Clinical trial NCT01332799
Conditions: Complications of Renal Transplant
Keywords: cardiovascular disease kidney transplantation
Sponsor: Roberto S Kalil
Start date: 2011-02-01; Completion date: 2018-08-10
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cardiovascular disease is the leading cause of mortality in kidney transplantation. The enzyme xanthine oxidase may play an important role in the cardiovascular disease of kidney transplant recipients. Inhibiting this enzyme with allopurinol may improve vascular health and protects against cardiovascular complications.

Detailed description:
This is a prospective, double-blind, placebo controlled, clinical trial examining vascular effects of allopurinol in patients who received a kidney transplant that are maintaining stable renal function for at least 1 year. End-points include pulse-wave velocity, systemic blood pressure and kidney function among others.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: allopurinol or placebo intervention 2: Placebo
Intervention descriptions: intervention 1: Daily active drug (allopurinol administered orally) administered orally for 3 years. intervention 2: Sugar pill administered orally for 3 years.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Xanthine Oxidase Inhibition in Renal Transplant Recipients   
NCT01332799 
07/27/17 


The XART study
Project Details
I. Project Introduction
PI:
Roberto Kalil
IRB ID #: 201010787
I.1 
Project to be reviewed by: 
IRB-01 
I.2 
Project Title: 
The effects of xanthine oxidase inhibition in renal transpalant patients. The 
XART study. 
I.3 
Short Title (optional): 
The XART study 
I.4 
Provide a short summary of the purpose and procedures of the study 
proposed in this IRB application. 
l DO NOT include information on studies not proposed in this 
application. 
l Use LAY terminology only. This must be easily understandable by 
IRB community members and nonscientists. 
l DO NOT cut and paste technical abstracts from funding 
applications that may not be understood by a general audience.
Cardiovacular disease is highly prevalent in patients with chronic kidney 
disease and recipients of kidney transplants. Oxidant injury to the 
endothelium is knwon to be one of the mechanisms of atherosclerosis in 
these patients. Xanthine oxidase is a enzyme involved in the oxidant injury 
pathway and can be effectvely inhibited by allopurinol. We intend to 
administer allopurinol to subjecrs who received a kidney transplant and 
study what happens to their vascular (endothelial) function, and if they 
have a lower rate of cardiovascular complications compared to patients 
who receive a placebo drug. 
I.5 
Specify your research question(s), study aims or hypotheses (do not 
indicate "see protocol") 
1-The impact of xanthine oxidase inhibition with allopurinol in endothelial 
function in recipients of kidney transplantation. 
2-The impact of xanthine oxidase inhibition with allopurinol on 
cardiovascular complications (fatal and non-fatal acute myocardial 
infaction, new onset angina, stroke, coroanry revascularization, peripheral 
arterial revascularization) in kidney transplant recipients. 
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I.6 
Background and significance and/or Preliminary studies related to this 
project.
(do not indicate "see protocol")
Xanthine oxidase is present in various organs: liver, kidney, heart, brain, 
bowels and in plasma and endothelium of coronary vessels. It catalyses the 
conversion of hypoxanthine to xanthine and xanthine to uric acid. These 
two steps also generate superoxide anions (reactive oxygen species) which 
can produce endothelial dysfunction. 1. Allopurinol, a xanthine-oxidase 
inhibitor, was discovered in the 1940s and approved by the Food and Drug 
Administration, in 1966 for treatment of gout. Most of its effects are via its 
active metabolite, oxypurinol. Both oxypurinol and higher concentrations 
of allopurinol are non-competitive inhibitors of xanthine oxidase. 1 
In adolescents newly diagnosed with stage I hypertension, Feig et al, 
showed blood pressure reduction with allopurinol for 4 weeks with a lack 
of adverse events. 2 
Allopurinol has also been shown to improve endothelial dysfunction in 
subjects with chronic heart failure, type II diabetes, mild hypertension, 
sleep apnea and heavy smokers, and more recently, subjects with chronic 
kidney disease 4 – 7. George et al showed that a 600 mg dose of 
allopurinol produced a superior endothelial function enhancement, by 
reducing vascular oxidative stress, as compared to a 300 mg dose or 
placebo. 8 Recent studies utilizing a lower dose of allopurinol in subjects 
with impaired renal function (Goicochea, Kao) revealed favorable results 
and will be discussed in the “Preliminary Studies” section. 
We plan to explore the effects of allopurinol 300 mg to 600 mg in kidney 
transplant recipients. 
I.7 
Literature cited / references (if attaching a grant or protocol enter N/A). 
1. Pacher P, Nivorozhkin A, Szabo C: Therapeutic Effects of Xanthine 
Oxidase Inhibitors: Renaissance Half a Century after the Discovery of 
allopurinol. Pharmacol Rev 2006; 58 (1): 87-114 
2. Feig DI, Soletsky B, Johnson RJ: Effect of allopurinol on Blood 
pressure of Adolescents with Newly diagnosed Essential Hypertension: A 
randomized trial. JAMA 2008; 300(8): 924-932 
3. Ogden CL, Carrol MD, McDowell MA, Flegal KM: Obesity among 
adults in the United States – no change since 2003-2004: NCHS Data Brief 
2007 
4. Farquharson CAJ, Butler R, Hill A, Belch JJ, Struthers AD: Allopurinol 
improves endothelial dysfunction in chronic heart failure. Circulation. 
2002;106:221-226 
5. Butler R, Morris AD., Belch JJ, Hill A, Struthers AD. Allopurinol 
Normalizes Endothelial Dysfunction in Type 2 Diabetes with Mild 
Hypertension. Hypertension 2000; 35(3);746-751 
6. El Solh AA, Saliba R, Bosinski T, Grant BJ, Berbary E, Miller N: 
Allopurinol improves endothelial function in sleep apnea: a randomised 
controlled study Eur Respir J 2006; 27(5):997-1002 
7. Guthikonda S, Sinkey C, Barenz T, Haynes WG: Xanthine oxidase 
inhibition reverses Endothelial Dysfunction in Heavy Smokers Circulation 
2003; 107(3);416-421 
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8. 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; 
2508-2516; 
9. Granger DN, Rutili G, McCord JM: Superoxide radicals in feline 
intestinal ischemia. Gastroenterology 1981; 81(1): 22-29 
10. Granger DN, McCord JM, Parks DA, Hollwarth ME: Xanthine oxidase 
inhibitors attenuate ischemia-induced vascular permeability changes in the 
cat intestine. Gastroenterology 1986; 90 (1): 80-84, 
11. Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H: 
Myocardial necrosis induced by temporary occlusion of a coronary artery 
in the dog. Arch Pathol 1960; 70: 68-78 
12. Liu PG, He, He SQ, Zhang YH, Wu J: Protective effects of apocynin 
and allopurinol on ischemia/reperfusion-induced liver injury in mice. 
World J Gastroenterol 2008 May 14; 14(18): 2832-2837 
13. Tripatara P, Patel NS, Webb A, et al: Nitrite-Derived Nitric Oxide 
Protects the Rat Kidney against Ischemia/Reperfusion Injury In Vivo: Role 
for Xanthine Oxidoreductase J. Am Soc Nephrol 2007; 18: 570-580 
14. Friedl HP, Smith DJ, Till GO, Thomson PD, Louis DS, Ward PA: 
Ischemia-reperfusion in humans: appearance of xanthine oxidase activity. 
Am J Pathol 1990; 136(3): 491-495 
15. Celermajer DS, Sorensen KE, Gooch VM, et al: Non invasive 
detection of endothelial dysfunction in children and in adults at risk of 
atheroscelerosis. Lancet 1992; 340(8828): 1111-1115 
16. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron 
AD: Obesity /insulin resistance is associated with endothelial dysfunction. 
