by the research study coordinator conducting the visit, daily doses will be administered by the 
participants themselves. 
 
13. Participant Evaluations- Study timeline, visits, and procedures ( See Protocol, Section F, for details on 
the study timeline, visit schedules, and procedures)   


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For each visit, the study coordinator and staff conducting the visit will systematically enter all participant 
information electronically to the Research Electronic Data Capture system (REDCap). Our team has extensive 
experience using the REDCap system. All data will be collected in REDCap. Additionally electronic records are 
kept by visit. The study coordinator and project manager will review all data collected on a regular basis. This 
will help ensure all electronic forms are being completed correctly, are intact, and have been entered into 
system correctly. Lab forms provided by the research study coordinator describing the blood work to be done 
should be filled out at all visits (See Appendix 3. Standard Operating Procedures for instruction of preparation 
and storage of biobanked samples). If any issues arise (including, but not limited to adverse events) during the 
visits that prevent the participant from continuing, these will be documented and reported to the principal 
investigator immediately. The laboratories and visits are outlined in the study Protocol, section F. 
 
14. Data Collection, Study Forms, and Logs   
All data for this study will be collected by study staff in accordance with 21 CFR Part 11 rules and will meet all 
regulatory requirements. Due to the fact that data is almost always recorded directly on a CRF, we developed 
electronic case report forms for all data entry using REDCap. Our team has extensive experience using the 
REDCap system. All forms will be completed electronically in REDCap by the study coordinator(s). All REDCap 
forms filled out by study personnel will be considered source documents and kept electronically. All electronic 
forms and logs in REDCap are encrypted and password protected and hard copies can be printed if required. A 
detailed listing of all current study forms is below.   
14a. Table 6. Study Participant Forms- Data will be collected by the study staff at each visit on study forms 
as described and presented below: 
Form 
Description 
Visit 
administered  
Instructions 
Location 
Informed consent 
Informed consent  
Screening visit  
Participant 
reads through 
consent and 
initials each 
page in the box. 
Participant, 
doctor 
obtaining 
consent and 
study staff 
should all sign, 
date and time 
stamp  
Appendix 1 
Study Binder 
 
Participant 
information/contact 
Detailed contact 
sheet for 
Screening visit 
Participant is 
asked for 
Appendix 2  


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participant and 
two other listed 
contacts 
contact 
information for 
his/herself and 
2 other persons 
 
 
Screening form 
Ensures eligibility 
by cross 
referencing 
participants labs in 
one 
form, and 
determining that 
all inclusion 
criteria are met. 
Screening visit 
Completed by 
study staff 
following 
prescreen and 
initial exam. 
Certified by 
study 
coordinator.  
Appendix 2  
Exclusions form 
Ensures eligibility 
by cross 
referencing 
participants labs in 
one 
form, and 
determining that 
no exclusion 
criteria are met. 
Screening visit 
Completed by 
study staff 
following 
prescreen and 
initial exam. 
Certified by 
study 
coordinator. 
Appendix 2  
Initial participant 
questionnaire 
including focused 
medical history and 
health 
Initial data 
collected on 
participants 
medical history, 
health status, 
anthropometric 
data, status, blood 
pressure, heart 
rate, and 
medication use. 
Screening visit 
Study 
coordinator 
queries 
participant on 
his/her medical 
history. Entered 
in REDCap 
Appendix 2  
Interval medical 
history 
Updates medical 
history of 
participant 
between visits, 
Visits 2-5 
Study 
coordinator 
queries  
participant on 
Appendix 2  


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blood pressure, 
heart rate, and 
medication use. 
updates to 
medical history. 
Entered in 
REDCap 
Concomitant 
medication  
Record of all 
prescribed and 
other the counter 
medication 
participant is 
currently using 
Screening visit 
and visits 2-5 
Completed by 
study 
coordinator and 
entered into 
REDCap 
Appendix 2  
Lab results 
All study lab data 
entered.  
Screening visit 
and visits 2-5 
Data Obtained 
from UAB labs 
and entered by 
study staff into 
REDCap system. 
Appendix 2  
FMD results 
Data collected 
during FMD 
procedure 
Visits 2-5 
Completed by 
Dr. Dudenbostel 
and entered in 
to REDCap 
system. 
Appendix 2  
24-hour ABPM 
Data collected by 
ambulatory blood 
pressure monitor 
Visits 2-5 
Data 
downloaded 
from device.   
Raw data 
files housed 
on secure 
server  
Adverse event 
Adverse event 
data entered on 
this form 
Visits-2-5, and 
during follow-
up phone calls 
Completed by 
study 
coordinator. PIs 
notified within 
24 hours of any 
adverse event 
Appendix 2  
 
14b. Table 7. Study Specific Administrative Forms, Logs, and Data Tables  
Form 
Description 
Location 
Study roster  
Complete study personnel roster and  
signature of all members of the study 
team. It is the responsibility of the 
Principal Investigator and/or Clinical 
Study Binder 
REDCap System  


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Research Coordinator to: designate 
individuals approved to make form 
entries and changes, and note the date 
when any study team member is 
removed from the team for any reason. 
Timeline 
Detailed study timeline  
Study Binder 
Protocol 
Protocol  
REDCap System 
Schedule of Visits and 
Evaluations 
Listing of all schedule study visits and 
evaluations 
Study Binder 
Protocol 
Protocol -Appendix 3 
REDCap System 
Screening log 
Log of individuals screened and 
enrolled  
EXCEL document 
Participant contact log 
Record of all calls/contact between 
study staff and participants. Study 
coordinator(s) complete log showing 
interval visit calls. Assess medication 
compliance and adverse events. 
Appendix 2  
Serious adverse event 
report 
Serious adverse event data entered on 
this form.  
Appendix 2  
Study drug accountability 
record 
Will be maintained in the Pharmacy by 
the research pharmacist and must not 
be shared with other members of the 
study team. 
Available by request at 
the IDS Pharmacy 
Record of Destruction of 
Clinical Product 
This log is used to document the 
destruction of any unused study drug. 
The date of incineration as well as how 
many vials were incinerated must be 
recorded. This record should be 
attached to the Study Drug 
Accountability Record. 
Available by request at 
the IDS Pharmacy 


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Enrollment tables 
Data Tables will be exported from 
REDCap database and entered into the 
NIAMS provided EXCEL template. 
Data Tables will be 
generated from REDCap 
database and 
downloaded into the 
NIAMS provided EXCEL 
template. 
Demographic 
characteristics 
Demographic characteristics of the 
study population (ex. Sex, Race, 
Ethnicity, Age) 
Data Tables will be 
generated from REDCap 
database and entered 
into the NIAMS provided 
EXCEL template. 
Randomization/Enrollment 
log 
Record of randomized and enrolled 
participants 
EXCEL screening log and 
REDCap system 
Study Completion form 
Record of participant study 
completion/withdrawal 
Appendix 2  
Adverse Events Summary  
Summary of all adverse events reported 
by participant during study period. 
Data Tables will be 
generated from REDCap 
database and entered 
into the NIAMS provided 
EXCEL template. 
Adverse Events 
Summary(by severity) 
Summary of all adverse events by body 
system and severity reported by 
participant during study period. 
Data Tables will be 
generated from REDCap 
database and entered 
into the NIAMS provided 
EXCEL template. 
Adverse Events-Details 
Summary of adverse events by specific 
participants upon entering study with 
details related to event.  
Data Tables will be 
generated from REDCap 
database and entered 
into the NIAMS provided 
EXCEL template 
Serious Adverse Events  
Summary of serious adverse events by 
participants upon entering study.  
Data Tables will be 
generated from REDCap 
database and entered 
into the NIAMS provided 
EXCEL template. 


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Death 
Descriptive summary of all participants 
who die during study by cause of death. 
Data Tables will be 
generated from REDCap 
database and entered 
into the NIAMS provided 
EXCEL template. 
 
All study personnel will agree to use of electronic signature for REDCap, defined by a private username and 
password, with the same legal significance as their traditional handwritten signature. We will define user roles 
(clinical investigators, clinical coordinators, and system administrators) with secured log-in. We will track 
current user, database accessed, date, and time and the application will be stopped automatically after 10 
minutes of user inactivity requiring a fresh log-in. All data will be collected on the eCRFs in REDCap and copies 
can be printed and included in the study binder after each visit or phone check in if necessary. The study 
coordinator and project manager will review all data collected weekly. This will help ensure all electronic 
forms are being completed correctly, are intact, and have been entered into system correctly. No data will 
leave the site, as this is a single site study. 
 
14c. General Instructions for Completing Forms in REDCap 
All data recorded in REDCap will be maintained according to FDA and ICH Good Clinical Practice (GCP) 
guidelines. Instructions for completing eCRFs to ensure quality and consistency in data collection are below.  
 
Sample instructions: When completing electronic study forms participants should only be identified by name 
on the screening document. Identification (ID) numbers will be used to reference the participant in all other 
eCRFs. 
 
Header: Complete the header information in every field, including fields for which no study data are recorded. 
From the drop down box choose Not Applicable, Unknown, or UNK for fields where no data can be provided.  
 
Participant ID:  The participant ID will be prepopulated in the header of each page.  
 
Time: Use a 24 hour clock (e.g., 14:00 to indicate 2:00 p.m.) unless otherwise specified. 
 
Dates: All dates will be verified by the study coordinator. Historical dates are sometimes not known (e.g., date 
of first symptom); in this case, chose Not Applicable, UNKNOWN or UNK to indicate missing data. 
 
Abbreviations: Do not use of abbreviations not specifically noted in the instructions for completing the forms. 
Comments should only be written where text fields to do so are provided. 
Correcting errors: Errors can be corrected within the REDCap system where a timestamp and date are 
associated with each entry and revision.   


