Clinical trial NCT03865407
Conditions: Hyperuricemia Chronic Kidney Diseases
Sponsor: Virginia Commonwealth University
Start date: 2019-03-10; Completion date: 2020-10-07
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Aim 1. To determine the effect of Allopurinol treatment on renal function (glomerular filtration rate, GFR) in pediatric chronic kidney disease (CKD) patients with high uric acid levels (hyperuricemia).

Aim 2. Establish whether Allopurinol treatment reduces Nlrp3 inflammasome and renal injury biomarkers.

Detailed description:
Uric acid levels often rise when kidney function declines. Historically, high uric acid has not been treated unless the uric acid crystallizes in the joint space and causes clinical gout disease, more typically seen in adults. However, new research has shown that high uric acid levels are associated with the development of hypertension, inflammation, and both acute and chronic kidney injury. Adult patients on renal dialysis who have hyperuricemia also have higher mortality rates. In several adult and in one pediatric clinical trial of uric acid lowering therapy (with Allopurinol or Febuxostat), treatment has demonstrated a slower rate of renal function decline and improved blood pressure compared to placebo. The pediatric trial was a 4-month placebo controlled trial of Allopurinol, and showed positive improvement in renal function and blood pressure, but did not adequately control for potential confounders in the outcome. Two known confounders that influence renal function (glomerular filitration rate, GFR) in pediatric CKD are race and glomerular or non-glomerular disease etiology. This study is designed to control for these confounders and establish whether Allopurinol for 6 months of treatment to a goal range of 3-5 mg/dL will improve renal function compared to standard of care. The secondary outcome is to determine whether blood pressure is affected by the treatment and the magnitude of change of serum uric acid. This study will also explore whether Allopurinol treatment alters activation of the Nlrp3 inflammasome or renal injury biomarkers.

Arms: arm 1: Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. arm 2: The treatment arm will be compared to a standard of care arm.
Interventions: intervention 1: Allopurinol
Intervention descriptions: intervention 1: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Title: Uric Acid Reduction as a Novel Treatment for Pediatric Chronic Kidney Disease 
 
NCT #: NCT03865407 
 
Document date: 02/25/2019 
 
Document Type: Protocol and Statistical Analysis Plan 
 
 
 


1 
 
RESEARCH PROPOSAL 
 
TABLE OF CONTENTS 
Page 1 
  
  
Content 
Page 
Abstract - Summary 
2 
Public Health Impact 
 
Compliance Statement 
 
Specific Aims 
3 
Background and Significance 
4 
Research Methods and Study Design 
 
5 
Study Intervention Administration  
7 
Data and Safety Monitoring Plan 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
ABSTRACT - Summary 
 
   Pediatric chronic kidney disease (CKD) is a devastating disease that not only limits quality of life, but life 
span. Although promising results have emerged from epidemiologic studies and adult CKD trials demonstrating 
that lowering serum uric acid (UA) levels with Xanthine Oxidase (XO) inhibitors can improve renal function and 
even blood pressure (BP), there is currently no well-established therapy that can reverse the rate of decline of 
renal function in pediatric CKD. A single published pediatric CKD trial using a XO inhibitor did demonstrate 
significant improvement in renal function and BP, however the study had some statistical and design flaws and 
the study findings have not yet been reproduced in the literature. Furthermore, while non-clinical studies have 
demonstrated that high UA leads to specific changes that promote inflammation, cardiovascular, and kidney 
injury, there is a lack of clinical studies showing how UA lowering therapy impacts humans. Our pilot 
randomized controlled clinical trial proposes to establish that the treatment of pediatric CKD patients with high 
UA using Allopurinol, a XO inhibitor, over a six month period can improve kidney function. We will also 
measure changes in biomarkers of inflammation and kidney injury after Allopurinol treatment. The results of 
this study will improve our understanding of UA mediated disease in pediatric CKD, and determine whether 
Allopurinol therapy can improve kidney function in this population.   
 
 
PUBLIC HEALTH IMPACT 
 
  The incidence and prevalence of pediatric CKD and renal replacement therapy is rising throughout the 
world, and higher in the United States (U.S.) compared to Western Europe[1]. Various non-modifiable factors, 
including race and disease etiology, and modifiable clinical factors of hypertension, proteinuria, and high uric 
acid (UA) negatively affect the rate of renal function decline [2]. In the U.S., African American children have a 
two-fold higher incidence of end stage renal disease than Caucasian children but are underrepresented in 
many clinical trials. The Children’s Hospital of Richmond at VCU Pediatric Nephrology Division has a unique 
CKD population composed of 50% Black race which is an important feature of this proposed clinical study. 
There is no therapy that has been proven to reverse renal function decline in pediatric CKD to date. However, 
UA lowering therapy with Xanthine Oxidase (XO) inhibitors has recently been shown to improve renal function 
in adults with CKD. The effectiveness of this therapy needs to be reproduced in large-scale pediatric clinical 
trials, and has important disease-modifying potential in the pediatric population. The XO inhibitor Allopurinol 
proposed for use in this pilot clinical trial is an inexpensive, universally available generic medication with a well-
documented safety side effect profile in pediatrics. Although the only published pediatric CKD trial of 
Allopurinol had study design flaws, it showed an impressive statistically significant positive increase in renal 
function over 4 months of therapy compared to placebo. A pediatric CKD study which addresses these study 
design flaws must be reproduced before a large multi-center trial is undertaken, and is proposed in this clinical 
trial. 
 