Implications for the syndrome of insulin resistance. J Clin Invest 1996; 97
(11): 2601-2610 
17. Arcaro G, Zamboni M, Rossi L. et al: Body fat distribution predicts the 
degree of endothelial dysfunction in uncomplicated obesity. Int J Obes 
Relat Metab Disord 1999; 23 (9): 936-942 
18. Baudry N, Laemmel E, Vicaut E: In vivo reactive oxygen species 
production induced by ischemia in muscle arterioles of mice: involvement 
on xanthine oxidase and mitochondria Am J Physiol Heart Circ Physiol 
2008; 294(2): H821-H828 
19. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP: Using the 
Berlin Questionnaire to identify patients at risk for the sleep apnea 
syndrome. Ann Intern Med. 1999; 131(7):485-491 
20. Pea F: Pharmacology of drugs for hyperuricemia: mechanisms, kinetics 
and interactions. Contrib Nephrol 2005; 147: 35-46 
21. Agabiti-Rosei E, Mancia G, O’Rourke MF et al:Central blood pressure 
measurements 
and antihypertensive therapy: A consensus document. Hypertension 2007; 
50(1):154-
160 
22. Roman MJ, Devereux RB, Kizer JR et al: Central pressure more 
strongly relates to 
vascular disease than does brachial artery pressure.The Strong Heart 
Study. 
Hypertension 2007;50 (1):197-203 
23. Heistad, D.D. and Armstrong, M.L: Sick vessel syndrome. Can 
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atherosclerotic 
arteries recover? Circulation. 1994; 89(5): 2447-2450. 
24. Rossi R, Nuzzo A, Origliani G, Modena MG: Prognostic role of flow-
mediated 
dilation and cardiac risk factors in post-menopausal women. J Am Coll 
Cardiol, 2008; 
51(10): 997-1002 
25. Avolio A, Grassi G: Flow-mediated dilatation as a biomarker for 
cardiovascular risk 
in hypertension. J. Hypertens. 2008; 26(8): 1546-1547. 
26. Chao J, Terkeltaub R: A critical reappraisal of allopurinol dosing, 
safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep. 2009 
Apr; 11(2): 135-140 . 
27. Grassi G, Facchini A, Trevano FQ, et al. Obstructive sleep apnea -
dependent and -independent adrenergic activation in obesity. Hypertension 
2005; 46:321-325. 
28. The Practical Guide: Identification, Evaluation, and Treatment of 
Overweight and Obesity in Adults. Public Health Service, National 
Institutes of Health, National Heart, Lung, and Blood Institute. NIH 
Publication No. 00-4084: p. 35, 2000. 
29. Gill JS, Tonelli M, Mix CH, Pereira BJG: The change in allograft 
function among long-term kidney transplant recipients. J Am Soc Nephrol 
14: 1636-42, 2003. 
30. Kukla A, Adulla M, Pascual J, Samaniego M et al: CKD stage-to-stage 
progression in native and transplant kidney disease. Nephrol Dial 
Transplant 23: 693-700, 2008. 
31. Marcen R, Pascual J, Tenorio M, Ocana EJ et al: Chronic kidney 
disease in renal transplant recipients. Transp Proc 37: 3718-20, 2005. 
31a.Abedini S, Holme I, Marz W, Weibrauch G et al: Inflammation in 
renal transplantation. Clin J Am Soc Nephrol 4: 1246-1254, 2009. 
32. Bandukwala F, Huang M, Zaltzman JS, Nash MM, Prasad R: 
Association of uric acid with inflammation, progressive allograft 
dysfunction and post-transplant cardiovascular risk. Am J Cardiol 103: 
867-871, 2009. 
33. Haririan A, Noguiera J, Zandi-Nejad K, Aiyer R et al: The independent 
association between serum uric acid and graft outcome after kidney 
transplantation. Transplantation 89:573-579, 2010. 
34. Karbowska A, Boratynska M, Kusztal M, Klinger M: Hyperuricemia is 
a mediator of endothelial dysfunction and inflammation in renal allograft 
recipients. 
35. Akalin E, Ganeshan S, Winston J, Muntner P: Hyperuricemia is 
associated with the development of the composite outcomes of new 
cardiovascular events and chronic allograft nephropathy. Transplantation 
86: 652-658, 2008. 
36. Smetana M, Weinstein T, Matas Z, Gafter U, Laina A et al: Secondary 
prevention with antioxidants of cardiovascular disease in endstage renal 
disease (SPACE): randomized placebo-controlled trial. Lancet 356:1213-
18, 2000. 
36. Goicoechea M, de Vinuesa S, Verdalles U, Ruiz-Caro C et al: Effect of 
allopurinol in chronic kidney disease progression and cardiovascular risk. 
Clin J Am Soc Nephrol…2010 
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II. Research Team
37. Kao M, Ang D, Gandy S, Lang C, Struthers A: Allopurinol reduces 
both left ventricular hypertrophy and endothelial dysfunction in patients 
with chronic kidney disease. Nephrol Dial Transplantation (S3) iii302, 
2010. 
38. Hande K, Noone R, Stone W: Severe allopurinol toxicity. Description 
and guidelines for prevention in patients with renal insufficiency. Am J of 
Medicine 76: 47-56, 1984. 
39. Vazquez-Mellado J, Morales E, Pacheco-Tena C, Burgos-Vargas R: 
Relation between adverse events associated with allopurinol and renal 
function in patients with gout. Ann Rheum Dis 60: 981-983, 2001. 
40. Dalbeth N, Kumar S, Stamp L, Gow P: Dose adjustment of allopurinol 
according to creatinine clearance does not provide adequate control of 
hyperuricemia in patients with gout. J Rheumatol 33: 1646-50, 2006. 
41. Dalbeth N, Stamp L: Allopurinol dosing in renal impairment: Walking 
the tightrope between adequate urate lowering and adverse events. 
Seminars in Dialysis 20: 391-395, 2007. 
42. Panomvana D, Sripradit S, Angthararak S: Higher therapeutic plasma 
oxypurinol concentrations might be required for gouty patients with 
chronic kidney disease. J Clin Rheum 14: 6-11, 2008. 
II.1 
Principal Investigator 
Name
E-mail
College
Roberto Kalil roberto-kalil@uiowa.edu Carver College of Medicine
II.2 
Team Members 
UI Team Members
Name
E-mail
College Contact Key 
Prsn
UI 
COI
VAMC 
COI
Roberto Kalil, MD
roberto-
kalil@uiowa.edu
Carver 
College 
of 
Medicine
Yes
Yes No
Graziela Kalil, PharmD graziela-
kalil@uiowa.edu
Carver 
College 
of 
Medicine
Yes
Yes No
Tamara Lowe, RA
tamara-
lowe@uiowa.edu
Carver 
College 
of 
Medicine
Yes
No No
Denice Wells, RA
denice-
wells@uiowa.edu
Carver 
College 
of 
No
No No
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III. Funding/Other Support
Non-UI Team Members
Medicine
Name Institution Location FWA Role DHHS Contact Key 
Prsn
UI 
COI
VAMC 
COI
Co
Pr
Invo
Nothing found to display.
II.3 
The Principal Investigator of this study is: 
Faculty 
II.6 
Identify the key personnel. The system will automatically designate the PI and 
all faculty members on the project as “key personnel.” For information about 
other team members who should be designated as “key personnel” please click 
on the help information. 
Name
Is Key Personnel
Roberto Kalil, MD
Yes
Graziela Kalil, PharmD
Yes
Tamara Lowe, RA
No
Denice Wells, RA
No
III.1 
Funding Sources 
* new source name
Type
Source
Federal Agency US Department of Health & Human Services, National Institute
III.2 
What type of funding agreement would be completed? 
Federal/State/Local Agency/Non-Profit Funded/Other 
III.3 
Does any member of the research team have a financial conflict of interest 
related to this project according to the Conflict of Interest in Research policy? 
If yes, please indicate which members below. 
Name
Has Conflict of 
Interest
SFI FCOI
Management 
Plan
Roberto Kalil, MD
No 
Graziela Kalil, PharmD
No 
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IV. Project Type
V. Other Committee Review
Institutional Conflict of Interest (ICOI):
ICOI Management Plan Status:
Tamara Lowe, RA
No 
Denice Wells, RA
No 
III.5 
What is the current status of this funding source? 
Source
Status
Other Status 
Description
US Department of Health & Human 
Services, National Institutes of Health
Awarded
IV.1 
Do you want the IRB to give this project 
Regular (expedited or full board) review 
IV.2 
Enter the date you will be ready to begin screening subjects/collecting 
data for this project. (If you do not have a specified date, add "upon IRB 
approval") 
11/01/2010 
IV.3 
Are you requesting a waiver of informed consent/authorization (subjects 
will not be given any oral or written information about the study)? 