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Completion of forms: 
All forms must be completed and saved in REDCap. The study team member responsible for the entry of data 
into the REDCap system must ensure that all fields have been entered and that the form has been saved and 
marked as complete. If a form cannot be completed or data cannot be verified the form should be marked 
incomplete or unverified. Forms should only be marked unverified if PI or investigator review is required. This 
may include questions surrounding lab or FMD values recorded in REDCap.  
 
14d. Missing or Incomplete data 
Data may not be available to complete the eform for various reasons. Electronic forms that are missing or not 
complete should be noted, in the REDCap system as INCOMPLETE and saved. Forms with missing data in fields 
or sections should be marked as INCOMPLETE in the REDCap form. Indicate the reason for the missing data in 
the text field when available. If the evaluation was not done, type NOT DONE or ND and provide a reason in 
the available text field or from the dropdown.  
 
Incomplete or Illegible forms:  
If any section or an entire page of the forms cannot be completed (e.g., no parts have any responses), and it is 
unlikely that it will be completed, choose or type NOT DONE/ND, NOT AVAILABLE/NA or NOT APPLICABLE, as 
appropriate in the text field. Do not leave forms incomplete or unused without explanation.  
 
All form header information must be completed even though no data are recorded on the electronic form. If 
an electronic form can only be partially completed at the time of visit, but will be completed when the 
information becomes available, note this in the MISSING FORMS / INCOMPLETE FORMS field and follow the 
direction of the study coordinator and principal investigator.  
 
Every effort should be made to obtain and ensure that the electronic forms are being completed correctly.  
 
14e. Retention of Study Documentation 
Investigators will adhere to rigorous requirements and should retain forms and all other study documents for 
a period of no less than 7 years. 
 
15. Data Management 
Data management will be the responsibility of the research assistants, study coordinator, project manager and 
study statistician. All data will be entered into electronic case report study forms using the REDCap (Research 
Electronic Data Capture) system. REDCap is a secure web application for building and managing online surveys 
and databases. REDCap provides audit trails for tracking data manipulation and user activity, as well as 
automated export procedures for seamless data downloads to Excel, PDF, and common statistical packages 
(SPSS, SAS, Stata, R). From REDCap all data will be exported into SAS files and stored on a secure and 


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encrypted server or hard drive. The study statistician will oversee the data management Data entry, editing 
and updating will be the responsibility of the research assistants, while tracking and corrections will be the 
responsibility of the entire staff. The study statistician and coordinator will train the research assistants on 
proper data entry in the REDCap system.  All efforts will be made to ensure the data is in compliance with the 
UAB Institutional Review Board (IRB) policies, Good Clinical Practice (GCP) guidelines, and Federal regulations. 
Since this is a single site study, no data will be transmitted between sites.  
 
15a. External Data 
The UAB Arthritis Clinical Intervention Program (ACIP) and Hypertension Clinic will handle all laboratory data 
collection. No external data will be collected. All Serum and DNA will be processed and stored in the lab of S. 
Louis Bridges, MD, PhD-the UAB CORT co-director. Serum and DNA processing and storage will be done by so 
in accordance with the standard operating procedures (see Appendix 3). The study coordinator will be 
responsible for the labeling and transport of all blood samples. The study coordinator will collect the lab 
results and record in the eCRFs for each study participant. 
 
15b. Data Entry  
A database will be designed for the current study in the REDCap system. These computerized templates, are 
accessible through a secure web interface. Data entered into the system will be downloaded weekly and the 
database will have range and validity checks built in. All abnormal values will be flagged for further 
investigation.  Research staff performing data entry will be trained in the use of the REDCap system and the 
study database. The study statistician will develop validity checks for outlier values, consistency, and 
completeness and will notify the principal investigator if issues are identified.  Discrepancies will be 
adjudicated by consultation with the principal investigators. Once data entry is complete, the study data will 
be transferred to SAS statistical software and reviewed by the statistician.   
 
16. Safety Monitoring and Reporting 
The following defines the types of adverse events that study staff should inquire about at each visit. The type 
and possible causes of the adverse event will be discussed with the principal investigator, an examination will 
be conducted if deemed necessary, and it will be reported to the required parties. It is the responsibility of 
each and every study staff member to determine the appropriate line of action, to take the action agreed 
upon with the participant, and to subsequently report the event. 
 
 Adverse Event (AE) - An AE is any unfavorable and unintended diagnosis, sign (including an abnormal 
laboratory finding), symptom, or disease temporarily associated with the study intervention, which 
may or may not be related to the intervention. AEs include any new events not present during the pre-
intervention period or events that were present during the pre-intervention period which have 
increased in severity.  
 


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 Serious Adverse Event (SAE) - An SAE is any untoward medical occurrence that results is life-
threatening, requires or prolongs hospitalization, causes persistent or significant disability/incapacity, 
results in congenital anomalies/birth defects, in death, or, in the opinion of the investigators, 
represents other significant hazards or potentially serious harm to research participants or others. All 
SAEs will be reported to the Safety officer (via KAI), Data Safety and Monitoring Board (DSMB), and IRB 
within 48 hours of the Principal Investigator becoming aware of the event. 
 Unexpected adverse event: Any adverse event, the specificity, frequency or severity of which is not 
consistent with either: 
o the known or foreseeable risk of adverse events 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 
o the expected natural progression of any underlying disease or condition of the participant(s) 
experiencing the adverse event. 
 
 
All AEs should be collected, analyzed, and monitored by using the serious adverse event form using the 
Adverse Event Reporting Form as well as the AE Tracking Log in the Research Electronic Data Capture system 
(REDCap). All laboratory abnormalities identified in the protocol as critical to participant safety must be 
reported. All AEs experienced by the participant from the time study drug administration through the end of 
the study are to be reported, as outlined in the protocol. The following delineates specific responsibilities of 
staff members: 
 
 The research coordinator will complete the Adverse Event Form and AE Tracking Log in REDCap; assist 
the PI to notify the IRB, and Safety Officer of all the SAEs, and assist them to prepare SAE reports to 
IRB, and Safety Officer. 
 The Principal Investigator will confirm that all AEs are correctly entered into the AE log with the study 
coordinator; be available to answer any questions that the coordinators may have concerning AEs; 
notify the IRB, FDA of all SAEs and AEs as appropriate. 
 
The study coordinator will confirm that the AEs are correctly entered into the Adverse Event form and log in 
REDCap. They will confirm that the adverse events are reported to the appropriate regulatory bodies, as 
required. Additionally the project Safety Officer will receive safety tables every 12 weeks during the study 
period that include AE and SAE reports. 
 
The proposed research meets the criteria of a clinical trial but it is not an NIH-Defined Phase III Clinical Trial 
since we propose to evaluate the mechanisms by which urate-lowering might contribute to blood pressure 


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control and to compare its effects to placebo in 112 participants with prehypertension and stage I 
hypertension.  Drs. Saag and Calhoun will be responsible for data safety and monitoring. As PIs they will 
complete and submit to the Project Advisory Committee monthly reports detailing the study progress and 
participant status, any adverse events, and any protocol deviations. Continuous, close monitoring of individual 
participant by the PIs will be assured throughout the study period. Events determined by the PIs to be serious, 
unanticipated problems involving risks, those not described in Table 8. Adverse Events, to the participants will 
be reported by the PIs to the IRB, DSMB, and the Safety Officer (via KAI) within 48 hours.  
 
 
Table 8. Adverse Events – This document will be updated as needed.  
Activities of Daily Living-ADL 
Body Surface Area- BSA 
Body System 
Cardiovascular 
Mild 
Moderate 
Serious
Myocardial Infarction 
 
 
All reported 
myocardial infarction 
will be classified as 
serious 
Increased Blood Pressure
Systolic 
BP 140 - 159 mm Hg 
or 
diastolic BP 90 - 99 
mm Hg; 
medical intervention 
indicated 
 
Systolic 
BP >=160 mm Hg or 
diastolic 
BP >=100 mm Hg; 
medical 
intervention indicated 
Life-threatening 
consequences (e.g., 
malignant 
hypertension, 
transient or 
permanent 
neurologic deficit, 
hypertensive crisis) 
Hematology  
Mild 
Moderate 
Serious
Anemia  
13-10 Hb g/dl) 
10-8 Hb g/dl 
<8 Hb g/dl 
 Thrombocytopenia 
150 000- 75 000/mm3 
<75,000 – 
50,000/mm3 
<50,000 – 
25,000/mm3 
 Neutropenia 
<LLN – 1500/mm3 
<1500-1000/mm3 
<1000-500/mm3 
Gastrointestinal 
Mild 
Moderate 
Serious
Vomiting
1 - 2 episodes 
(separated by 5 
minutes) in 24 hrs 
3 - 5 episodes 
(separated by 5 
minutes) in 24 hrs 
>=6 episodes 
(separated by 5 
minutes) in 24 hrs; 
tube 
feeding, TPN or 
hospitalization 
indicated 
Diarrhea
Increase of <4 stools 
per day 
over baseline; mild 
increase in 
ostomy output 
compared to 
normal 
Increase of 4 - 6 
stools per 
day over baseline; 
moderate 
increase in ostomy 
output 
compared to normal 
Increase of >=7 stools 
per day 
over baseline; 
incontinence; 
hospitalization 
indicated; 
serious increase in 
ostomy 


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output compared to 
normal or death 
 
Other
Asymptomatic or mild 
symptoms; clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
 
 
Minimal, local or 
noninvasive 
intervention 
indicated; limiting age 
appropriate 
instrumental ADL 
Medically significant 
or  immediately life 
threatening; 
hospitalization or 
urgent intervention 
 indicated 
 
Musculoskeletal
Mild 
Moderate 
Serious
Joint pain
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Serious pain; limiting 
self-care 
 
 
 
Nervous
Mild 
Moderate 
Serious
Any patient reported event
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Moderate symptoms; 
limiting 
instrumental ADL 
Serious symptoms; 
limiting self 
care ADL or death 
 
 
 