 
COMPLIANCE STATEMENT 
 
  I certify that this submission contains an Applicable Clinical Trial and that I will ensure compliance with 
registration and results reporting submissions to ClinicalTrials.gov as required under the FDA Amendments Act 
of 2007 and the Final Rule (42 CFR Part 11). 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
SPECIFIC AIMS 
 
Chronic kidney disease (CKD) is a life-long condition with significant morbidity and premature mortality 
due to progressive decline in renal function towards end stage renal disease (ESRD). Once on dialysis, the 
expected remaining lifetime for a child with pediatric-onset ESRD is 18 years [3]. With mortality rates 30-150 
times higher than the general pediatric population, the management of CKD to prevent or slow the progression 
of renal dysfunction is crucial. Pediatric-onset CKD originates predominately from congenital anomalies of the 
kidney and urinary tract (CAKUT, 50%), glomerular disorders (22%), and other hereditary nephropathies 
whereas the majority of adult-onset CKD is due to chronic diabetes and hypertension (HTN). Differences in 
disease etiology (glomerular vs. non-glomerular), race, and having modifiable conditions of proteinuria, 
hyperuricemia, or HTN significantly impacts CKD disease duration and rate of progression [4, 5]. Both the strict 
control of blood pressure (BP) and reduction of proteinuria are incompletely effective and can only slow the 
rate of renal function decline [6].  
The association of faster CKD progression with hyperuricemia is a relatively recent discovery resulting 
from large epidemiologic studies [7, 8]. Historically hyperuricemia was defined by a serum uric acid (UA) level 
>6.8-7 mg/dL, the supersaturation point of UA in the blood at physiologic pH. However, there is a growing body 
of literature that identifies an increased risk for acute kidney injury, incident CKD, and HTN at UA levels lower 
than this historical definition [9-11]. Animal models and in vitro studies confirm that mild hyperuricemia below 
the supersaturation point induces: 1) a reversible endothelial dysfunction through the production of oxygen 
radical species [12], 2) HTN through activation of the renin-angiotensin system [13], 3) activation of pro-
inflammatory mediators through the Nlrp3 inflammasome [14], and 4) both direct UA-mediated and indirect 
Nlrp3-mediated renal dysfunction through tubular injury and modification of the renal vasculature [15, 16]. As a 
result, hyperuricemia is increasingly defined as a serum UA level ≥5.5-6 mg/dL in clinical trials [17, 18]. 
Adult CKD clinical trials of Xanthine Oxidase (XO) inhibitors, which block the production of UA via the 
enzyme XO, have reduced UA and increased renal function, i.e. the glomerular filtration rate (GFR), over trial 
periods of 12 weeks to 2 years [19-21]. To date, only one 4-month pediatric CKD trial has been published by 
Sharbaf et al that showed treatment with Allopurinol, a XO inhibitor, improved GFR by a mean increase of +16 
ml/min/1.73m2, SD=9.3 compared to placebo [18]. The treatment also demonstrated a significant improvement 
in BP similar to another clinical trial of Allopurinol in a randomized 4-week crossover trial of hyperuricemia in 
pediatric essential hypertension [17]. The Sharbaf trial (2018) had study design flaws in that it did not use 
intention-to-treat principles, was not stratified for known modifiers of GFR decline, and did not report race. 
Additionally, none of the aforementioned clinical trials have explored the mechanism of how XO inhibitors 
improve GFR or BP, revealing an area for research. If benefits of GFR improvement from XO inhibition are 
reproduced in a well-designed pediatric CKD trial, this therapy could potentially offer hyperuricemic patients a 
significant improvement in disease burden. We propose here a pilot clinical trial to identify the rate of GFR 
change following 6 months of Allopurinol treatment versus standard of care amongst pediatric 
hyperuricemic CKD patients. We hypothesize that Allopurinol therapy will reduce serum UA level and 
improve the rate of GFR change. We will simultaneously explore a possible mechanism of Allopurinol 
therapy via reduced Nlrp3 inflammasome activity and expect to see a reduction of renal injury biomarkers. This 
study will address the feasibility of a design that stratifies the population for known modifiers of GFR decline 
with adequate power, essential preliminary data for designing a future large-scale multicenter pediatric trial. 
Aim 1. To determine the effect of Allopurinol treatment on GFR of hyperuricemic pediatric CKD 
patients. In a randomized controlled study, pediatric CKD patients with hyperuricemia (serum UA ≥5.5 mg/dL) 
will be allocated 2:1 to Allopurinol versus standard of care (SOC) control for 6 months. Participants will be 
stratified into two cohorts by disease etiology (cohort A: non-glomerular, cohort B: glomerular). Equal allocation 
of race is expected as our local population is composed of 50% black race. The primary outcome measure is 
the amount of GFR change from baseline to 6 months compared to the control group in both cohorts. 
Secondary outcomes are measurement of the amount of UA and BP change from baseline to 6 months.  
 