No 
V.1 
Does this project involve any substance ingested, injected, or applied to the 
body? 
l Do not answer yes, if the involvement includes a device, wire, or 
instrument
Yes 
V.1.a 
What is/are the substance(s): 
allopurinol or placebo 
V.1.b 
Are any of these substances defined as a Schedule I - V Controlled 
Substance? 
No 
V.2 
Are any contrast agents used for any purpose in this study? 
No 
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V.4 
Are all drugs or substances in this study being used within the FDA 
approved population (i.e., children, adults)? 
Yes 
V.5 
Are all drugs or substances in this study being used within the FDA 
approved indication (i.e., disease, condition)? 
No 
V.6 
Are all drugs or substances in this study being used within the FDA 
approved dose? 
Yes 
V.7 
Are all drugs or substances in this study being used within the FDA 
approved route of administration? 
Yes 
V.8 
Drugs used in study that are not FDA approved for the population, 
indication, dose, or route of administration 
allopurinol (allopurinol) 
Name of Sponsor 
Investigator's Brochure 
Version 
Investigator's Brochure 
Date 
Planned Use in this Study
Condition/Disease 
Indication(s) 
Atherosclerosis 
Subject Population 
Kidney transplant recipients 
Dose(s) 
up to 600 mg daily 
Administration 
Oral 
Dosing Regimen 
Daily single dose 
FDA Approved Use
Approved 
Condition/Disease 
Indication(s) 
hyperurecemia 
Approved Patient 
Population 
adult 
Approved Dose(s) 
Up to 8oo mg daily 
Approved Administration Oral 
Approved Dosing 
Regimen 
Daily single dose 
Is this study intended to 
No 
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be reported to the FDA as 
a well-controlled study in 
support of a new 
indication or a significant 
change in the labeling for 
this product? 
Is this study intended to 
support a significant 
change in the advertising 
for this product? 
No 
Does this planned use of 
the product in this study, 
taking into consideration 
the route of 
administration, the dosage 
level, and the subject 
population, significantly 
increase the risk (or 
decrease the acceptability 
of the risk) associated 
with the use of this 
product? 
No 
Rationale: 
Allopurinol is routinely used in kidney 
transplant recipients who develop gout 
and/or hyperuricemia for many years. 
In this study, the goal is to examine the 
anti-oxidant effects of this drug that are 
believed to be beneficial in 
cardiovascular diseases. The maximum 
dose to be used (600 mg)will be below 
the maximum FDA approved dose (800 
mg) 
V.9 
Will any subject be asked to undergo a diagnostic radiation procedure 
(including radiographic, nuclear medicine, DEXA)? 
No 
V.14 
Will any subject be asked to undergo a radiation therapy procedure (including 
external beam therapy, brachytherapy, or nuclear medicine therapy)? 
No 
V.20 
Does this project involve the deliberate transfer of recombinant or synthetic 
nucleic acid molecules, or DNA or RNA derived from recombinant or synthetic 
nucleic acid molecules, into one or more human research participant? 
No 
V.21 
Will any portion of this project be conducted in the CRU, or does it use any 
CRU resources? 
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VI. Subjects
Yes 
V.22 
Will this project use any resource/patients of the HCCC? 
No 
V.25.a 
Will the study involve any of the following activity at UI Health Care, even if 
subjects or their insurance will not be billed for the item or service, and 
regardless of the study funding source (including studies with departmental or 
no funding)?
l Procedures, tests, examinations, hospitalizations, use of Pathology 
services, use of clinic facilities or clinical equipment, or any patient care 
services, including services conducted in the Clinical Research Unit; or 
l Physician services or services provided by non-physicians who are 
credentialed to bill (ARNPs, Physician Assistants, etc.)
Yes 
V.26 
The study involves nursing, nursing resources or evaluates nursing 
practices. 
No 
VI.1 
How many adult subjects do you expect to consent or enroll for this project? 
120 
VI.2 
What is the age of the youngest adult subject? 
18.0 
VI.3 
What is the age of the oldest adult subject? 
90.0 
VI.4 
What is the percentage of adult male subjects? 
50 
VI.5 
What is the percentage of adult female subjects? 
50 
VI.6 
How many minor subjects do you expect to consent or enroll for this project? 
0 
VI.13 
Describe EACH of your subject populations 
l Include description of any control group(s) 
l Specify the Inclusion/Exclusion criteria for EACH group 
l Studies under IRB-03 enrolling non veterans as part of the subject 
population must present a compelling argument to the IRB for the 
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inclusion of non-Veterans (e.g., insufficient number of Veterans; survey 
of VA employees; study of active duty military; study involving Veterans’
family members), and the research is relevant to the care of Veterans or 
active duty military personnel.
Subject selection procedures 
1. Age: 18 years of age or older 
2. Sex: Both male and female population 
3. Recipients of kidney transplantation and with stable kidney function 
4. Ethnic background: subjects of all ethnicities 
Exclusion Criteria: 
* Current use of allopurinol 
* History of Gout 
* History of non-adherence with routine clinic and laboratory visits. 
* Recent diagnosis of acute rejection (3 months) 
* Baseline estimated glomerular filtration rate of < 30 ml/min 
* Difficult to control hypertension (subjects requiring 4 or more anti-
hypertensive medications) 
* Pregnancy and/or lactation 
* History of allergy/adverse reaction to allopurinol 
* History of allergy/adverse reaction to adhesive. 
* EKG showing atrial fibrillation. 
* Clinically significant hepatic insufficiency 
* History of positive stress test in the past 6 months 
* Current use of amoxicillin, ampicillin, aluminium hydroxide, phenprocoumon, 
coumadin, vidarabine, azathioprine, cyclophosphamide, didanosine, 
theophylline, mercaptopurine or warfarin. 
* Medical conditions requiring continuous use of phosphodiesterase inhibitors 
and/or the inability to withhold phosphodiesterase inhibitors for 48 hours prior to 
Nitroglycerin administration. 
VI.14 
Provide an estimate of the total number of subjects that would be eligible for 
inclusion in each of your study populations (include your control population if 
applicable) 
We follow approximately over 1200 patients with kidney transplants in the organ 
transplant center. This will be a placebo controlled study. 
VI.15 
Describe how you will have access to each of your study populations in 
sufficient number to meet your recruitment goals. 
List of active clinic patients seen on a regular basis in the outpatient transplant 
clinic. 
VI.16 
Do you plan to recruit/enroll non-English speaking people? 
No 
VI.18 
Do you propose to enroll any of the following in this study as subjects? 
l Employee of the PI or employee of a research team member 
l Individual supervised by PI or supervised by member of research team 
l Individual subordinate to the PI or subordinate to any member of the 
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VII.A. Project Description (A)
VII.B. Project Description (B)
research team 
l Student or trainee under the direction of the PI or under the direction of 
a member of the research team
No 
VI.20 
Will subjects provide any information about their relatives? 
No 
VI.23 
Will anyone (other than the subject) provide you with information about the 
subject (e.g. proxy interviews)? 
No 
VI.26 
Is this project about pregnant women? 
No 
VI.27 
Will this project involve fetuses? 
No 
VI.28 
Does this project involve adult subjects who may be incompetent or have 
limited decision-making capacity on initial enrollment into the study? 
No 
VI.32 
Does this project involve subjects whose capacity to consent may change over 
the course of the study? 
No 
VI.37 
Does this project involve prisoners as subjects? 
No 
VII.A.1 
Where will project procedures take place (check all that apply)? 
l CRU 
VII.A.2 
Is this project also being conducted by other researchers at their own sites (e.g. 
a multi-site collaborative project)? 
No 
VII.B.1 
Does this project involve any of the following (Check all that apply): 
l
Registry – The collection and maintenance of data (not including 
biologic samples) in which: (1) the individuals in the registry 
have a common or related condition(s), and/or (2) the individuals 
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in the registry are interested in being contacted for future studies 
by investigators other than those listed in Section II of this 
project.(UI Guide)
l
Repository – The collection, storage, and distribution of human 
biologic samples and/or data materials for research purposes. 