Skin and subcutaneous tissue 
disorders 
Mild 
Moderate 
Serious
Rash- characterized by a 
circumscribed and elevated skin 
lesion 
Papules and/or 
pustules 
covering <10% BSA 
Papules and/or 
pustules 
covering 10-30% BSA 
Papules and/or 
pustules 
covering any % BSA, 
with 
life threatening 
consequences or 
death 
Stevens Johnson Syndrome
 
Skin sloughing 
covering <10% 
BSA with associated 
signs 
(e.g., erythema, 
purpura, 
epidermal 
detachment and 
mucous membrane 
detachment) 
Skin sloughing 
covering 10 - 
30% BSA with 
associated 
signs (e.g., erythema, 
purpura, epidermal 
detachment and 
mucous 
membrane 
detachment) or death 
Itch
Asymptomatic or mild 
symptoms; clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
 
Minimal, local or 
noninvasive 
intervention 
indicated 
Medically significant 
or  immediately life 
threatening; 
hospitalization or 
urgent intervention 
 indicated 


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Hepatobiliary
Mild 
Moderate 
Serious
Abnormal liver enzymes
Above the upper limit 
to 2x ULN 
2x ULN to 4X - 
Greater than 4x ULN 
 
Values and definitions derived from: 
 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Published: May 28, 2009 (v4.03: June 14, 2010) U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES 
National Institutes of Health National Cancer Institute 
 
All adverse events will be reported to the UAB IRB, our study DSMB and the Safety Officer (via KAI) at the time 
of continuing review. All serious adverse events (SAEs) will be reported to KAI and the DSMB within 48 hours 
of the Principal Investigator becoming aware of the event. All study staff members will be informed by the PIs 
about any unanticipated problems involving risks to the participant. If any protocol changes are needed, the 
PIs will submit a modification request to the IRB and NIH. Protocol changes will not be implemented prior to 
IRB and NIH approval unless necessary to eliminate apparent immediate hazards to the research participant.  
In such case the IRB will be promptly informed of the change following implementation (within 1 week).   
 
17. Study compliance 
All deviations will be reported to the appropriate parties, including the Principal Investigator and the Safety 
Officer (via KAI), within 48 hours of occurrence or as soon as they are discovered. In addition, if monitors 
discover any of these deviations during a monitoring visit, they should notify Safety Officer (via KAI) of the 
occurrence in writing. The study staff and research assistants will maintain the log of all protocol  
 
Protocol deviations include, but are not limited to, the following: 
 Randomization of an ineligible participant 
 Failure to obtain Informed Consent 
 Entering a participant into another study 
 Failure to keep IRB approval up to date 
 Wrong treatment administered to participant 
 
18. Quality Control and Standard Operating Procedures 
All study procedures are to take place at the University of Alabama at Birmingham and will do so in 
accordance with the PROTOCOL.  
 
18a. Standard Operating Procedures 
Standard operating procedures for this project can be found in Appendix 3.  
 
18b. Data and Form Control 
All data collection and operating procedures are to take place at UAB and will be done in accordance with the 
PROTOCOL.  Study files will be monitored by research assistants on a weekly basis, and will also be monitored 


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by other study staff members (study coordinator, manager, statistician, and PIs) on a monthly basis to ensure 
quality control. The appropriate regulatory and IRB documentations will be kept on file and up to date by the 
research assistants and administrative staff.  
 
 
IRB documents 
 All IRB Correspondence is electronically archived  
 The study staff are IRB approved prior to performing any study procedures 
 Adverse events and deviations are reported to IRB per current guidelines 
 All versions of the IRB protocols and informed consent forms are electronically archived 
 Reporting all protocol deviations (exceptions and violations) are reported to IRB as required. 
Informed Consent 
 Ensure that participant identification is on all pages of the ICF  
 There is documentation that the participant is given a copy of the consent form 
 The participant and study representative signed and dated the consent form for him/herself. 
 The participant initialed and dated all appropriate pages on the informed consent form. 
 Note to file made for any informed consent deviations. 
 Ensure a valid (current version date) copy of the consent form was used 
 Contact information collected on study participant and two additional study contacts.  
Protocol: 
 Confirm that the study staff is conducting the study in compliance with the protocol 
 
approved by IRB and if applicable, FDA. 
 The protocol deviations (exceptions and violations) are documented appropriately and 
reported to IRB as required. 
Electronic Case Report Forms: 
 Review participant files to ensure that accuracy, and completeness of the data 
 Any correction made to the eCRFs is automatically dated in REDCap. The original entry is archived and 
hard copies can be printed.  
 Note files made for missing or incomplete data and to explain any discrepancies or additional 
comments in appropriate text fields. 
Other documents: 
 CVs for all study staff are on file and updated every 2 years 
 Medical licenses for the PIs and Co-Investigators are on file and updated prior to expiration 
 Yearly financial disclosures for PIs and consultants 
 
18c. Clinical Monitoring 
No clinical monitoring will take place in this study as it is a single site trial. 


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18d. Reports 
Reports as outlined in the communications plan above will be prepared to keep the study staff up to date and 
engaged, as well as help to check quality control. These reports will take the form of: 
 
 Weekly status emails to the PI by the research assistants and study coordinator 
 Data and safety monitoring reports prepared by the study investigator and other staff to be reported 
to the Safety Officer, DSMB, and the UAB IRB as requested.  
 Monthly reports that will be compiled by the research assistant and staff statistician in presentation 
form for study meetings will include  
o Target and actual enrollment,  
o Individuals screened with reasons for screen failure,  
o Enrollment status (enrolled, active, completed, discontinued treatment, and lost to follow-up).  
o Electronic forms completed  and entered 
o Missing or erroneous data. 
o AEs and SAEs 
 
19. Study Closeout 
At the conclusion of the study the following procedures will be done to verify all study related obligations have 
been met. Verification that all study procedures have been completed including, but not limited to the 
following procedures include: 
 
 All data has been collected 
 All data queries have been completed. 
 All electronic source materials have been properly documented and archived 
 Any study related supplies and unused medication is returned for destruction. 
 Assurance that correspondence and study files are accessible for audits. 
 Reminder to investigators of their ongoing responsibility to maintain study records and to report any 
relevant study information to the KAI. 
 IRB notification of the study completion and stored copy of the notification. 
 Preparation of a report summarizing the study’s conduct and results. 
 Participant notification of the study completion. 
 
20. Policies 
All staff will be instructed in their study specific responsibilities regarding data safety and confidentiality. 
Additionally all staff will be cautioned against the release of data to any unauthorized individuals and no data 
will be released to any individual without first obtaining approval from  NIAMS and/or the UAB IRB.  
 


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This section of the PROTOCOL will discuss the safeguards which have been put in place by the PIs to ensure 
participant confidentiality and data security.  
 
The following is a list of study participant confidentiality safeguards: 
 Data flow procedures – As this is a single site study and therefore no data identifying participants will 
be transmitted between sites. The study statistician and coordinator will provide thorough data entry 
and confidentiality training to all staff involved in data collection and data entry. All eCRFs and copies 
will be included in participant electronic study binder on day of visit or phone check in. The study 
statistician, project manager, and coordinator will review all data collected weekly to ensure all forms 
are being completed correctly in REDCap and are intact. No data will leave the site, as this is a single 
site study, so no other data flow will occur. 
 Electronic files – All data identifying participants will be stored electronically will be maintained by the 
study statistician and will be maintained behind the UAB firewall. 
 Data listings – Data or information containing the participant name, study ID, medical information, 
record number, Social Security Number, or any other unique identifier will under no circumstances be 
included in any published data listing. 
 Data distribution - data listings that contain participant name, name code, or other identifiers easily 
associated with a specific participant will not be distributed. 
 Data disposal - computer listings that contain participant-identifying information should be disposed of 
in an appropriate manner. 
 Access - participant records stored in the data center should not be accessible to persons outside the 
center without the express written consent of the participant. 
 Storage – All data collected during this will be stored on UAB Department of Medicine Servers. No data 
will leave the site, as this is a single site study, so no other data flow will occur. Any printed study forms 
and related documents created both during and after study completion will be stored in a secure 
location in UAB Faculty Office Tower. 
 Passwords – Each study related file will be password protected. Additionally, limitations will be placed 
on general access to the study’s REDCap system and to the functions that individuals can use. All 
passwords will be changed on a regular basis. 
 User Training - Study staff with access to clinical computer systems will be trained in their use with an 
emphasis on, and the importance of, system security.  
 System Testing - Prior to the use of the Redcap system, and subsequent to any modifications, the 
system will be tested to verify that it performs as expected. Testing will verify that the password-
activated access system performs as intended. 
 System Backups - Backup copies of electronic data will be made by the study coordinator or study 
statistician.  
 
21. Publications 


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Upon completion of the study we will publish our findings in peered reviewed journals.  
 
Authors must participate in the writing of the paper in accordance with the International Committee of 
Medical Journal Editors guidelines (N Engl J Med 1991;324:424-8). First authors are expected to delete names 
from the final list of authors if those individuals have not satisfied criteria for authorship in accordance with 
those guidelines. The first author on proposed or active writing projects will be decided on by the project’s 
Publication Working Group. The project’s Publication Working Group will develop a listing of first (lead), 
second and senior (last) author for all potential reports. In general, the researcher who first conceived of the 
project and submitted a plan for the manuscript should have the option of serving as first author. Conflicts in 
first authorship should be resolved by all members of the Publication Working Group. In the event that the 
Publication Working Group is unable to resolve a conflict, the UAB CORT Executive Committee will adjudicate 
and may assign the first authorship. 
 
All project manuscripts must be approved by the Publication Work Group prior to submission to journal or 
presentation. The UAB CORT Executive Committee will assist in the review of all manuscripts or scientific 
presentations with the goal to ensure their content and face validity.  
 
UAB CORT project investigators are required to inform and submit copies to the UAB CORT Executive 
Committee of all abstracts, posters, presentations, slides and manuscripts. It is the responsibility of the first 
(lead) author to ensure that appropriate journal submission procedure is adhered to. Any substantial changes 
to an approved manuscript prior to publication whether required by the journal or not, must be discussed 
with the co-authors. The co-authors should receive the proposed re-submissions at least 1 week prior to the 
journal re-submission.  
 