Aim 2. Establish whether Allopurinol treatment reduces Nlrp3 inflammasome and renal injury 
biomarkers. In this exploratory aim, urine and serum biomarkers of Nlrp3 inflammasome activation (hs-CRP, 
XO enzyme activity, Nlrp3, IL-1β, IL-18) and renal injury (KIM-1, ET-1, NAG, and NGAL) will be collected at 3 
and 6 months and compared to baseline of cohorts A and B treatment and control groups.  
 
Impact: GFR change from baseline to 6 months by treatment and cohort will be used to directly inform 
the effect size and sample size calculations required for a randomized controlled multicenter pediatric 
intervention trial. The simultaneous and novel exploration of the effect of XO inhibition on inflammation and 
renal injury biomarkers will provide crucial data that may identify mechanism of the XO inhibition effect. 
 


4 
 
BACKGROUND AND SIGNIFICANCE 
 
 
Uric acid (UA) is a purine nucleotide and fructose breakdown product via the enzyme Xanthine Oxidase 
(XO) which also generates harmful reactive oxygen species (ROS) byproducts. Two-thirds of serum UA is 
excreted by the kidneys through multiple regulation transporters, which can become inefficient in chronic 
kidney disease (CKD). Hyperuricemia develops by increased UA production, for example through a high purine 
meat or fructose diet, impaired renal UA excretion, or both. Large epidemiologic studies have recently 
associated hyperuricemia with incident acute and chronic kidney injury, a faster rate of renal function decline in 
both pediatric and adult chronic kidney disease (CKD), and an increased risk for death in CKD and dialysis 
patients [4, 8]. UA-mediated damage occurs along a “J” shaped pattern of injury, where it functions as a 
powerful anti-oxidant at mid-range levels and pro-oxidant at the extremes [10, 22]. Rat models of 
hyperuricemia show that mildly elevated UA causes crystal-independent renal injury through direct activation of 
the renin-angiotensin system, endothelial dysfunction through NADPH oxidase activation and ROS release 
[12]. In these animal models, induction of a mild hyperuricemia also results in pathologic changes to the renal 
functional nephron unit, i.e. glomerular hypertrophy and hyperfiltration, afferent arteriolar constriction, and 
tubular fibrosis which can be reversed with Allopurinol, a XO inhibitor [16].  
Adolescents with UA levels above 5.5 mg/dL in the National Health and Nutrition Examination Survey 
(NHANES) 1999-2006 had a 2-fold increased odds of elevated blood pressure (BP)[9]. This value has since 
been used as a pediatric definition for hyperuricemia in several clinical studies and applied in this proposal [15, 
17, 18]. A cross-over randomized controlled trial also demonstrated reduction of UA significantly improved 
systolic and diastolic BP in pediatric essential hypertension patients with hyperuricemia[17]. Clinical trials of 
XO inhibitors in adult CKD patients have demonstrated a reduced rate and in some, a reversal of decline in 
glomerular filtration rate (GFR) [21]. 
Pediatric CKD epidemiology is different from adult CKD in the following ways. First, the etiology is 
primarily due to non-glomerular diseases (e.g. congenital anomalies of the kidney and urinary tract [CAKUT], 
the most common cause at 50%), and glomerular diseases (e.g. acute glomerulonephritis) rather than the 
primary adult causes of diabetes and hypertension. CAKUT conditions and the resultant, often insidiously 
progressive, CKD is present from birth. Whereas the typical age of onset of glomerulonephritis is the teenage 
years with acute onset renal dysfunction leading often to a more rapid chronic progressive disease than non-
glomerular CKD. In pediatrics, factors that affect the rate of renal function decline and lead to a faster 
progression of CKD towards end stage renal disease (ESRD) are black race, glomerular disease etiology, and 
modifiable disease phenotypes of hypertension, proteinuria, and hyperuricemia [2, 4].  
Results from adult clinical trials are often extrapolated to the pediatric population, but with the above 
listed differences in CKD epidemiology, the beneficial effect of UA lowering therapy should be tested 
separately in pediatrics. The effect of UA lowering therapy may differ for those with glomerular versus non-
glomerular disease etiology, race, or for those with proteinuria versus none. There are data to support a similar 
beneficial effect from XO inhibitors in pediatrics as in adults, but the effect modification, if any, of these factors 
is not specifically known. For example, a single randomized placebo-controlled pediatric CKD trial of 
Allopurinol for 4 months demonstrated a statistically significant increase in the mean glomerular filtration rate 
(GFR) from baseline to endpoint of +16 ml/min/1.73m2 (SD=9.3). However, this study did not report race, did 
not stratify participants by glomerular or non-glomerular disease etiology or presence of proteinuria, and did 
not use intention to treat principles when those with a pre-specified adherence rate <80% were excluded at the 
end of the study, leading to an overall study power of 78%. The reported rate of GFR change in adult trials 
range from approximately +1 to +3 ml/min/1.73m2 (SD=1-3) [20]. While we recognize results in pediatric 
populations may differ from adults, further confirmation is needed before progressing to large scale trials. A 
feasibility pilot clinical trial proposed here will test the effect of XO inhibition on GFR using study design 
principles of blocked allocation of participants to control for known factors that affect GFR decline. 
  