Repository activities involve three components: (i) the collection 
of data and/or specimens such as blood, tissue, saliva, etc.; (ii) 
the storage of data or specimens, and data management function; 
and (iii) the sharing of data/specimens with recipient 
investigators other than the original investigators. (paraphrased 
from OHRP)
l
Expanded Access – A process regulated by the Food and Drug 
Administration (FDA) that allows manufacturers to provide 
investigational new drugs to patients with serious diseases or 
conditions who cannot participate in a clinical trial. Examples of 
expanded access include non-protocol access to experimental 
treatments, including protocol exception, single-patient IND, 
treatment IND, compassionate use, emergency use, continued 
access to investigational drug, and parallel track 
(ClinicalTrials.gov & FDA).
l
Clinical (or Treatment) trial – A prospective biomedical or 
behavioral research study of new treatments, new drug or 
combinations of drugs, new devices, or new approaches to 
surgery or radiation therapy. (NIH and ClinicalTrials.gov & 
FDA) 
l
Physiology intervention/study – A pharmacologic or 
measurement study aimed at understanding basic mechanisms of 
disease and/or of normal human physiology, often without any 
therapeutic intent (though a clinical trial could include such 
components, often labeled as “translational” or “basic science”
aims.) Measurements in such studies could include, but are not 
limited to, a blood draw, EKG, EEG, MRI, auditory or sensory 
testing, checking vital signs, DEXA scans, eye tracking, 
specimen collection, exercise, fasting, special diets, etc.
l
Behavioral intervention/study – May be used to refer to studies 
of individual or group behavior. This option does not include 
drugs, biologics, or devices but could include psychotherapy, 
lifestyle counseling, behavior modification, etc.
l
Diagnostic trial – Protocol designed to evaluate one or more 
interventions aimed at identifying a disease or health condition 
(ClinicalTrials.gov & FDA)
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VII.B.1.a 
Does this project involve any of the following (Check all that apply): 
VII.B.1.b 
Provide the NCT (National ClinicalTrials.gov Identifier) number 
NCT01332799 
VII.B.2 
Does this project involve a drug washout (asking subject to stop taking 
any drugs s/he is currently taking)? 
No 
VII.B.6 
Will any subjects receive a placebo in this study when, if they were not 
participating, they could be receiving an FDA-approved treatment for 
their condition? 
No 
VII.B.11 
Is there a separate, written protocol that will be submitted in addition to this 
IRB New Project form? (Note: a grant application is not considered to be a 
l
Non-clinical – any college/department that would regularly 
submit to IRB-02
l
Other
l
Phase I trials – include initial studies to determine the 
metabolism and pharmacologic actions of drugs in humans, 
the side effects associated with increasing doses, and to 
gain early evidence of effectiveness; may include healthy 
participants and/or patients (ClinicalTrials.gov & FDA)
l
Phase II trials – include controlled clinical studies 
conducted to evaluate the effectiveness of the drug for a 
particular indication or indications in patients with the 
disease or condition under study and to determine the 
common short-term side effects and risks
(ClinicalTrials.gov & FDA)
l
Phase III trials – include expanded controlled and 
uncontrolled trials after preliminary evidence suggesting 
effectiveness of the drug has been obtained, and are 
intended to gather additional information to evaluate the 
overall benefit-risk relationship of the drug and provide an 
adequate basis for physician labeling(ClinicalTrials.gov & 
FDA)
l
Phase IV trials – studies of FDA-approved drugs to 
delineate additional information including the drug’s risks, 
benefits, and optimal use(ClinicalTrials.gov & FDA)
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VII.C. Project Description (C)
VII.D. Project Description (D)
protocol) 
No 
VII.B.18 
Does this project involve testing the safety and/or efficacy of a medical 
device? 
No 
VII.C.1 
Does this project involve any research on genes or genetic testing/research? 
No 
VII.D.1 
Check all materials/methods that will be used in recruiting subjects (you will 
need to attach copies of all materials at the end of the application): 
l Letter -
l Use of any information available to the researchers or their colleagues 
because this person is a patient OR use of any information considered to be 
Protected Health Information (PHI) OR review of patient/clinic records -
EPIC 
VII.D.2 
List the individual data elements you will need to access/use from the 
patient or clinic records to identify potential subjects for recruitment 
Age, date of transplant, creatinine levels (to estimate glomerular filtration 
rate GFR), history of hyperucemia, medications list (to check for current 
use of allopurinol or potential interactions), allergy history, and history of 
non-compliance with medical or laboratory visits. 
VII.D.3 
Describe why you could not practicably recruit subjects without access to 
and use of the information described above 
It is not reasonable to approach subjects that easily meet exclusion criteria. 
It would be very time consuming for the research team and for the subjects 
to be aswering questions that they do not need to spend their time if they 
are not eligible. 
VII.D.4 
Describe why you could not practicably obtain authorization from 
potential subjects to review their patient or clinic records for recruitment 
purposes. 
The large number of potential subjects to be screened by sending letters or 
calling would make this study extremely difficult to conduct, impractical. 
Furthermore, the amouunt of information needed to screen is minimal (see 
VIID.2). 
VII.D.5 
Describe plans to protect the identifiers from improper use or disclosure 
Subjects will be de-identified with a coding system that does not use any 
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information related to their identifiers. Only the research team will have 
access to the code. 
VII.D.6 
Describe plans to destroy identifiers at the earliest opportunity consistent 
with conduct of the research 
All identifiers will be destroyed and use of de-identifiers will be 
immediately applied after enrollment in participating in the study. 
Database will contain only the de-identified research code. We will keep 
idenfifiers to avoid re-approaching an individual that has previiously 
declined participation in the study or was determined to be ineligible. This 
list will be kept confidential in a separate file. 
VII.D.7 
Does the research team agree that the requested information will not be 
reused or disclosed to any other person or entity, except as required by 
law, for authorized oversight of the study, or for other research for 
which the use or disclosure of the requested information would be 
permitted by the HIPAA Privacy Rule 
Yes 
VII.D.8 
Will a member of the research team discuss the study with the subject in 
person prior to the subject agreeing to participate? 
Yes 
VII.D.9 
Describe the physical location where the consent process will take place: 
Kidney transplant clinic in person, or over the Clinical Research Unit alsoo 
in person. 
VII.D.10 
Will a member of the research team discuss the study with the subject by phone 
prior to the subject agreeing to participate? 
Yes 
VII.D.11 
Describe: 
Potential study subjects will receive a letter by mail with the consent form 
to review before discussion with the research team. They will have a 
number available in the consent form to call my office and/or the office of 
the research assistant. Alternatively, we plan to call after 2 weeks if we 
don't hear from the potential study subjects by letter or phone. 
VII.D.12 
Who will be involved in the consent process (including review of consent 
document, answering subjects' questions)? 
Name
Consent Process Involvement
Roberto Kalil, MD
Yes
Graziela Kalil, PharmD
No
Tamara Lowe, RA
Yes
Denice Wells, RA
Yes
VII.D.15 
Check all materials that will be used to obtain/document informed consent: 
l Consent Document 
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VII.D.16 
Are you requesting a waiver of documentation of consent (either no subject 
signature or no written document)? 
No 
VII.D.19 
Before the subject gives consent to participate are there any screening 
questions that you need to directly ask the potential subject to determine 
eligibility for the study? 
Yes 
VII.D.20 
List any screening questions you will directly ask the potential subject to 
determine eligibility. 
History of allergy to allopurinol. History of gout. In the event that the 
electronic medical records are incomplete or inacurate it is important to 
make sure that the information on allergy to the study drug is reliable 
reason why we plan to ask these questions. 
All other questions will be answered using information from the electronic 
medical records detailed in section VII D.2 
VII.D.21 
Will you keep a screening log or other record that would include 
information on people who do not enroll in the study? 
Yes 
VII.D.22 
Describe the information being collected and the purpose for 
keeping this information. 
Only basic demographic information such as name and date of the 
documentation. No need to store clinical information. 
VII.D.23 
Will this information be shared with anyone outside the UI 
research team members? 
No 
VII.D.25 
After the subject agrees to participate (signs consent), are there any screening 
procedures, tests, or studies that need to be done to determine if the subject is 
eligible to continue participating? 