22. Protocol Maintenance 
The Protocol will be maintained and updated throughout the study by the study staff as necessary. The most 
current copies of the Protocol will be kept on a shared project drive, and a hard copy, in loose leaf form, will 
be kept in staff issued binders along with other study files for staff for their reference. Each page of the 
Protocol is numbered, dated, and contains the version number to eliminate any confusion. As a living 
document the Protocol will be continuously reviewed by study staff to ensure the operating procedures 
described are accurate. If any procedures are changed or modified, the protocol will be updated and the new 
version will be emailed and printed for study binders for all study staff members. 
 
 
 
 
 
 
 


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23. Referencesp 
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Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy 
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Sanchez-Lozada LG, Tapia E, Bautista-Garcia P, Soto V, Avila-Casado C, Vega-Campos IP, et al. Effects of 
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Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Wessale JL, et al. Effect of febuxostat on the 
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2008;108(4):p69-78. 
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Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Zhao L, et al. Treatment with the xanthine 
oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental 
hyperuricaemia. Nephrol Dial Transplant. 2008;23(4):1179-85. 
56. 
Kanbay M, Ozkara A, Selcoki Y, Isik B, Turgut F, Bavbek N, et al. Effect of treatment of hyperuricemia with 
allopurinol on blood pressure, creatinine clearence, and proteinuria in patients with normal renal functions. Int Urol 
Nephrol. 2007;39(4):1227-33. 
57. 
Ruggiero C, Cherubini A, Ble A, Bos AJ, Maggio M, Dixit VD, et al. Uric acid and inflammatory markers. Eur Heart 
J. 2006;27(10):1174-81. 
58. 
Ruggiero C, Cherubini A, Miller E, 3rd, Maggio M, Najjar SS, Lauretani F, et al. Usefulness of uric acid to predict 
changes in C-reactive protein and interleukin-6 in 3-year period in Italians aged 21 to 98 years. Am J Cardiol. 
2007;100(1):115-21. 
59. 
Fulop T, Rule AD, Schmidt DW, Wiste HJ, Bailey KR, Kullo IJ, et al. C-reactive Protein among Community-Dwelling 
Hypertensives on Single-agent Antihypertensive Treatment. J Am Soc Hypertens. 2009;3(4):260-6. 
60. 
Palmas W, Ma S, Psaty B, Goff DC, Jr., Darwin C, Barr RG. Antihypertensive medications and C-reactive protein in 
the multi-ethnic study of atherosclerosis. Am J Hypertens. 2007;20(3):233-41. 
61. 
Kanbay M, Huddam B, Azak A, Solak Y, Kadioglu GK, Kirbas I, et al. A randomized study of allopurinol on 
endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal 
function. Clin J Am Soc Nephrol. 2011;6(8):1887-94. 


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62. 
Izzard AS, Rizzoni D, Agabiti-Rosei E, Heagerty AM. Small artery structure and hypertension: adaptive changes 
and target organ damage. J Hypertens. 2005;23(2):247-50. 
63. 
Prewitt RL, Rice DC, Dobrian AD. Adaptation of resistance arteries to increases in pressure. Microcirculation. 
2002;9(4):295-304. 
64. 
Rossi R, Chiurlia E, Nuzzo A, Cioni E, Origliani G, Modena MG. Flow-mediated vasodilation and the risk of 
developing hypertension in healthy postmenopausal women. J Am Coll Cardiol. 2004;44(8):1636-40. 
65. 
Shimbo D, Grahame-Clarke C, Miyake Y, Rodriguez C, Sciacca R, Di Tullio M, et al. The association between 
endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort. Atherosclerosis. 
2007;192(1):197-203. 
66. 
Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, et al. Predictive value of brachial flow-mediated 
dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. 
Circulation. 2009;120(6):502-9. 
67. 
Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial 
dysfunction. Kidney Int. 2005;67(5):1739-42. 
68. 
George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by 
profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114(23):2508-16. 
69. 
Loeb JN. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum. 1972;15(2):189-
92. 
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Winkleby MA, Kraemer HC, Ahn DK, Varady AN. Ethnic and socioeconomic differences in cardiovascular disease 
risk factors: findings for women from the Third National Health and Nutrition Examination Survey, 1988-1994. Jama. 
1998;280(4):356-62. 
71. 
Gaffo AL, Jacobs DR, Jr., Lewis CE, Mikuls TR, Saag KG, editors. Race is associated with the risk of developing 
hyperuricemia in men: Findings from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Meeting 
of the American College of Rheumatology; 2009 October 16-21; Philadelphia, PA. 
72. 
Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 
1971-1992. National Health and Nutrition Examination Survey. Jama. 2000;283(18):2404-10. 
73. 
Becker MA, Meenakshi J. Clinical Gout and the Pathogenesis of Hyperuricemia. In: Koopman WJ, Moreland LW, 
editors. Arthritis and allied conditions : a textbook of rheumatology. 15th ed. Philadelphia: Lippincott Williams & Wilkins; 
2005. p. 2 v. (xxiv, 2699, 108 p). 
74. 
Hughes LB, Morrison D, Kelley JM, Padilla MA, Vaughan LK, Westfall AO, et al. The HLA-DRB1 shared epitope is 
associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis 
Rheum. 2008;58(2):349-58. 
75. 
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the 
ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the 
International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39(2):257-65. 
76. 
Harris RA, Nishiyama SK, Wray DW, Richardson RS. Ultrasound assessment of flow-mediated dilation. 
Hypertension. 2010;55(5):1075-85. 
77. 
Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, et al. Assessment of flow-mediated dilation in 
humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011;300(1):H2-12. 
78. 
Stamp L, Searle M, O'Donnell J, Chapman P. Gout in solid organ transplantation: a challenging clinical problem. 
Drugs. 2005;65(18):2593-611. 
79. 
Ockene IS, Matthews CE, Rifai N, Ridker PM, Reed G, Stanek E. Variability and classification accuracy of serial 
high-sensitivity C-reactive protein measurements in healthy adults. Clin Chem. 2001;47(3):444-50. 
80. 
Meirelles Cde M, Leite SP, Montenegro CA, Gomes PS. Reliability of brachial artery flow-mediated dilatation 
measurement using ultrasound. Arq Bras Cardiol. 2007;89(3):160-7, 76-83. 
81. 
James GD, Pickering TG, Yee LS, Harshfield GA, Riva S, Laragh JH. The reproducibility of average ambulatory, 
home, and clinic pressures. Hypertension. 1988;11(6 Pt 1):545-9. 


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monitoring. The Fourth International Consensus Conference on 24-Hour Ambulatory Blood Pressure Monitoring. 
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Kim SC, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous reactions requiring hospitalization in 
allopurinol initiators: a population-based cohort study. Arthritis Care Res (Hoboken). 2013;65(4):578-84. 
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guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to 
hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-46. 
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Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, Toba K, et al. Modulation of endothelium-dependent 
flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation. 1995;92(12):3431-5. 
 
 
 
 


Appendix 1


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screening visit to complete any outstanding screening tests. If you continue to qualify to participate in this 
study by meeting all study requirements, you will be scheduled to return to the study center two weeks after 
the screening visit.
It is also possible that you may not meet certain study requirements at some study visits and the study doctor 
may discontinue your participation. If you are unable to continue in the study, you will stop receiving the study 
medication and your study doctor may advise you to start on other treatments to control your blood pressure. 
At that point, your participation in the study will end.
If you qualify, you will be randomly assigned, like the flip of a coin, and have a 50-50 chance of receiving either 
placebo or a dose (300mg) of allopurinol. You will not know whether you are receiving allopurinol or the 
inactive placebo. All participants will receive placebo at some point in the study. During the screening visit, 
you will be given a two-week supply of study medication. You will take one pill once every morning between 8 
and 10 am. 
Blood Tests: Blood will be drawn five times during this study. Needle sticks are painful for short period of time 
and sometimes will bruise at the spot for a couple of days. You might feel dizzy or faint during a
blood draw but this generally passes within a few minutes. Each time we draw blood, we will take
approximately about 1½ tablespoons of blood. We will do several tests including ones to make sure it is safe to 
use the study medicines, to look for any side effects of the study medicine and to measure several chemicals 
in the blood that control blood vessels and blood pressure.
Urine Test and Collection: Women capable of becoming pregnant will have a urine pregnancy test to exclude 
pregnancy at the beginning of the study before enrollment. The study doctor or study staff will tell you if the 
pregnancy test results are positive. The results of the pregnancy test must be negative in order for you to be in 
the study. At visits 1-5, urine will be collected from men and women using a collection cup.  Will do several 
tests including ones to make sure it is safe to use the study medicines, to look for any side effects of the study 
medicine and to measure several chemicals in the urine that affect blood pressure.
Blood Pressure Tests: We will do two types of blood pressure tests during this study. The first will use a
common blood pressure cuff just like in any doctor's office. At each visit we will measure blood
pressure twice on each arm. The second blood pressure test is called ambulatory blood pressure monitoring. 
You will wear a blood pressure cuff on one arm for 24 hours and an automatic monitor will measure and 
record blood pressure 2-3 times an hour while you are at home, work, or school. 
Flow Mediated Dilation (FMD): At visits 2-5 a FMD will be done to measure the function of your blood vessels. 
You will wear a cuff, similar to a blood pressure cuff, on your upper and lower arm while an image of your 
blood vessel is recorded. 
Survey: At visits 2-5, you will complete a survey that asks questions about your feelings and behavior.  The 
survey will take approximately 5 minutes to complete.
Screening Visit (Visit 1)
Before the study starts, you will be asked to sign this consent form and give your health history. The study 
doctor will perform procedures and tests to find out if you can be in the study. These tests include:


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
Review inclusion and exclusion criteria to assess your eligibility for the study.