 
 
 
 
 
 
 
 


5 
 
RESEARCH METHODS – Study Design 
 
Specific Aim 1. To determine the effect of Allopurinol treatment on GFR of pediatric CKD patients with 
hyperuricemia. 
 
1.1. Rationale and Objective: While there is support in the literature for beneficial effect of XO inhibitor 
therapy on GFR and BP in pediatric CKD, the degree of expected change in GFR based on disease etiology is 
uncertain. Therefore, we propose a randomized controlled trial of hyperuricemic pediatric CKD participants in a 
2:1 allocation between Allopurinol and standard of care (SOC) therapy, and stratified by disease etiology 
(cohort A: non-glomerular, cohort B: glomerular). Randomization procedure will be blinded, but the allocation 
will be unblinded to investigator and participant because of the lack of placebo. Allopurinol will be titrated to 
reach a normal range of serum UA 3-5 mg/dL by 6 months. Local SOC practice for pediatric CKD includes 
control of blood pressure with anti-hypertensives, control of acidosis, control of proteinuria, and frequent 
laboratory monitoring to measure the rate of renal function decline. The primary outcome of Aim 1A is change 
in GFR between baseline and 6 months by treatment group. The secondary outcomes are change in serum 
UA, and change in BP over the same time. An exploratory sub-aim (Aim 1B) will identify and compare GFR 
change by cohort characteristics (disease etiology, proteinuria, and race) that may influence future trial 
designs.  
1.2. Experimental Design (Table 1): We will conduct a 6-month randomized treatment (Allopurinol) vs. 
SOC clinical trial to measure change in GFR over time in pediatric hyperuricemic CKD participants. We will 
conduct this study after obtaining appropriate consent and assent. Our recruitment pool will include all patients 
receiving medical care from the CHoR Pediatric Nephrology Division, new and recurring outpatient encounters. 
The division currently sees approximately 3,500 outpatient encounters per year. The study visits will coincide 
with SOC visits with the possible exception of visit V1A (some but not all participants will normally be seen for 
SOC 1 month after the baseline visit). The following inclusion and exclusion criteria apply:  
- Inclusion Criteria: CKD stage 1-5; Age 2-20 years old at time of enrollment; Hyperuricemic 
- Exclusion Criteria: Contraindication to Allopurinol; Elevated baseline liver function tests; Receiving acute 
or chronic dialysis; Primary metabolic disorder; Sickle cell disease; Autosomal Dominant Polycystic Kidney 
Disease; Cystinosis; Bartter or Gitelman Disease; Pregnant or nursing. 
The allocation will be unblinded to investigators and participants. We plan to over-sample the 
glomerular cohort B and limit enrollment of the non-glomerular cohort A to ensure adequate distribution of the 
sample by disease etiology in a proportion generalizable to the national pediatric CKD population (2:1). The 
proposed allocation distribution is detailed in Section 1.3 and Table 2.  
Hyperuricemia is defined in this protocol as having at least two measures of serum UA ≥5.5 mg/dL in 
the last 12 months, or actively treated with a XO inhibitor for a previous diagnosis of hyperuricemia. 
Participants actively treated with a UA lowering agent (Allopurinol, Febuxostat, or Losartan) will undergo a 
washout period of a minimum of 1 month (up to 3 months) prior to enrollment in the trial, then randomized to 
treatment versus control groups. None of the patients in the CHoR Pediatric Nephrology group practice actively 
treated with these agents had/have symptomatic hyperuricemia, and only 3 out of 14 treated have reached the 
target UA level of 3-5 mg/dL which will be applied in this study protocol. As it is unknown to what degree 
patients are benefiting from a minimal reduction of UA but with a persistent hyperuricemia, the CHoR Pediatric 
Nephrology Division has concluded that it is ethical for consenting participants actively receiving a XO inhibitor 
to be randomly assigned to treatment or control after a wash-out period.  
Allopurinol dose will be initiated using standard weight-based dosing at the Baseline Visit 1 (V1), and 
titrated at Visits 1A and 2 (V1A, V2) to achieve a goal UA level in the normal range of 3-5 mg/dL by Visit 3 
(V3).  
At baseline, demographic and anthropometric data, CKD disease etiology and duration since diagnosis, 
current medications, and presence of proteinuria or hypertension will be collected. At baseline and 6 months, 
casual clinic BP will be obtained (the average of three measurements) for hypertension assessment. Serum 
and non-invasively obtained urine will be collected at baseline, 3, and 6 months for basic or comprehensive 
metabolic panel, UA, cystatin C and creatinine-based GFR measurements. An additional serum and urine 
sample for purposes of dose titration and safety will be collected from the treatment group but not control at 
Visit V1A. The residual serum and urine samples will be bio-banked for the analyses of Aim 2. Adverse events 
will be collected and adherence will be measured at the V1A, V2, and V3 visits by pill count and through a 
validated visual analogue scale of adherence [26]. Participants will also receive a one-time monetary 
compensation at the conclusion of the study (V3). 
 