Yes 
VII.D.26 
List and describe screening 
Female subjects of childbearing potential will be tested for pregnancy 
before starting the study. iF positive, they can not participate in the study. 
VII.D.27 
Discuss how much time a potential subject will have to agree to consider 
participation and whether or not they will be able to discuss the study with 
family/friends before deciding on participation. 
2 weeks 
VII.D.28 
How long after the subject agrees to participate do study procedures begin? 
It can start immediately or at patient convenience. 
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VII.D.29 
Provide a description of the enrollment and consent process for adult subjects 
l Describe each study population separately including control population 
l Include when recruitment and consent materials are used 
l Use 3rd person active voice “The Principal Investigator will identify 
subjects. For example, the principal investigator will identify potential 
subjects, the study coordinator will discuss the study with subjects over 
the telephone and schedule the first study visit, etc...”
l Describe the steps that will be taken by the research team to minimize the 
possibility of coercion or undue influence during the consent process
Recruitment will occur from potential participants from the Kidney Transplant 
Clinic at the University of Iowa Hospitals and Clinics meeting inclusion criteria. 
1-A list of potential study participants will be identified by the research team, 
obtained from our routine outpatient schedule. 
2-Consent document will be obtained at the transplant clinic, or the Clinical 
Research Unit, or by mail. By mail, potential participants will receive a consent 
form and a cover letter summarizing the protocol to facilitate understanding of 
the study. The consents may be mailed or distributed during a clinic visit to the 
Transplant Organ Center at UIHC. A telephone number will be listed in the 
consent document for further information if needed by potential participants. A 
return card with the option to participate or not in the study, in a self addressed, 
stamped envelope will be included in the same letter containing the consent 
document. 
There will be plenty of time (2 weeks) for the potential participant to decide to 
enroll or not in the study. They will be given a number to call to ask any question 
they have about the study. 
Potential study subjects will receive a call in 2 weeks if we don't receive the card 
with an answer accepting or declining participation in the study. We will offer to 
answer and clarify any questions about the study, the study visits, duration of 
each visit, and what happens in each study visit. 
If patient is not decided about the study, we will be available to answer further 
questions should this be necessary for the patient to make a decision. We will 
again make clear that the participation in the study does not interfere with routine 
transplant care, and the participation it is totally voluntary. 
3-If we don't receive the consent document or a call from the potential subjects in 
2 weeks after sending the letter, we will contact them by phone to known if they 
are interested in the study or not. If potential study subjects request more time to 
consider participating in the study, we will allow as much time possbile at the 
study subject convenience to decide. 
4-After agreeing in being in the study, we will schedule the first (randomization) 
study visit in the Clinical Research Unit over the phone with the study subject or 
in person at the transplant clinic. 
VII.D.37 
Does the study include any form of deception (e.g., providing participants with 
false information, misleading information, or withholding information about 
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VII.E. Project Description (E)
certain study procedures)? 
Examples:
l Procedure includes a cover story that provides a plausible but inaccurate 
account of the purposes of the research. 
l Participants will be provided with false information regarding the 
particular behaviors of interest in the research. 
l Procedures include a confederate pretending to be another participant in 
the study. 
l Participants will be told that the research includes completion of a 
particular task, when in fact, that task will not be administered. 
l Study is designed to introduce a new procedure (or task) that 
participants are not initially told about. 
l If yes, a waiver of informed consent must be requested under question 
IV.3.
No 
VII.E.1 
Will subjects be randomized? 
Yes 
VII.E.1.a 
Will any subjects be blinded to which study arm they have been 
assigned? 
Yes 
VII.E.1.b 
Does the protocol permit telling subjects their treatment 
assignment at the end of the entire study? 
Yes 
VII.E.1.c 
Describe the circumstances under which subjects will 
be told what study arm they have been assigned. 
In case of adverse reaction to the study drug, besides 
discontinuing the drug, it will be very important to 
inform the patient immediately about his/her allergy to 
the drug to protect them from being exposed again to 
this drug and prevent serious adverse reactions. 
In the end of the study, we will notify the patient about 
what arm of the study ne/she was on, and if ther was a 
benefit from the active drug to the participants. 
VII.E.2 
Describe randomization scheme/assignment including ratio such as 1:1, 
2:1 etc. 
Randomization will be performed using a software to a ratio of 1:1 with 1 
arm for active drug (allopurinol) and 1 arm for placebo. 
VII.E.3 
Will any questionnaires, surveys, or written assessments be used to obtain data 
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directly from subjects in this study? 
No 
VII.E.5 
Does this project involve creating any audiotapes, videotapes, or photographs? 
No 
VII.E.6 
Provide a detailed description in sequential order of the study procedures 
following the consent process - DO NOT cut and paste from the Consent 
Document.
Describe study populations separately if they will be participating in different 
procedures - include CONTROL population if applicable.
DESCRIBE: 
l What subjects will be asked to do/what happens in the study (in 
sequential order) 
l The time period over which procedures will occur 
l The time commitment for the subject for individual visits/procedures 
l Long-term followup and how it occurs
Each visit will last approximately 2 hours. There is a total of 5 visits as follows: 
baseline (0 week), 2 months, 12 months, 24 months, and 36 months post 
randomization. 
After the last visit at 36 months, no long-term follow-up is planed. 
Below is a detailed explanation of the initial randomization procedure, and each 
test performed in each visit. 
Administration: Study drug or placebo administration will occur at the time of 
randomization after completion of pre-assessment. The specific agent will be 
coded with an identification number label. Assignments will be made in a 
sequential order as subjects are randomized. Accountability will be maintained 
with a hardcopy log. The log will contain the date dispensed, date returned, 
subject name, code, pill count, drug lot number and expiration date, and 
information for a perpetual inventory. 
Pulse Wave Velocity and Estimated Aortic Pressure 
We will assess two markers of vascular stiffness, namely pulse wave velocity 
(PWV) and estimated aortic pressure by reflected pulse waves. These techniques 
provide an assessment of subclinical vascular damage, and are impaired by both 
endothelial dysfunction and vascular structural abnormalities. In particular, 
hypertension can increase vascular stiffness through reduced endothelial 
production of mediators such as nitric oxide (which would usually reduce 
vascular stiffness), hypertrophy and fibrosis of the medial layer, and (eventually) 
sub-intimal atherosclerotic plaques. As vascular stiffness increases, the speed at 
which the pulse wave travels increases, and this can be measured using EKG-
tonometric techniques. 21 Increased PWV leads to a more rapid return to the 
central aorta of the peripherally reflected wave during diastole. Ultimately, the 
reflected wave can return so fast it superimposes itself on the aortic systolic 
wave, and can significantly augment aortic pressure. Such augmentation cannot 
be detected in usual brachial pressure measurements. However, the contour 
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(though not the amplitude) of the radial pulse wave can be used to analyze the 
position of the reflected wave in the cardiac cycle, and a derived aortic systolic 
pressure can be calculated from radial pulse tonometry using an algorithm 
(validated versus directly measured aortic pressure). Such non-invasive estimates 
of central aortic pressure have been shown to be better predictors of 
cardiovascular events than usual brachial pressure in epidemiological studies. 22 
In addition, and importantly for our study, estimated aortic pressure has been 
shown to be predictive of the effects of anti-hypertensive drugs to reduce 
cardiovascular events. 21 The European Society of Hypertension Consensus 
Statement on central blood pressure recommends combining pulse wave analysis 
derived estimates of central aortic pressure with measures of pulse wave velocity 
for a more comprehensive assessment of vascular function. 21 
Technique: We measure estimated aortic pressure and PWV using arterial 
applanation tonometry and EKG (SphygmoCor SCOR PVX system). This uses a 
noninvasive, pen-like probe (a tonometer) applied to three superficial artery sites: 
the radial, carotid, and femoral arteries. The total testing time is under one hour. 
Initially, radial artery tonometry is performed to obtain central blood pressure by 
pulse wave analysis. The system uses mathematical transforms to derive the 
central aortic pressure pulse waveform and then calculates a range of central 
indices of ventricular-vascular interaction, which are displayed both graphically 
and numerically. The pulse wave analysis method provides a quality score based 
on the standard deviation of individual pulse analyses obtained over 10 seconds. 