Recording of your personal information, such as your name, age, race, etc.

Recording of your medical and surgical history including documentation of blood pressure.

Recording of all prior and current prescription medications, over the counter medications, vitamins and 
herbs. The study doctor may instruct you not to take certain medications within 48 hours of the next 
visit.

Measurement of your pulse rate, respiratory rate (your breathing rate), temperature, height, and 
weight.

A complete physical exam. You should ask the study doctor about what will happen during this exam.

Collection of urine and blood samples (about 1½ tablespoons of blood) for clinical laboratory analysis 
and pregnancy screening for women of childbearing potential. The study doctor or study staff will tell 
you if the pregnancy test results are positive. The results of the pregnancy test must be negative in 
order for you to be in the study
Visits 2, 3, 4, 5
You will return to the UAB Hypertension Clinic every 2-4 weeks (weeks 3, 6, 9, and 12) for scheduled clinic 
visits. These clinic visits will last about 60 minutes (1 hour). During these visits you will have your blood drawn, 
urine collected, blood pressure measured and a flow mediated dilation will be performed to evaluate 
endothelial function. You will be given a 24-hour blood pressure monitoring device and will have the 
opportunity to report any problems or concerns you have. Additionally, you will be given a survey that will 
take approximately 5 minutes to complete.
Starting at Visit 2 (week 3) you will be given a 4-week supply of allopurinol or placebo. You will take one pill 
once every morning between 8 and 10 am. Neither the physician nor you will know if you are taking 
allopurinol or placebo. At visit 4 you will receive a new 4-week supply of supply of allopurinol or placebo. All 
participants will receive placebo at some point in the study.
The following procedures will be performed at Visits 2, 3, 4, 5:

Confirm you did not exercise, smoke, drink any caffeinated beverages, or eat or drink grapefruit for at 
least two hours prior to this visit

Review of your current medications and any medical complaints or improvements you may have had 
since your last visit.

Measurement of your blood pressure and heart rate between 6:30 am and 10 am.

Collection of fasting blood samples (about 1.5 tablespoons of blood) for clinical laboratory analysis. If 
you are not fasting at least 8 hours at the time of the visit, the visit will be re-scheduled within 1-2 
days. Fasting means you are to have no food or drink except for water for at least 8 hours before the 
study visit.

A flow mediated dilation will be performed. 

You will be assigned a 24-hour blood pressure monitor and provided materials to return it to the UAB 
Hypertension Clinic in the provided stamped addressed box. 

You will complete a brief survey.

At Visit 2, dispense study medication to last 4 weeks until the next study visit. You will be instructed to 
take one pill each morning between 8 am and 10 am

At Visit 3, collection of all used/unused study medication.  No medication will be dispensed at this visit.

At Visit 4, dispense study medication to last 4 weeks until the next study visit. You will be instructed to 
take one pill each morning between 8 am and 10 am

At Visit 5, you will return all unused study medication.


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 RESEARCH PARTICIPANT RESPONSIBILITIES
As a participant in this research study, it is asked that you  carefully follow the instructions of the study doctor 
and study staff. You will be asked to :

Follow the instructions you are given.

Read this Information and Consent Form and ask as many questions as needed.

Provide the study doctor with a complete history of illnesses (and medications) you have had in the 
past.

Tell the study doctor or study staff about any changes in your health or the way you feel.

Tell the study doctor or study staff if you want to stop being in the study at any time.

Provide the study doctor with the name, address and phone number of your current regular doctor, 
and whether or not the study doctor can contact this doctor about your being in this study or to 
request your medical records.

Schedule and attend visits with the study center in the morning to ensure that blood pressure 
measurements are taken between 6:30 am and 10 am.

Keep to the schedule of visits and if there is a problem, call the study staff to reschedule.

Take your study medication as directed. Do not abruptly stop taking study drug.

Complete all tests and procedures to the best of your ability.

Inform the study doctor or study staff of any medications you may have taken between visits.

Ask questions during the study about anything you may be concerned about.

Refrain from drinking excessive amounts of alcohol (no more than 2 drinks per day) and refrain from 
taking any illegal substances during this study.

Refrain from exercise, smoking, drinking any caffeinated beverages, and eating or drinking grapefruit 
for at least two hours prior to each visit.

Refrain from taking medications that the study doctor has asked you not to take while participating in 
this study.

Fast overnight and the morning before coming to certain study visits if instructed to do so. Fasting 
means you are to have no food or drink except water for at least 8 hours before your study visit.

Keep the study medication at room temperature and out of the reach of children or other adults. The 
study medication must be taken only by you, the person participating in the study.

Do not donate blood while you are participating in the study and for up to one month after you have 
completed the study.

You cannot participate in this study if you are pregnant.
POSSIBLE HAZARDS, RISKS, AND DISCOMFORTS OF PARTICIPATING IN THE STUDY
Participation in this study may involve some inconvenience, risks, or discomforts. The most common side 
effect for allopurinol is stomach upset. Allopurinol can also rarely irritate the liver or cause blood counts to fall 
and changes to blood, skin, and liver are not always reversible.
Another uncommon side effect of allopurinol is skin rash.  Very rarely (less than one in one-thousand people) 
this skin rash may be followed by a severe reaction known as allopurinol hypersensitivity syndrome (AHS), a 
condition that may become life-threatening.  You should not take part in the study if you have ever had a 
serious reaction to allopurinol.  You should tell the study doctor immediately if you have a rash or another 
allergic reaction during the study.  


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Other side effects of allopurinol include:
•
diarrhea
•
nausea
•
Drowsiness (sleepiness) 
Ask the study doctor if you have questions about these or other risks of taking allopurinol.
Venous blood sampling will rarely cause bruising or a superficial skin infection. 
The 24-hour ambulatory blood pressure monitoring can cause some mild discomfort during cuff inflation. The 
24 hour ambulatory blood pressure monitors must be worn overnight and may interrupt sleep. The blood 
pressure may remain elevated during the study period, which does increase risk of having a stroke, heart 
attack, heart failure, or kidney damage. 
The flow mediated dilation procedure can cause some mild discomfort during cuff inflation.
The survey may cause some mild unease when answering questions about your feelings and behavior.
Information for Women of Childbearing Potential
The risks to pregnant women or an unborn baby when taking allopurinol is not fully known.  For this reason, 
women must have a pregnancy test before the study starts and again throughout the study.  You must not 
become pregnant during this study.  If you are a woman of childbearing potential, you must use an effective 
non-hormonal form of birth control during this study and for 30 days after completion of the study.  
Acceptable methods of birth control include a double-barrier method (diaphragm with spermicide, condom 
with spermicide) or abstinence.  
If you suspect that you may have become pregnant during the study, you must contact the study doctor 
immediately and stop taking your study medication.  If it is confirmed that you are pregnant, you will be 
withdrawn from the study.  Your study doctor may want to follow you and the outcome of your pregnancy.  
Your pregnant partner may be asked for permission for the study doctor to follow the pregnancy to its 
outcome.  
Taking allopurinol may involve unknown risks to a nursing infant.  If you are breastfeeding, you cannot 
participate in the study.
ALTERNATIVE 
The alternative is to not participate in this study and receive standard care for high blood pressure.
SIGNIFICANT NEW FINDINGS
All new findings discovered during this research study that may reasonably influence your willingness to 
continue participation in this study will be provided to you when they become available.


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BENEFITS OF THE STUDY
There may be no direct benefit to you. If successful, the study results may allow for safer treatment of 
hypertension.
COSTS
There is no cost for participating in this study. There will be no charge for the study visits or study procedures. 
The cost of any routine medical care needed during the study period will be billed to your insurance company 
in the usual manner. The study medication will be provided to you at no charge. 
Payment for Participation 
You will be paid $25 for each completed clinic visit and flow mediated dilation procedure. In addition, you will 
receive $100 for each complete 24-hour ambulatory blood pressure recording session. Should you withdraw 
from the study, you will be paid for the completed visits up to the date of withdrawal. If you complete all 
study visits and procedures you will receive up to a total of $525.00.  Ask the study staff about the method of 
payment that will be used for this study (e.g., check, cash, gift card, direct deposit).
CONFIDENTIALITY
Your personal information will be entered into a study database. Access to this database will be limited to 
study personnel. Research information that identifies you may be shared with the UAB Institutional Review 
Board (IRB) and others who are responsible for ensuring compliance with laws and regulations related to 
research, including the U.S. Food and Drug Administration (FDA), the Office for Humans Research Protections 
(OHRP); and the study sponsor the National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS).  Because of the need to release information to these parties, absolute confidentiality cannot be 
guaranteed.  The information gathered during this study will be kept confidential to the extent permitted by 
law.  The results of this study may be published in scientific journals or presented at medical meetings, but 
your identity will remain confidential. 
Information relating to this study, including your name, medical record number, and date of birth may be 
shared with the billing offices of UAB and UAB Health System-affiliated entities so that claims may be 
appropriately submitted to the study sponsor or to the participant’s insurance company for clinical services 
and procedures provided to participant during the course of this study.
COMPENSATION FOR INJURY
In the event that you experience an injury during the course of this study, you should immediately contact Drs. 
The University of Alabama at Birmingham (UAB) and the study sponsor the National Institute of Arthritis and 
Musculoskeletal and Skin Diseases (NIAMS) have not provided for any payment if you are harmed as a result 
of taking part of this study. If such harm occurs, treatment will be provided. However, this treatment will not 
be provided free of charge.
STUDY RIGHTS AND STUDY WITHDRAWAL
Participation in this study is entirely voluntary. Your treatment and the attitude of your doctor toward you will 
not be affected should you decide not to take part in this study.  Refusal to participate will not affect any 
benefits to which you are otherwise entitled. If you agree to participate, you may withdraw from the study at 
any time.