6 
 
Table 1. Study Timeline and Data Collection 
 
 
1.3. Statistical Analysis: We will report means/medians and standard deviations (SD)/interquartile range 
(IQR) for all continuous measures, and frequency and proportions for categorical variables. Assuming a 
clinically significant difference between treatment groups of 3 ml/min/1.73m2 and individual group SDs=3.5, a 
one-sided analysis t-test performed at α=0.05 will achieve at least 80% power for a sample size of 42 if the 
participants will be allocated in a 2:1 ratio between treatment and control. We will also enroll participants into 
two cohorts to assure proportional distribution between non-glomerular (cohort A) and glomerular (cohort B) 
disease etiology. Our local pediatric CKD population composition by disease etiology is similar to national 
proportions of approximately 70% non-glomerular and 30% glomerular disease etiology. We will therefore 
over-sample the glomerular sub-population in cohort B and limit enrollment of the non-glomerular cohort A to 
n=19, maintaining roughly a 2:1 proportion. The goal allocation enrollment by treatment group and cohort size 
is summarized in Table 2. Two-sample t-tests on the GFR change score will be used to address Specific Aim 
1A while separate 2-way ANOVA models with an interaction will be used to address Aim 1B. Repeated 
measures ANOVA models will be used to inform from all three time points in an intent-to-treat fashion. 
 
Table 2: Goal allocation enrollment 
 
 
 
 
 
 
Specific Aim 2. Determine the effect of Allopurinol treatment on Nlrp3 inflammasome and renal injury 
biomarkers.  
 
2.1. Rationale and Objective: To our knowledge there are no studies that explore the effect of XO 
inhibition on the known mechanism of hyperuricemia induced Nlrp3 inflammasome activation and renal injury 
in a clinical trial setting. We therefore propose to establish whether XO inhibition reduces levels of these 
biomarkers at 3 and 6 months compared to baseline. If our hypothesis is correct that inflammasome-mediated 
renal injury is improved by Allopurinol, we expect to find that after 3 and 6 months of Allopurinol treatment, the 
biomarker levels will be reduced from baseline in both treated cohort groups compared to control participants. 
  
2.2. Experimental Design: The study design of Aim 2 is the same as Aim 1 (see Table 2). We will 
measure the following biomarkers from reserved serum and urine samples at the baseline, 3, and 6 month 
visits. Activity of the Nlrp3 inflammasome will be measured via: serum high sensitivity CRP, Xanthine Oxidase 
Study Visit 
Subject 
identification 
Baseline Visit   
(V1) 
Visit 1A 
(V1A) 
Visit 2 
(V2) 
Endpoint Visit 
(V3) 
Time 
-1 to -3 months 
0 
+1 month 
+3 months 
+6 months 
Encounter Purpose  1-3 month 
Allopurinol washout 
Study 
enrollment,  
Randomization, 
baseline values 
UA titration, 
Adherence & 
Safety check 
UA titration, 
Adherence 
& Safety 
check 
Study 
endpoint 
Data Collection of 
Treatment group 
C, G 
A-E, G 
D, F 
C, E, F 
A-F 
Data Collection of 
Control group 
C 
A-E 
No visit 
C 
A-E 
Data Collection key A: Demographic, anthropometric, medication history, clinic BP 
B: Vital signs including 3 casual clinic BP measurements 
C: Standard of care lab work: Serum – Basic metabolic panel, UA, cystatin C; Urine – 
Protein, creatinine, UA 
D: Serum Comprehensive metabolic panel; urine UA, creatinine. 
E: Reserve residual serum and urine samples for biomarker analysis 
F: Pill count, Adherence visual analogue scale, Evaluation of adverse events 
G: Urine pregnancy test if applicable to females of reproductive age 
Treatment Group 
Allopurinol Group 
Control Standard of Care Group 
Cohort A: Non-glomerular disease etiology 
19 
7 
Cohort B: Glomerular disease etiology 
9 
7 
Total 
28 
14 