The measurements will be repeated multiple times, and only accept recordings 
that have a quality score above 90, and when two consecutive augmentation 
pressure measurements are within 10% of each other. The quality score is also 
recorded for each subject so it can be used if necessary to help identify outliers 
(and perhaps for endpoint weighting in future analyses). The primary endpoint 
for this test is augmentation pressure (corrected for heart rate), which is the 
pressure added to aortic systolic pressure by the reflected wave. A secondary 
endpoint will be aortic systolic pressure. 
Pulse wave velocity is estimated using the same tonometer to transcutaneously 
record pressure pulse waveforms in the two arteries at different distances from 
the heart. The pressure pulse waveform is recorded simultaneously with an 
electrocardiogram (EKG) signal, which provides an R-wave timing reference. 
We use the carotid and femoral artery sites so the pulse wave velocity can be 
measured in a section of artery that includes the aorta. The software processes 
each set of pressure pulse and EKG waveform data to calculate the mean time 
difference between the R-wave and the pressure wave- on a beat–by-beat basis. 
The PWV is then calculated using the mean time difference and the arterial path 
length between the two recording sites (measured on each subject at the start of 
the study). We use similar quality control measures to the pulse wave contour 
analysis, including duplicate measurements, and recording of quality scores for 
individual subjects. The primary endpoint for this test is pulse wave velocity (in 
m/sec). 
Flow Mediated Dilatation of the Brachial Artery: 
We will assess endothelial function by measuring flow-mediated dilatation 
(FMD) of the brachial artery. The vascular endothelium produces multiple 
factors that regulate vascular tone, platelet adhesion and aggregation, lipid 
transport, macrophage migration, vascular smooth muscle proliferation, 
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thrombosis, and fibrinolysis. Most in vivo assessments of endothelial function 
focus on vascular tone as an index of overall endothelial health. Endothelial 
dysfunction contributes both to the pathogenesis and subsequent complications 
of atherosclerosis, and changes in endothelial modulation of vascular tone 
precede development of atherosclerotic lesions in monkeys. 23 Though there are 
multiple techniques for measuring endothelial function in humans, we chose 
brachial FMD because it is non-invasive, relatively rapid and well validated. 
Flow-mediated vasodilatation is endothelium-dependent in animals and 
abolished by local inhibition of nitric oxide generation in man. Thus, brachial 
FMD likely reflects conduit vessel endothelial function. Brachial FMD correlates 
with coronary artery endothelial function, is abnormal in patients with 
obstructive coronary artery atherosclerosis, and predicts atherosclerotic events 
beyond conventional risk factor profiling (Framingham scores).24 Even in 
patients without evidence of atherosclerosis, impaired brachial FMD is 
associated with hypertension, hypercholesterolemia, diabetes mellitus, cigarette 
smoking, increasing age, male gender, and menopause. 25 In hypertension, 
impaired brachial FMD correlates with evidence of target organ damage (heart, 
vascular and kidney), and is improved by chronic but not acute blood pressure 
lowering.25 Of particular relevance to this study, subjects who exhibit 
improvements in brachial FMD have fewer coronary events on long-term follow-
up than subjects who do not improve. As a control, nitroglycerin-mediated 
brachial dilatation is used to test endothelium-independent dilatation of the 
brachial artery. 
Technique: The brachial artery is imaged with a 13 MHz linear array transducer 
ultrasound system (AU4, BioSound). A continuous ECG recording is obtained, 
and non-invasive arterial pressure measured at baseline and after each 
intervention. A 5 cm length of the brachial artery is imaged in longitudinal 
section above the antecubital fossa and the optimal probe site on the skin 
marked. The non-dominant arm will be used. Baseline images of brachial artery 
diameter and Doppler velocities from the center of the vessel are obtained and 
displayed on a split screen. An occluding forearm cuff placed 5 cm below the 
antecubital fossa is inflated to 240 mmHg for 5 min, and then deflated to induce 
reactive hyperemia. Brachial artery diameter and velocity are continuously 
measured during cuff inflation and for 2 min after cuff deflation, when brachial 
artery diameter has peaked. At the end of the study (after ischemia-reperfusion 
intervention has finished), flow mediated vasodilatation (reactive hyperemia will 
be repeated post ischemia-reperfusion. Once basal diameter and flow have been 
restored, nitroglycerin (400 µg) is administered sublingually, and brachial artery 
diameter and Doppler velocity recorded for 6 min. Our ultrasound operator has to 
demonstrate the ability to obtain reproducible images of the brachial artery with 
a coefficient of variation of <2% for brachial artery diameter and <10% for 
brachial artery flow. This assessment is based on the results from one subject 
studied on five different days and is repeated in a manner every 3 months. In our 
hands we have shown using this protocol that experimental 
hyperhomocysteinemia and cigarette smoking blunt brachial FMD, and xanthine 
oxidase inhibition improves it. 
Analysis: Brachial artery diameter and blood velocity measurements are 
analyzed by a dedicated research sonographer, blinded to the identity of the 
subject, diagnosis, and study intervention. Video tapes of brachial artery images 
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are digitized and transferred to a workstation. B mode images of the longitudinal 
section of the brachial artery at baseline are digitized in a gated manner using the 
onset of the QRS complex to trigger frame capture at end- diastole. An 
automated neural network based method for complete near and far wall border 
detection is used to measure arterial diameter in each frame (Brachial Analysis 
Tool, Medical Imaging Applications, Iowa City, USA). Peak Doppler flow 
velocity is calculated and averaged over 5 consecutive cardiac cycles. Percentage 
change in diameter and velocity is calculated for the interventions of reactive 
hyperemia and sublingual nitroglycerin. The maximal flow-mediated change in 
vessel diameter occurs at 1 minute post-hyperemia, and this is the primary 
endpoint. Changes in diameter induced by nitroglycerin (maximal response at 6 
min) are used as an index of vascular smooth muscle sensitivity to nitric oxide, 
and will be a secondary endpoint. 
Nitroglycerin Mediated Vasodilatation of the Brachial Artery: 
Once basal diameter and flow have been restored, brachial artery diameter and 
velocity are continuously measured at base and 6 minutes post administration of 
sublingual nitroglycerin (400 mcg). 
Blood Pressure and Pulse Rate Variability 
The measurement of indirect arterial pressure with a beat-to-beat finger systolic 
and diastolic blood pressure recording (Finapres 2350; Ohmeda) during 
ultrasound and Doppler procedures described in the previous paragraph (“Flow-
mediated dilatation of the brachial artery). Rationale: Data from this 
measurement will allow us to assess blood pressure variability. 
24 hour ambulatory blood pressure monitoring: Subjects will be instructed to 
refrain from bathing or showering within that 24 hour time frame. The blood 
pressure cuff will be worn on the arm with the higher SBP (if applicable). The 
monitor measures blood pressure every 30 minutes during the day and hourly at 
night. The mean day and night-time ambulatory blood pressure will be used for 
analysis. 
Laboratory (blood and urine) assays during each study visit: 
i) Blood work for creatinine, uric acid, random urine for protein-to-creatinine, 
and a CBC will be performed in UIHC Pathology Laboratory. Il-6 and hsCR-P 
will be performed at the Analytical Laboratory of the CRU in the Institute for 
Clinical and Translational Science (ICTS). Measurements of allopurinol 
metabolite (Oxypurinol) will be conducted at a outside commercial laboratory 
designated by the UIHC 
ii) Urine test for urine beta-hCG to evaluate for pregnancy will be performed 
using a commercially available kit in the CRU. 
iii) Voluntary blood sample collection at each visit for storage and use in 
potential future research studies. 
Visit 1 (week 0) 
A research team member will discuss the study details described in this informed 
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consent document. A physician or nurse practitioner will review the medical 
history and perform a physical examination. 
Heart rate, respirations (breathing), temperature, blood pressure, weight and 
height will be obtained. 
After sitting for 5 minutes, blood pressure will be obtained twice in each arm. 
The arm with the highest blood pressures will be used for all further 
measurements during this study. 
The weight and height will be used to determine the body mass index (BMI). The 
BMI is one way to indicate weight status (i.e., lean or over weight). 