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 If you are a UAB student or employee, taking part in this research is not a part  of your  UAB class work or 
duties.  You can refuse to enroll or withdraw after enrolling at any time before the study is over with no effect 
on your class standing, grades, or job at UAB. You will not be offered or receive any special consideration if 
you take part in this research.
You may refuse to participate or even withdraw once the study has started. In either case, you will not be 
penalized or lose any benefits to which you are otherwise entitled.  
QUESTIONS
While you are participating in this study, if you have any questions or concerns, you should contact Drs. Saag, 
Calhoun, or a member of their staff at 
 After regular business hours (after 4pm and before 
7am), please call the UAB operator at 
 and ask for Dr. Kenneth G. Saag or Dr. David Calhoun to 
be paged.
You will be given a copy of this informed consent document and may ask for additional information at any 
time during the study from Drs. Saag or Calhoun or a member of their staff at 
If you have questions about your rights as a research participant, or concerns or complaints about the 
research, you may contact the Institutional Review Board for Human Use (OIRB) a
egular hours for the Office of the IRB are 8:00 a.m. to 5:00 p.m. CT, Monday through Friday. You may 
also call this number in the event the research staff cannot be reached or you wish to talk to someone else.
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. 
LEGAL RIGHTS
You are not waiving any of your legal rights by signing this consent form.
STORAGE OF SPECIMENS FOR FUTURE USE
As part of this study, we would like to store some of the blood and urine specimens collected from you for 
future research in hypertension and rheumatology. The future research may be conducted by Dr. Kenneth 
Saag or Dr. David Calhoun or by other researchers that obtain IRB approval for their research. The specimens 
will be labeled with a code that only Dr. Kenneth Saag and Dr. David Calhoun can link back to you. Results of 
any future research will not be given to you or your doctor. The specimens obtained from you in this research 
may help in the development of a future commercial product. There are no plans to provide financial 
compensation to you should this occur.
You do not have to agree to allow your blood and urine specimens to be stored in order to be part of this 
study.
You may request at any time that your research samples be removed from storage and not be used for future 
research. If you decide you want your samples removed, you may contact Dr. Kenneth Saag or Dr. David 
Calhoun at the University of Alabama at Birmingham at 205-996-6086. Once the request is received, and if 
your samples have not already been used for other research, they will be destroyed. If you do not make such a 
request, your specimens will be stored indefinitely or until used.


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Initial your choice below:
___ I agree to allow my samples to be kept and used for future research on hypertension.
___ I do not agree to allow my samples to be kept and used for future research .
SIGNATURES
Your signature below indicates that you agree to participate in this study. You will receive a copy of this signed 
informed consent.
_________________________
Printed Name of Participant
_________________________
______________
Signature of Participant
Date
    
_________________________
_______________
Signature of Witness
Date
_________________________
_______________
Signature of Person Obtaining
Date
Consent 


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University of Alabama at Birmingham
AUTHORIZATION FOR USE/DISCLOSURE OF 
PROTECTED HEALTH INFORMATION (PHI) FOR RESEARCH
Participant Name:  
UAB IRB Protocol Number:  F130408004
Principal Investigator: Kenneth Saag, MD and David Calhoun, MD
Research Protocol:  Project 2: Serum Uric acid Reduction 
to Prevent HypERtension Study
Sponsor:  National Institute of Arthritis and Musculoskeletal and 
Skin Diseases (NIAMS)
What is the purpose of this form?  You are being asked to sign this form so that UAB may use and release your protected health 
information for research.  Participation in research is voluntary.  If you choose to participate in the research, you must sign this 
form so that your protected health information may be used for the research.
Why do the researchers want my protected health information?  The researchers want to use your protected health 
information as part of the research protocol listed above and as described to you in the informed consent.
What protected health information do the researchers want to use?  All medical information, including but not limited to 
information and/or records of any diagnosis or treatment of disease or condition, which may include sexually transmitted 
diseases (e.g., HIV, etc.) or communicable diseases, drug/alcohol dependency, etc.; all personal identifiers, including but not 
limited to your name, social security number, medical record number, date of birth, dates of service, etc.; any past, present, and 
future history, examinations, laboratory results, imaging studies and reports and treatments of whatever kind, including but not 
limited to drug/alcohol treatment, psychiatric/psychological treatment; financial/billing information, including but not limited to 
copies of your medical bills,  and any other information related to or collected for use in the research protocol, regardless of 
whether the information was collected for research or non-research (e.g., treatment) purposes.
Who will disclose, use and/or receive my protected health information?  All Individuals/entities listed in the informed consent 
documents, including but not limited to, the physicians, nurses and staff and others performing services related to the research 
(whether at UAB or elsewhere); other operating units of UAB, HSF, UAB Highlands, Children’s of Alabama, Eye Foundation 
Hospital, and the Jefferson County Department of Health, as necessary for their operations; the IRB and its staff; the sponsor of 
the research and its employees and agents, including any CRO; and any outside regulatory agencies, such as the Food and Drug 
Administration, providing oversight or performing other legal and/or regulatory functions for which access to participant 
information is required.
How will my protected health information be protected once it is given to others?  Your protected health information that is 
given to the study sponsor will remain private to the extent possible, even though the study sponsor is not required to follow the 
federal privacy laws. However, once your information is given to other organizations that are not required to follow federal 
privacy laws, we cannot assure that the information will remain protected.
How long will this Authorization last?  Your authorization for the uses and disclosures described in this Authorization does not 
have an expiration date.
Can I cancel this Authorization?  You may cancel this Authorization at any time by notifying the Principal Investigator, in writing, 
referencing the research protocol and IRB Protocol Number. If you cancel this Authorization, the study doctor and staff will not 
use any new health information for research. However, researchers may continue to use the protected health information that 
was provided before you cancelled your authorization.
Can I see my protected health information?  You have a right to request to see your protected health information. However, to 
ensure the scientific integrity of the research, you will not be able to review the research information until after the research 
protocol has been completed.
Signature of participant: 
Date: 
or participant's legally authorized representative: 
Date: 
Printed Name of participant’s representative: 
Relationship to the participant: 


 
 
Appendix 2‐ Study Forms and Screenshots from the REDCap System 
Screen shots from the REDCap System 
Project 2: The Effects of Urate Lowering Therapy on Inflammation, Endothelial 
Function, and Blood Pressure (NIAMS: CORT) 
1. 
Prescreening call #1 – Eligibility criteria 
2. 
Prescreening call #2 – Contact information 
3. 
Screening visit #1 – Blood pressure measurement 
4. 
Screening visit #2 – Medical history, sample collection and pill distribution 
5. 
Screening visit #3 – Laboratory results 
6. 
Phone Check‐in #1 
7. 
Phone Check‐in #2 
8. 
Visits 2, 3, 5 #1 – Pill count, adverse event check, and physical exam 
9. 
Visit 4 #1 – Adverse event check and physical exam 
10. 
Visit 2‐5 #2 – Current medical conditions and medications, blood pressure 
measurement 
11. 
Visit 2‐5 #3 – Sample collection and laboratory results 
12. 
Visit 2‐5 #4 – Flow‐mediated dilation 
13. 
Between visits phone check‐in 
14. 
Adverse event report 
15. 
Study completion  
 
Following the screening visit (visit 1) the screen shots for study visits 2‐5 repeat in 
the system.  
 
 


Appendix 2 
 
 
 
Page 1 of 15 
Screenshot 1. Prescreening call #1 – Eligibility criteria 
 


Appendix 2 
 
 
 
Page 2 of 15 
Screenshot 2. Prescreening call #2 – Contact information 
 


Appendix 2 
 
 
 
Page 3 of 15 
Screenshot 3. Screening visit #1 – Blood pressure measurement 
 


Appendix 2 
 
 
 
Page 4 of 15 
Screenshot 4. Screening visit #2 – Medical history, sample collection and pill distribution 
 


Appendix 2 
 
 
 
Page 5 of 15 
 
Screenshot 5. Screening visit #3 – Laboratory results 
 
 
 
 
 


Appendix 2 
 
 
 
Page 6 of 15 
Screenshot 6. Phone Check‐in #1 
 
 
 
Screenshot 7. Phone Check‐in #2 
 
 
 
 
 
 


Appendix 2 
 
 
 
Page 7 of 15 
Screenshot 8. Visits 2, 3, 5 #1 – Pill count, adverse event check, and physical exam 
 


Appendix 2 
 
 
 
Page 8 of 15 
Screenshot 9. Visit 4 #1 – Adverse event check and physical exam 
 
 
 
 


Appendix 2 
 
 
 
Page 9 of 15 
Screenshot 10. Visit 2‐5 #2 – Current medical conditions and medications, blood pressure measurement 
 


Appendix 2 
 
 
 
Page 10 of 15 
Screenshot 11. Visit 2‐5 #3 – Sample collection and laboratory results 
 


Appendix 2 
 
 
 
Page 11 of 15 
Screenshot 12. Visit 2‐5 #4 – Flow‐mediated dilation 
 


Appendix 2 
 
 
 
Page 12 of 15 
Screenshot 13. Between visits phone check‐in 
 
 
 


Appendix 2 
 
 
 
Page 13 of 15 
Screenshot 14. Adverse event report 
 
 
 


Appendix 2 
 
 
 
Page 14 of 15 
Screenshot 14 (continued). Adverse event report 
 


Appendix 2 
 
 
 
Page 15 of 15 
Screenshot 15. Study completion  
 


MOOP Appendix 3- Revised 4/12/2018 
Page 1 of 11 
 
 
APPENDIX 3. Standard Operating Procedures 
 
A. Standard Operating Procedure - Obtaining Consent 
1. The informed consent will be obtained before any study procedures are performed 
(including washout from any medications). 
2. Study coordinator will check the shared drive to ensure the correct and current IRB 
approved consent form is used for consenting. 
3. Use the most recently approved consent form to give to the patient. 
4. All patient will be given adequate time to read the informed consent in a quiet room. 
5. Study coordinator will administer the informed consent and will provide an opportunity 
to discuss any questions the patient might have. Dr. Angelo Gaffo will also be available 
to answer any questions prior to or on the day of enrollment of the patient into a study. 
 