7 
 
activity level, Nlrp3, Interleukins 1β and 18, and urine Nlrp3 and IL-18. Renal injury biomarkers will be 
measured from serum NGAL, urine NGAL, NAG, KIM-1, and ET-1.  
 
2.3. Statistical Analysis: We will report means/medians and standard deviations (SD)/interquartile range 
(IQR) for all continuous measures. Similar analyses will be used for Specific Aim 2 as Specific Aim 1. All 
sample size calculations were performed with nQuery Advisor v.7.0.  
 
 
STUDY INTERVENTION ADMINISTRATION 
The proposed intervention uses a study drug (Allopurinol) and concomitant therapy (Candesartan) that 
are available as generic. The PI is proposing to study the effects of Allopurinol under FDA-approved 
indications, which is approved for use in children and adults for the reduction of high uric acid levels. 
Candesartan is approved for use in children and adults for the reduction of high blood pressure. The 
concomitant therapy, Candesartan, is required in this protocol to reduce drug-drug interactions with Allopurinol. 
The medications Lisinopril, Enalapril, and Benazepril are commonly prescribed for hypertension but increase 
the risk of moderate to severe adverse reactions when used concomitantly with Allopurinol. Losartan is also a 
blood pressure lowering medication that uniquely lowers uric acid levels which could affect the results of the 
trial, but does not interact with Allpurinol so will be converted for a different and specific reason. Any participant 
in the trial who is prescribed Lisinopril, Enalapril, Benazepril, or Losartan at the time of randomization will be 
converted to a similar or same class of blood pressure lowering medication, Candesartan, which does not 
interact with Allopurinol or lower uric acid levels. Approximately 1/4 of participants in this trial will qualify for the 
Candesartan conversion. Candesartan will be supplied by the investigational pharmacy at no cost to 
participants. Allopurinol will also be supplied by the investigational pharmacy to the treatment group 
participants. 
 
Recruitment and pre-trial medication adjustments:  
Participants will be recruited during a standard of care (SOC) visit and consented at that visit or by 
phone if they meet study criteria. Subjects will be randomized in a blinded manner to treatment or control 
groups at the time of consent if they do not require a washout or medication conversion.  If they do require a 
washout or medication conversion to Candesartan, the randomization will occur once the washout is 
completed and after a  If applicable, the Allopurinol washout and/or Candesartan conversion will be initiated 4 
weeks before the participant's next scheduled SOC visit.  In the case of Allopurinol washout, the PI or research 
coordinator will provide the participant with the Allopurinol stop-date and call the participant to remind them to 
discontinue within 7 days of the medication change. Uric acid level will be measured with SOC labs at their 
next SOC visit and if participants are hyperuricemic (UA≥5.5 mg/dL), will continue in the trial in their pre-
determined treatment group. However if participants are normouricemic (UA <5.5 mg/dL), UA will be checked 
again at their next SOC visit up to 3 months later, and participants will proceed in the trial if they are then 
hyperuricemic. Otherwise they will be withdrawn from the trial, and their primary nephrology provider will 
decide whether to resume or discontinue Allopurinol treatment off-study at their own discretion.  
 
In the case of Candesartan conversion, the PI along with consultation from the participant's primary 
nephrologist will prescribe the starting dose of Candesartan. The PI or research coordinator will instruct the 
participant to STOP Losartan/Lisinopril/Benazepril/Enalapril and START Candesartan on a specific date 
scheduled 4 weeks before their next SOC visit. The research coordinator or PI will confirm the start/stop date 
with the participant by phone within 7 days, and if unable to reach the participant or his/her guardian, the 
Candesartan will NOT be mailed to the participant by the investigational pharmacy.  The participant's BP will 
be checked at their next SOC visit as part of routine care, and their primary nephrologist will make adjustments 
to the medication as necessary to achieve adequate BP control. If a participant decreases or remains in the 
same stage of hypertension (as defined by national pediatric BP guidelines) as before the Candesartan 
conversion (for example, remains in Stage 1 hypertension pre- and post-Candesartan, or moves from Stage 1 
to normal pre- and post-), then the participant may continue in the trial. If, however, the participant increases in 
hypertension stage pre- and post-Candesartan conversion (for example, normal to Stage 1 hypertension pre- 
and post-) the primary nephrologist will either adjust the Candesartan dose or decide to withdraw the 
participant from the trial and revert back to the prior medication as they deem necessary. Similarly, if the BP is 
determined to be too low, the dose will be adjusted or discontinued by the primary nephrologist. Signs and 
symptoms of low BP will be reviewed with participants prior to the conversion, and participants will be 