An electrocardiogram (EKG - a tracing of the heart’s electrical activity) will be 
obtained. 
Waist circumference will be obtained with a measuring tape. 
About 1 ounce of blood will be drawn from a vein in the arm. These samples will 
test your blood for substances that are potentially harmful to your blood vessels. 
Study subjects will be instructed to present to the Clinical Research Unit in the 
morning. The visit will take approximately 1 and 1/2 hour. Measurement of Flow-
Mediated Dialation (FMD) will be obtained as described in the previous section. 
Laboratory tests will be collected (blood and urine), and randomization will take 
place. Blood pressure and pulse rate variability will be obtained using the 
Finapress digital device simultaneously with the FMD measurement. The final 
procedure during this visit is to place the 24h BP monitor and provide the 
appropriate instructions as described above. 
Following randomization, study subjects will be assigned to allopurinol or 
placebo. The starting dose of allopurinol is 300 mg daily. Patients will receive 
this dose for 1 week and will have an increase of 100 mg each week for 3 weeks 
to achieve the maximum (final) dose of 600 mg as maintenance dose for the 
remaining of the study (3 years). Study subjects will be contacted by phone to 
monitor any adverse effect of the study drug on a weekly basis for the first 4 
weeks to monitor for adverse effects, and will be oriented to call for any of these 
signs described above at any time and immediately discontinue the study drug. 
If no adverse reactions and good tolerance of the study drug, we don't plan to call 
study subjects further for this purpose. Study subjects will have our number to 
call 24/7. 
In case of suspected allopurinol toxicity at any point, study subjects will be 
advised to stop taking the study drug immediately and drink plenty of fluids, at 
least 10-12 glasses per day. 
Visit 2 (month 2) 
Procedures will be identical to visit 1. Duration of the visit is the same. Labs with 
this visit and all future visits will include oxypurinol levels. 
Visit 3 (12 months) 
Same as visit 2 
Visit 4 (24 months) 
Same as visit 3 
Visit 5 (36 months) 
Same as visit 3 
Completion of the study. 
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VIII. Risks
ADDENDUM: 
Patients will receive a letter informing the completion of treatments and 
discontinuation of further research visits due to lack of research funding. 
Detailed instrucions and phone for contact if any questions provided in the letter. 
VII.E.7 
Will you attempt to recontact subjects who are lost to follow-up? 
No - followup is not required in this study 
VII.E.9 
Will subjects be provided any compensation for participating in this study? 
Yes 
VII.E.10 
Cash 
No 
VII.E.11 
Gift Card 
No 
VII.E.12 
Check 
Yes 
VII.E.13 
Who will be providing the research compensation check to 
the subject? 
Accounting Services directly via the e-Voucher system 
VII.E.16 
Other 
No 
VII.E.19 
Describe the compensation plan including 
l Compensation amount and type per visit 
l Total compensation 
l Pro-rating for early withdrawal from study
The total number of visits will be 5. For each visit the participant will 
receive $50.oo. The total compensation will therefore be $250.00. We will 
pro-rate the compensation if early withdrawal from the study according to 
the number of visits. 
Your parking expenses will be covered for the time where you are in the 
Clinical Research Unit for the study visits. 
VIII.1 
What are the risks to subjects including
- emotional or psychological
- financial
- legal or social
- physical? 
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Medications (Drugs) Used During This Study: 
Nitroglycerin - Sublingual (under the tongue): Nitroglycerin may cause light-
headedness, dizziness, headache, and low blood pressure. You could experience 
light-headedness and dizziness with change in position from lying to sitting. If 
so, your blood pressure will be monitored. You will be asked questions to 
determine if you are having any of these symptoms. These effects usually last for 
only a few minutes. There is a small risk of infection from the spray bottle when 
giving you this drug under the tongue. 
Allopurinol - Oral (by mouth): The following are some of the potential side 
effects that may result from use of Allopurinol. Most of the side effects are rare 
and occur in about 1% of people on Allopurinol. We have listed potential side 
effects and the rate of occurrence below. The most common side effect is a skin 
rash. You will be monitored weekly by telephone call from the research team. If 
any indication of side-effects the study drug will be discontinued. You will be 
asked to report for follow up. 
Life Threatening 
• Jaundice (0-0.05%) 
• Liver Damage (0-2%) 
• Kidney Failure (0-0.05%) 
• Severe allergic reactions (0.4%) 
• Stevens-Johnson syndrome (less than 1 %) 
Serious 
• Anemia (0-0.05%)Bruising (0-2%) 
• Fever (Drug fever: 0-3%) 
• Diarrhea (0-3%) 
• Vomiting (less than 1%) 
• Acute gout (0-2%) 
Mild 
• Headache (less than 1%) 
• Body aches (less than 1%) 
• Stomach disorder (stomach upset less than 1%) 
• Painful voiding (less than 1%) 
• Nausea, (nausea +/- vomiting 0-2%) 
• Pruritus (less than 1%) 
• Skin rash (less than 1%) 
Women Capable of Becoming Pregnant: If you are a woman who is capable of 
becoming pregnant, we will ask you to have a pregnancy test before beginning 
and while participating in this study. You must use effective birth control 
methods and try not to become pregnant while participating in this study. This 
involves using two barrier methods such as male and female condoms, 
diaphragms, spermicides (which are creams or gels that contain a chemical to kill 
sperm), or an intrauterine device (IUD). Women can use birth control pills, shots 
or patches during this study according to their primary care physician. If you 
become pregnant, there may be unknown risks to your fetus, or risks to your 
fetus that we did not anticipate, associated with being in the study. There may be 
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long-term effects of the treatment being studied that could increase the risk of 
harm to an unborn child. If you believe or know you have become pregnant 
while participating in this research study, please contact Dr. Roberto Kalil, M.D. 
(319) 384-7998 as soon as possible. 
Pulse wave analysis and velocity: Although this test is entirely safe, some people 
may feel uncomfortable with the sensor placement and location of the sensor at 
the hip (or groin area over the artery). Minimal skin area will be exposed. You 
will be able to wear shorts or underwear and a sheet to cover the area will be 
used for your privacy. 
Blood loss: About 1/2 cup of blood in total will be drawn during the 3-year study 
period. No significant side effects are expected with this volume of blood loss 
over the study period. The risk of anemia (or low blood count) with this amount 
of blood draw is small as the body continually makes red blood cells. 
Blood sampling: Blood samples will be drawn from your arm. The risks and 
discomfort of drawing blood include bruising or the possibility of pain at the site 
of the draw, light-headed or a dizzy feeling, bruising where the needle was 
inserted, and rarely, infection at the site of the blood draw. 
Adhesive electrode patches: The patches used for electrocardiogram (EKG) and 
heart monitoring during the procedures may cause minor local irritation to the 
skin. 
Information will be kept in password protected files, and will be deidentified. 
Only research team members will have access to data. 
VIII.2 
What have you done to minimize the risks? 
l If applicable to this study ALSO include: 
¡ How you (members of your research team at Iowa) will monitor 
the safety of individual subjects. 
¡ Include a description of the availability of medical or 
psychological resources that subjects might require as a 
consequence of participating in this research and how referral will 
occur if necessary (e.g. availability of emergency medical care, 
psychological counseling, etc.)
Oral allopurinol: Prior to enrollment in the study, subjects with history of adverse 
reaction to allopurinol will be excluded from study participation. Current FDA-
approved labeling is that doses of up to 800 mg of allopurinol can be given to 
patients with GFR 80 ml/min. Considering the potential renal dysfunction of 
renal transplant recipients, we plan to start all patients with a dose of 300 mg, 
which is less than 50% of the maximum dose allowed by the FDA. If well 
tolerated, the dose will be escalated by 100 mg each week with maximum dose 
up to 600 mg at 4 weeks for the remaining of the study. Levels of oxypurinol and 
uric acid will be measured regularly although there has been some recent debate 
about whether side effects with allopurinol are even due to high circulating levels 
(versus a dose-independent idiosyncratic reaction). 26 In addition, once weekly 
telephone calls will be made to subjects to evaluate for side effects of nausea, 
pruritus, skin rash, weight loss, anorexia, vomiting or diarrhea. If a subject 
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IX. Benefits
X. Privacy & Confidentiality
reports skin rash, he/she will be instructed to return to the clinical research unit 
for evaluation and will be instructed to discontinue the study medication. 
c) Monitoring and documentation and reporting of Adverse Events: 
Monitoring, documentation and reporting of adverse events will be performed by 
the members of the research team: Roberto S. Kalil, MD, William Haynes MD, 
Christine Sinkey RN, Tammy Lowe RA, Rebecca Beek RA and will be reported 
to the Clinical Research Unit Safety Committee for review. 
d) Frequency for review of summarized safety information: 
Screening questions for possible side effects of allopurinol such as skin rash, 
pruritis, anorexia, nausea, vomiting will be also asked during weekly telephone 
calls during the first 4 weeks until study subjects reach the maximun study dose 
(600 mg daily). 