Review the following details with the patient: risks, benefits, alternative treatments, 
length of the study, interval of visits including time involvement, purpose of the study, 
any placebo use, FDA approval of medication, procedures to be performed along with 
risks, side effects of drug(s) used, need for compliance in the study, and benefits. 
 
6. Any patient who states either they cannot see or cannot read will have the consent read 
to them 
7. After the consenting process is completed the patient will sign and date each required 
page. Verify participant signatures and authorization to store lab samples for future use 
(not required for participation). 
8. Review the consent for completeness of signatures and dates. 
9. After the participant has signed the consent form, the Principle Investigator and/or the 
study coordinator must sign and date the Informed Consent document. 
10. A signed version of the consent form will be kept by the study staff in the study binder. 
11. An additional copy of the signed consent form will be given to the patient the same day 
along with the visit reminder brochure and instruction for ambulatory blood pressure 
monitor. 


MOOP Appendix 3- Revised 4/12/2018 
Page 2 of 11 
 
B. Standard Operating Procedure - Blood Pressure Measurement 
1. Patient Preparation 
 
Have patient sitting comfortably for at least 5 minutes. The patient’s legs should be 
uncrossed with his or her feet flat on the floor. The arm to be used for assessing blood 
pressure must be exposed and free of constrictive clothing and supported by a table or 
armrest.  The patient should remain quiet during the examination process. 
 
2. Sphygmomanometer Placement 
 
The sphygmomanometer should be at the eye level of the examiner. The cuff when 
placed on the patient’s arm should be at his or her heart level. 
 
3. Proper Cuff Size 
 
The arm circumference is measured at the midpoint of the upper arm, between the 
olecranon and the acromion processes.  Arm circumferences of 22 cm-26.9 cm require use 
of a small adult/pediatric cuff; arm circumferences between 27cm-32.9 cm require a regular 
adult cuff; circumferences between 33 and 40.9 cm require use of a large adult cuff; arm 
circumferences between 41cm and 52cm require use of a thigh cuff. 
 
4. Cuff Placement 
 
Locate the patient’s brachial artery at the midpoint of the upper arm. Wrap the cuff 
smoothly and snugly around the arm with the bladder center directly over the palpated 
artery and lower edge of the cuff 2.5 cm above the antecubital fossa. 
 
5. Procedure 
 
Press the START/STOP button. The cuff will inflate automatically. The patient should remain 
still and not move their arm prior to measurement completion. Inflation stops automatically 
and the measured is started. When complete, the arm cuff automatically deflates and 
SBP/DBP and HR are displayed. A minimum of 3 recorded measurements taken 5 min apart 
are necessary.  
 
Special Techniques 
6. Standing Blood Pressure 
 
Standing blood pressure is measured after making sitting assessments. Using the same arm 
used to obtain sitting values, have the patient stand fully upright. While supporting the arm 
in which the blood pressure is being measured, determine values as above. By convention, 
pressures are obtained 1 and 3 minutes after standing. 
 
7. Korotkoff Sounds Poorly Heard 


MOOP Appendix 3- Revised 4/12/2018 
Page 3 of 11 
 
If the Korotkoff sounds are poorly heard, ensure proper placement of stethoscope directly 
over the brachial artery, attempt using the diaphragm of the stethoscope instead of the 
bell, and/or have the patient hold his or her arm upright for a few minutes before repeating 
procedures. 
 
C. Standard Operating Procedure – Brachial Artery Ultrasound Protocol (Flow Mediated 
Dilation) 
FMD are recorded on tapes, but simultaneously digitalized all recording can be electronically 
emailed and archived. This ensures that all investigators can easily exchange recordings, peer- 
review recordings, analyze data over the study period. Project Co-investigator Dr. Tanja 
Dudenbostel will administer and monitor all FMDs. 
 
Ultrasound machine: Philips Agilent SONOS 5500, the ultrasound head is 15-6L. 
Software system to be used: Vascular Research Tool 5, by Medical imaging Applications, LLC. 
Steps: 
1. Baseline 
 Acquire 15 baseline 2D images 
 Acquire 10 cycles of baseline Doppler 
 
2. Inflation 
Inflate cuff pressure 50 mm/Hg>SBP (or until vessel occludes) for 5 minutes 
 
3. Deflation 
 Acquire 10 cycles of hyperemic Doppler 
 Acquire 120 seconds of 2D images 
 
D. Standard Operating Procedure- 24-hour Ambulatory Blood Pressure Monitoring 
Twenty-four hour ABPM monitors (Spacelabs Healthcare, Snoqualmie, WA) are to be worn by 
the enrolled participants for the entire 24-hour period. 
Software system: Reports of 24-hour ABPM are available as PDF and can be easily exported to 
an EXCEL database. 
Monitor: 90207, 90217 from Spacelabs Healthcare 
 
1. Determine Cuff Size 
Using incorrect cuff size could result in erroneous and misleading blood pressure 
measurements. Determine correct cuff size before beginning. 
 Wrap the cuff around the patients upper arm without sliding the arm through 
the sleeve 
 Use the color coded RANGE indicator on the inside of the cuff and the bold 
INDEX marker to check that the arm circumference falls within the cuff range 
 If the arm is within range, this cuff is the correct. If the measurement is outside 
the RANGE indicator, select a new cuff size as indicated by color. 
2. Apply the Cuff 
 Simply slide the sleeve up the patients arm, ensuring the artery arrow points 


MOOP Appendix 3- Revised 4/12/2018 
Page 4 of 11 
 
down the arm. The cuff should be midway between the elbow and shoulder. 
 Be sure the artery indicator is over the patient’s brachial artery, between the 
biceps and triceps muscles (see illustration below) 
 
 Wrap the cuff snugly around the patients upper arm 
 Take the initial BP reading and ensure hook up is working properly. 
 
3. Prepare the Patient 
Preparing the patient is the most important step in obtaining accurate, reliable blood 
pressure measurement. 
The following must be reviewed with all participants: 
 
 Avoid excess movement during readings 
 Relax the instrumented arm, slightly away from body 
 Avoid hand movement 
 Avoid flexing muscles during reading 
 Do not remove the cuff between readings 
E. Standard Operating Procedure- Adverse And Serious Adverse Event Reporting 
1. Definition 
The International Conference on Harmonization (ICH) Good Clinical Practice defines an 
adverse event as an “untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment.” An Adverse Event can become a Serious 
Adverse Event. A Serious Adverse Event is defined by the ICH as “any untoward medical 
occurrence that at any dose: 
 results in death, 
 is life-threatening, 
 requires inpatient hospitalization or prolongation of 
existing hospitalization, 
 results in persistent or significant disability/incapacity, 
or 
 is a congenital anomaly/birth defect 
 
2. Observation 
At each visit after screening during the study, a patient will be queried and observed in 
an objective manner for any changes in signs or symptoms or any new signs or 
symptoms that may have occurred since the preceding visit. If any adverse event has 


MOOP Appendix 3- Revised 4/12/2018 
Page 5 of 11 
 
occurred, the investigator or a designated member of his staff will determine the 
following in regards to the adverse event: 
 the location of the sign or symptom 
 
 the time of the start and end of the sign or symptom 
 
 the clinical description and measurement of the sign or symptom 
 
 how the sign or symptom came about in terms of setting, activity, or previous 
episodes 
 possible causes of the sign or symptom 
 
 the intensity of the sign or symptom 
 
 the degree to which the sign or symptom may be related to the study drug. 
 
 
3. Management 
The investigator or a designated staff member will take action to assure that patient 
receives whatever treatment for the adverse event is required or appropriate, either by 
providing treatment or instructing the patient to seek the care of a physician of the 
patient’s choice, such as the patient’s primary care physician. The investigator or a 
designated staff member will continue to follow the patient with regard to the progress 
and/or resolution of the adverse event. 
Whether the study medication should be interrupted or discontinued in response to an 
adverse event is a determination made at the investigator’s discretion unless it is 
specified in the study protocol. If an acute emergency arises in the patient’s condition, 
the randomization code may be broken, if this is required for the welfare of the patient. 
 
4. Documentation 
The description of the adverse event, including all of the above observations and 
management, will be recorded in Adverse Event Form, in REDCap and printed for the 
principal investigator to review and sign the documentation of the adverse event. This 
signed document will be archived electronically and in hard copy in the study binder. 
 
5. Reporting 
It is the responsibility of the investigator to report any adverse event to the sponsor and 
the institutional review board (IRB) of the study as soon as possible or “within 10 
working days after the investigator learns of the adverse event.” (ICH) If the Adverse 
Event is determined to be a Serious Adverse Event (SAE), it is the responsibility of the 
investigator to report the Serious Adverse Event to the sponsor immediately, and no 
later than 48 hours. Appropriate reports will be filed or faxed to the sponsor according 
to the study protocol. 
 
F. General Instructions for Completing Forms in REDCap 
 


MOOP Appendix 3- Revised 4/12/2018 
Page 6 of 11 
 
All data recorded in REDCap will be maintained according to FDA and ICH Good Clinical Practice 
(GCP) guidelines. Instructions for completing eCRFs to ensure quality and consistency in data 
collection are below. 
 
When completing electronic study forms participants must not be identified by name on any 
study document submitted with the forms (e.g. lab reports). Replace the participant name with 
the participant initials and study identification (ID) number. 
 
Participant ID:  The participant ID will be prepopulated in the header of each page. 
 
Dates: All dates will be entered using the calendar feature in REDCap. For AEs historical dates 
are sometimes not known (e.g., date of first symptom); in this case, chose Not Applicable, 
UNKNOWN or UNK to indicate missing data. 
 
Abbreviations: Do not use abbreviations not specifically noted in the instructions for 
completing the forms. Comments should only be written where text fields are provided. 
 
Correcting errors: Errors can be corrected within the REDCap system where a timestamp and 
date are associated with each entry and revision.  
 