8 
 
encouraged to report any symptoms once they are converted. Participants who experience side effects, or 
those that are withdrawn from the study due to Candesartan conversion will be reported to the PI/research 
coordinator and Independent Monitor. The Data and Safety Monitoring Plan documents will review this in more 
detail. 
 
 
Figure 1. Washout and Medication Conversion Decision Tree 
 
The investigational pharmacy (IP) will purchase the generic Allopurinol and Candesartan tablets, the 
cost of which is included in the IP’s administrative fees. This is a pilot clinical trial that uses a standard of care 
control group. It does not involve placebo encapsulation or blinding. The IP is responsible for packaging, 
labeling, and distributing the study drug Allopurinol as well as the concomitant therapy, Candesartan.  
DOSING OF ALLOPURINOL:  We will utilize a weight-based dosing strategy, starting at 5mg/kg/day divided 
twice daily. A maximum daily dose per day will be restricted at 400 mg per day. Table 3 lists the starting dose 
by weight range. 
 
Consent obtained
Is patient currently 
on Allopurinol?
No: Proceed with 
Randomization
Yes. Washout 
indicated
Discontinue 
Allouprinol 4 weeks 
before next clinic 
visit. 
At next clinic visit: 
Is uric acid > 5.5 
mg/dL?
Yes: Proceed with 
Randomization
No: Repeat uric 
acid level at next 
clinic visit.
If uric acid is <5.5 
at 12 weeks, 
withdraw from 
trial. Report to PI 
as screen fail.
Is patient currently 
on Losartan?
No: Proceed with 
Randomization
Yes. Washout 
indicated
Convert Losartan 
to Candesartan 4 
weeks before next 
clinic visit.
At next clinic visit: 
Is uric acid > 5.5 
mg/dL?
Yes: Proceed with 
Randomization
No: Repeat uric 
acid level at next 
clinic visit.
If uric acid is <5.5 
at 12 weeks, 
withdraw from 
trial. Report to PI 
as screen fail.
At next clinic visit: 
Is BP stable or 
improved?
Yes: Proceed with 
study
No: discuss with 
primary provider 
any necessary BP 
dose adjustments; 
report safety 
concerns to PI


9 
 
Table 3. Allopurinol weight-based starting dose 
  
Weight range 
Dose 
15-25 kg  
50 mg TWICE DAILY 
25.1 – 35 kg 
75 mg TWICE DAILY 
35.1 – 50 kg  
100 mg TWICE DAILY 
50.1 – 70 kg 
150 mg TWICE DAILY 
  
To target a uric acid level of 3-5 mg/dL used in this protocol, the Allopurinol dose will be escalated at Visit 1A 
and Visit 2 if the participant’s uric acid level is >5 mg/dL. Similar to other Allopurinol dose escalation trials, the 
dose will be increased by 50mg/d for those participants with an estimated glomerular filtration rate (GFR) 
<60ml/min and 100mg/d in those with GFR ≥60ml/min. 
 
DOSING OF CANDESARTAN:  We will utilize an age and weight-based dosing strategy as recommended by 
the FDA dosing guidelines (Table 4). The participant’s doctor is responsible for titrating Candesartan within the 
recommended dosing range to achieve the desired blood pressure control.  
 
Table 4. Candesartan age and weight-based starting dose and dosing range 
Age 
Starting Dose 
Titratable Dose Range 
1 to <6 years 
0.2 mg/kg once daily 
0.05 – 0.4 mg/kg daily 
6 to <17 years 
 
 
    <50 kg 
4-8 mg once daily 
4-16 mg once daily 
    >50 kg  
8-16 mg once daily 
4-32 mg once daily 
>17 years 
16 mg once daily 
8-32 mg total daily dose 
 
DATA AND SAFETY MONITORING PLAN  
This randomized controlled trial aims to test the hypotheses that treatment of hyperuricemia with a xanthine 
oxidase inhibitor (Allopurinol) reduces the rate of decline of kidney function in chronic kidney disease, and 
markers of renal injury and inflammation. The Data and Safety Monitoring Plan (DSMP) is outlined below. 
During this study, all data collected will be kept confidential in an encrypted database using identification 
codes. Only approved research team members will have access to the database. The study staff will review all 
data collection forms on an ongoing basis for data completeness and accuracy as well as protocol compliance. 
Reviews of subject accrual, including compliance with protocol enrollment criteria and adherence data, will be 
performed by the PI and study staff on a monthly basis.  
 