All adverse events will be reported to the Clinical Research Unit Committee. 
e) Stopping Rules: 
Subjects will be withdrawn from the study and the study medication 
discontinued, if they report a skin rash while on the study medication. They will 
be requested to present to the nearest healthcare facility for evaluation for 
Stevens-Johnson syndrome. In case of suspected drug-toxicity, besides stopping 
the drug, subjects will be instructed to drink plenty of fluids (10 to 12 glasses of 
water a day). 
VIII.3 
Does this study have a plan to have an individual or committee review 
combined data from all subjects on a periodic basis (such as summary or 
aggregate safety and/or efficacy data)? 
No 
IX.1 
What are the direct benefits to the subject (do not include compensation or 
hypothesized results)? 
No direct benefits are expected. 
IX.2 
What are the potential benefits to society in terms of knowledge to be gained as 
a result of this project? 
The need for improvement in cardiovascular outcomes in recipients of kidney 
transplantation is critical. Finding a treatment that is effective, safe and at very 
low-cost such as allopurinol would be highly beneficial for recipients of kidney 
transplantation. 
X.1 
What are you doing to protect the privacy interests of the subjects? 
Obtaining the consenting and all contact with study subjects will take place in a 
private room in the Clinical Research Unit with one of the research team 
members. Information will be kept in locked cabinets, and computers with 
password protected access. Data will be de-identified for analysis. Presentations 
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and publications will follow standard norms of not using any potential identifier. 
X.2 
Are you collecting the Social Security Number of any subjects for any 
purpose? 
Yes 
X.3 
Provide the intended usage of SSN: 
l To provide compensation to subjects 
X.4 
How will information/data be collected and stored for this study (check all that 
apply): 
l Paper/hard copy records (hard copy surveys, questionnaires, case report 
forms, pictures, etc.) - ANy hard copy records will be kept in a locked 
cabinet with access restricted to the research team only. The cabinet is 
located at T311-GH. We anticipate a minimum use of hard copy records as 
most of the information needed will be obtained from the electronic 
medical records. 
l Electronic records (computer files, electronic databases, etc.) - Data from 
EPIC will be extracted in a de-identified fashion. Computers with 
password protected access can be used for data storage. Patient 
information is immediately de-identified as it is entered in the study 
database for statistical analysis.Patient level, clinician level, and clinic 
level data for this study will be stored electronically in the REDCap 
platform. The REDCap platform is managed by the Institute for Clinical 
and Translational Science at the University of Iowa. Only IRB approved 
research team members will have access to the REDCap data platform. 
Each team members will be granted access to the REDCap data system 
through a secure login. In the REDCap data platform, primary data is 
secured in HCIS Pomerantz Data Center. Data backups are secured in ITS 
Lindquist Data Center. Operating system security includes: secure logins, 
data encryption at rest, remote system logging and configuration and 
change management. Data backups are encrypted both in flight and at rest. 
Copies of data are replicated to the remote data center every 15 minutes. 
There are 100+ point in time copies of data available at any time. Disaster 
recovery has been tested. 
¡ Name - Lee Carmen 
¡ Title - BSEE 
¡ University Job Classification - VP of IT security at UIHC 
l Biologic samples (blood draws, check swabs, saliva samples, tissue 
samples, etc.) - All labels in study specimens will have a code that de-
identifies study participants information and stored in a secure freezer at 
the Clinical Research Unit. 
¡ Name - Tamara Lowe 
¡ Title - Research Assistant II 
¡ University Job Classification - UIHC staff RA 
X.5 
Do the confidentiality protections indicated above allow only members of the 
research team to access the data/specimens? 
Yes 
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XI. Data Analysis
XII. Future Research
X.7 
Does your study meet the NIH criteria for a Certificate of Confidentiality or 
will you be applying for Certificate of Confidentiality? 
No 
XI.1 
Describe the analysis methods you will use, including, if applicable, the 
variables you will analyze 
Primary endpoints 
1. Changes in endothelial function measured by flow mediated dilation of the 
brachial artery. 
2. Changes in 24h ambulatory blood pressure monitoring. 
3. Changes in Augmentation Index (AIx) and Pulse Wave Velocity (PWV) 
3. Rates of cardiovascular events 
4. Changes in renal function (eGFR) and proteinuria 
5. Cardiovascular variability (HR and BP) assessed by Finapress® 
Secondary endpoints 
1. Changes in markers of inflammation: hs CRP and IL-6 
2. Changes in renal function (eGFR) and proteinuria 
Analysis: 
Linear mixed model analysis for repeated measures will be used to compare 
mean response in sAMBP, dAMBP, and FMD between allopurinol and placebo. 
The fixed effects in the model will include treatment (allopurinol vs. placebo), 
time (baseline vs. 2 month, 12, 24 and 36 months), and treatment*time 
interaction. The test for the treatment*time interaction effect will correspond to 
comparing the mean change in sAMBP, dAMBP, FMD or BP variability at 2, 
12, 24 and 36 months from baseline levels between the allopurinol treated group 
and the placebo group. The same model will be used to compare changes in 
laboratory parameters over time. 
XI.2 
Provide the rationale or power analysis to support the number of subjects 
proposed to complete this study. 
Based on a standard deviation of 3.06%, assuming that the absolute difference in 
FMD between allopurinol and placebo group will at least 1.9%, our sample size 
(n=60 per group) will be powered at 80% to detect a 0.05 significance level, 
applying the Bonferroni corrected T test to detect this difference in one or more 
data point. We believe this is a conservative estimate as the predicted magnitude 
in change in FMD was calculated using published data from trials administering 
300 mg of allopurinol (Kao et al). We plan to use a higher dose of 600 mg, and it 
is well known that there is a dose-dependent improvement in FMD therefore we 
may observe a larger difference with a higher statistical power in this study. 
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XII.1 
Do you wish to keep any information about subjects involved with this research 
project so that members of the current research team may contact them in the 
future for your own research projects? 
Yes 
XII.2 
Do you wish to keep any information about subjects involved with this research 
project so that other researchers may contact them for future research? 
No 
XII.3 
List the data or information you will keep: 
Basic clinic and demographic data for possible participation in follow-up 
studies. These will include, age, gender, race, type of transplant (living 
donor or deceased-donor), number of transplants, history of cardiovascular 
disease, hypertension, diabetes mellitus, hyperlipidemia, smoking status, 
obesity, history of cardiovascular revascularization or peripheral vascular 
disease and revascularization, pre-transplant and post-transplant cardiac 
stress tests, coronary angiogram, echocardiograms,history of acute or 
chronic transplant rejection. Laboratoy data will include serum creatinine, 
electrolytes, lipid profile, CBC, calcium, phosphorus, vitamin D 
levels,intact PTH levels,urine analysis, random urine tests for protein and 
creatinine measurement,Interleukin-6, C-reactve protein levels,uric acid, 
and oxypurinol levels. Flow-mediated dilatation scores, blood pressure 
measurements, pulse wave analysis, blood pressure and pulse monitoring 
will be kept with the demographic, laboratory and clinical data detailed 
above. 
XII.4 
Does this project involve storing any data, tissues or specimens for future 
research? 
Yes – contribution for future use is optional 
XII.5 
Describe how you will keep track of those who consent to future use and 
those who do not and how you will prevent future use for those who do 
not consent. 
Screening logs will document patient's option. 
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