Missing or Incomplete data 
Data may not be available to complete the eform for various reasons. Electronic forms that are 
missing or not complete should be noted, in the field INCOMPLETE/UNVERIFIED field and 
brought to the attention of the investigator. Forms with missing data in fields or sections should 
be marked as such. Indicate the reason for the missing data in the field. If the evaluation was 
not done, type NOT DONE or ND and provide a reason in the available text field or from the 
dropdown. 
 
Incomplete or Illegible forms: 
If any section or an entire page of the forms cannot be completed (e.g., no parts have any 
responses), and it is unlikely that it will be completed, choose INCOMPLETE/UNVERIFIED, as 
appropriate. Do not leave forms incomplete or unused without explanation in the MISSING 
FORMS / INCOMPLETE FORMS field. 
 
All form header information must be completed even though no data are recorded on the 
electronic form. If an electronic form can only be partially completed at the time of visit, but 
will be completed when the information becomes available, note this in the 
INCOMPLETE/UNVERIFIED field and follow the direction of the study coordinator and principle 
investigator. 
 
Every effort should be made to obtain and ensure that the electronic forms are being 
completed correctly. 


MOOP Appendix 3- Revised 4/12/2018 
Page 7 of 11 
 
G. Standard Operating Procedures- Serum and DNA Processing And Storage 
 
If specimen collection is scheduled the day before a holiday, check with Dr. Bridges’ lab manger 
to see if lab personnel will be available. 
 
 
Processing of Blood Samples 
 
Blood Collection, Processing and Storage 
Instructions and forms 
Sample Processing Instructions 
(Serum/DNA) 
Laboratory Test 
Procedures 
Serum Sample 
 
 
 
 
 Collect blood into one 10.0 cc red/black tiger top tube (SST 
tube) 
 
Invert the tube gently 8 times, then let the tube sit at 
room temperature for approximately 30 minutes or until 
the blood has completely clotted. 
 
Record draw date and time). 
 
Process SST tube per protocol for separation of serum. 
DNA Testing: 
Purple EDTA Tube 
 
 
 
 
 
 
 
 
Collect blood into TWO purple top 10 ml (EDTA) tubes and 
one 4 cc EDTA for CBC and ESR. 
 
Invert the tube several times gently after the blood draw. (Do 
NOT Centrifuge samples!) 
 Place the aliquot tube in a 100 position box, record the 
locations in an excel file and place the box in a -80C freezer. 


MOOP Appendix 3- Revised 4/12/2018 
Page 8 of 11 
 
 Pr o cessin g in D r. Brid ges’ Lab  
Upon receipt of blood, Dr. Bridges’ research assistant(s) will process the blood as follows: 
Document receipt of blood samples including number of each type of tube, and date, on the 
Specimen Processing Sheet. 
1.)  Purple top tubes: 
a. Extract genomic DNA from one 500µl aliquot of whole blood using the Gentra 
PureGene Kit: 
(Cell Lysis) 
 Add 500ul whole blood to a 2.0ml microfuge tube containing 1500ul RBC 
Lysis Solution. Invert to mix and incubate 10 minutes at room temp; 
invert again once during incubation 
 Centrifuge for 1 minute at 13K-16K x g. Remove supernatant with a 
micropipette leaving behind visible white cell pellet and 5-10ul of residual 
liquid 
 Vortex tube vigorously to resuspend white blood cells in the residual 
supernatant 
 Add 300ul Cell Lysis Solution to tube and pipet up and down to lyse cells. 
If clumps are visible after mixing, incubate at 37ºC or room temp until 
solution is homogenous. Samples are stable in Cell Lysis Solution at room 
temp for at least 18 months 
(Rnase A Treatment) 
 Add 1.5ul RNase A Solution to the cell lysate 
 Mix the sample by inverting the tube 25 times and incubate at 37ºC for 
15 minutes 
(Protein Precipitation) 
 Cool sample to room temp 
 Add 100ul Protein Precipitation Solution to the cell lysate 
 Vortex vigorously at high speed for 20 seconds to mix 
 Centrifuge at 13K-16K x g for 3 minutes. The precipitated proteins will 
form a tight, dark brown pellet 
(DNA Precipitation) 
 Pour supernatant containing DNA (leaving behind the protein pellet) into 
a clean 1.5ml microfuge tube containing 300ul 100% Isopropanol 
 Mix sample by inverting gently 50 times until the white threads of DNA 
form a visible clump 
 Centrifuge at 13K – 16K x g for 1 minute; the DNA will be visible as a 
small white pellet 
 Pour off supernatant and drain tube on clean absorbent paper. Add 
300ul 70% Ethanol. Invert tube several times to wash DNA pellet 
 Centrifuge at 13K – 16K x g for 1 minute. Carefully pour off the ethanol. 
Pellet may be loose so pour slowly and watch pellet. 


MOOP Appendix 3- Revised 4/12/2018 
Page 9 of 11 
 
 Drain tube on clean absorbent paper and allow to air dry at room temp 
for 15 minutes 
(DNA Hydration) 
 Add 150ul DNA Hydration Solution 
 Allow DNA to rehydrate by heating at 65ºC for 1 hour 
 Determine [DNA] with spectrophotometer and store at –70ºC 
 
b. Let the tube stand in a rack for 30 minutes at room temperature. 
c. Spin in Hamilton tabletop centrifuge for 15 minutes. The three portions are 
plasma, buffy coat at interface, and red blood cells on the bottom. 
d. Transfer with a pipet 2 ml aliquots of plasma into 2 – 4 cryovials. 
e. Label vials with bar-coded FreezerWorks labels. Discard any volume of plasma 
more than 7.2 ml (enough to fill 4 cryovials). 
f. Isolate the buffy coat layer from the remaining blood and aliquot into two 
cryovials. Label all vials with bar-coded FreezerWorks labels. 
g. Isolate 1 ml of Red blood Cells from the bottom of the purple top tube and 
aliquot into one cyrovial. Add 500ul of saline to the tube and spin at 1500 rpm 
for 1 min. Discard supernatant. Label tube with packed RBCs or pRBCs and store 
in -70° C. 
h. Store the plasma, genomic DNA, and buffy coat (for future DNA extraction) at - 
70º C. 
i. Enter the location of all tubes in the Freezer Works database. 
 
 
2.)  Red/gray SST tube: 
a. Centrifuge sample for 15 minutes at room temperature. Transfer with a pipet 2 ml 
aliquots of serum into 2 – 4 cryovials with preprinted, bar-coded WrapAround 
labels. Discard any volume of serum more than 7.2 ml (enough to  fill  4 cryovials). 
b. Store the serum samples at –80C. 
c. Record the location of all tubes in the FreezerWorks database. 
 
3.) File the completed Specimen Processing Sheet in 3 ring binder that is properly 
labeled in the laboratory. 


MOOP Appendix 3- Revised 4/12/2018 
Page 10 of 11
 
Specimen Processing Sheet 
 
Dr. Bridges’ Lab 
 
Patient ID Number   
 
 
  
Date of Processing   
 
  
Visit No.    
                            
Number of blood tubes received: 
Purple 
  
 
SST/Tiger 
  
 
Green 
  
 
Aliquots of plasma from purple top tube: 
Number of cryovials   
 
Barcode 
Freezer location 
Aliquots of buffy coat from purple top tube: 
Number of cryovials   
 
Barcode 
Freezer location 
Genomic DNA extracted from 500 microliters whole blood from purple top tube 
Yield of DNA 
  
 
Barcodes 
Freezer location 
Aliquots of serum from red/gray top tubes: 
Number of cryovials   
 
Barcode 
Freezer location 
 
Blood Collection Information 
 
The table shows the quantity of each sample type along with volume and other processing 
information. All aliquots will be processed and stored in 1.8 ml Nunc tubes. 
 
 
Sample 
Type 
BD 
Collection 
Tube or 
Collection 
Container 
Final 
Tube 
Type 
Final 
Num 
ber 
of 
Aliqu 
ots 
Volume 
(ML) 
Date 
drawn 
Storage 
Temperature 
Date 
Processed 
DNA/Plasm 
a 
EDTA 10 cc 
(1) 
EDTA 
Sent directly to 
lab for 
processing 
Serum 
SST 10cc 
(1) 
1.8 
5 
-80 
 
 
 
 
 
 


MOOP Appendix 3- Revised 4/12/2018 
Page 11 of 11
 
 
H. High Performance Liquid Chromatography (HPLC) Assay for Allopurinol and Oxypurinol in Plasma 
 
Allopurinol and oxypurinol in plasma (extraction protocol above) were analysed by HPLC with ultraviolet 
(UV) detection. Plasma (0.1 ml) was mixed with 0.1 ml of water, vortexed briefly and 0.1 ml of 1 M 
perchloric acid added to precipitate the proteins. After centrifugation, 20 l of supernatant was injected 
into the HPLC system. Chromatographic separation was performed on a C8 column (Agilent Zorbax 
Eclipse XDB-C8 5 m, 150 x 4.6 mm i.d.). The mobile phase was 0.01 M sodium phosphate buffer pH 3.5 
containing 0.8% acetonitrile at a flow rate of 1.0 ml/min. Eluting peaks were detected at 254 nm. Under 
these conditions, allopurinol and oxypurinol eluted at 3.9 and 4.8 min respectively. The chromatogram 
was free of interference from endogenous substances present in blank plasma. Allopurinol and 
oxypurinol standard curves were linear (r2>0.99) up to 294 µmol/L. Absolute recoveries from plasma 
were >90% for both allopurinol (at 1.2, 37 and 294 µmol/L) and oxypurinol (at 1.0, 33 and 263 µmol/L). 
Intra- and inter-day coefficients of variation at the above concentrations were <9%, and the limit of 
quantification was 0.2 mol/L, for both allopurinol and oxypurinol. All the plasma samples were analysed 
in duplicate and the mean values used in subsequent analyses.