Data on adherence to the treatment protocol will be collected on an ongoing basis by research staff and 
reviewed quarterly by the PI. Adherence of participants will be evaluated by performing pill counts at study 
visits and by a validated visual analogue scale of adherence (patient self-report) at the end of study visit. An 
intention to treat protocol is applied to this study. However, if adherence falls below a rate of 75% which might 
inhibit the ability of the study to test its primary hypotheses, the study investigators and statistician will convene 
to discuss methods for improving adherence. 
 
The PI will designate an Independent Monitor to perform an independent review of ongoing study progress 
and safety. The Independent Monitor will not be a part of the key research personnel, and will be qualified to 
review the patient safety data. Progress reports, including patient recruitment, retention/attrition of the study as 
a whole as well as retention of subjects undergoing washout or conversion therapy to study initiation, and 
adverse events (AE), will be provided to the Independent Monitor every 6 months. The reports will be 
generated only from aggregate for the entire study population. A closed safety report with masked group 
assignment will be generated for the Independent Monitor by an unmasked member of the study team 
(research coordinator).  
 
An Annual Report will also be compiled and will include a list and summary of AEs. In addition, the Annual 
Report will address (1) whether AE rates are consistent with pre-study assumptions; (2) reason for dropouts 
from the study; (3) whether all participants met entry criteria; (4) whether continuation of the study is justified 
on the basis that additional data are needed to accomplish the stated aims of the study; and (5) conditions 


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whereby the study might be terminated prematurely. The Annual Report will be sent to the Independent 
Monitor and will be forwarded to the IRB. 
 
AE reports and annual summaries will not include identifiable material. Each report will refer only to the 
subjects’ identification code. An AE is any untoward medical occurrence in a subject during participation in the 
clinical study or with use of the intervention agent being studied. An adverse finding can include a sign, 
symptom, abnormal assessment (laboratory test value, vital signs, skin reaction or physical exam finding), or 
any combination of these. A serious adverse event (SAE) is any adverse event that results in one or more of 
the following outcomes: 
• 
Death 
• 
A life-threatening event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly or birth defect 
• 
An important medical event based upon appropriate medical judgment 
AEs will be labeled according to severity, which is based on their impact on the patient. An AE will be 
termed “mild” if it does not have a major impact on the patient, “moderate” if it causes the patient some minor 
inconvenience, and “severe” if it causes a substantial disruption to the patient’s well-being. AEs will also be 
categorized according to the likelihood that they are related to the study intervention and labeled: definitely 
unrelated, definitely related, probably related, or possibly related to the study intervention. AEs will be reviewed 
with participants at each study visit. 
 
Occasional 1-10% mild AEs are mild nausea, mild elevation in liver transaminase levels, and are not 
expected to impact a patient. These risks are considered minimal and will be addressed in the protocol and 
consent form.  
 
The rate of moderate AEs is expected to be <1%. The protocol includes measures to reduce the risk of 
moderate to severe AEs. Moderate AEs include skin reaction, gastrointestinal distress, moderate elevation in 
liver transaminases. Subjects will be encouraged to report these occurrences at any time during the intervention 
period by telephone within 24 hours of experiencing an event. Any adverse event rate over 5% in 12 months will 
be reported to the IRB. 
 
Severe AEs include skin reaction as with development of Stevens-Johnson syndrome, or a significant 
elevation in liver transaminase levels that require hospitalization, and will be reported immediately to the IRB if 
this occurs. SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported 
to the Independent Monitor and IRB in accordance with requirements.  The Independent Monitor will be a 
clinician appointed by the PI who is not involved with the study design or analysis and is not a study 
investigator. 
 
Unexpected fatal or life-threatening AEs related to the intervention will be reported to the IRB within 7 days. 
Other serious and unexpected AEs related to the intervention will be reported to the IRB within 15 days. 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the Independent 
Monitor and IRB. In the annual AE summary, the Independent Monitor Report will state that they have reviewed 
all AE reports. 
 
The study staff, PI, and Independent Monitor will review the conglomerate adverse event rates every 6 
months. Review of AE and SAE reports will also occur on an ongoing basis by the PI and study staff.  
 
This study will be stopped prior to its completion if: (1) the intervention is associated with adverse effects 
that call into question the safety of the intervention; (2) difficulty in study recruitment or retention will 
significantly impact the ability to evaluate the study endpoints; (3) any new information becomes available 
during the trial that necessitates stopping the trial; or (4) other situations occur that might warrant stopping the 
trial. 
 
 


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