Assessing the Feasibility of N-of-1 Trials in Children With Hypertension and Chronic Kidney Disease: a Pilot Study
Phase: NA
Conditions: Hypertension, Chronic Kidney Diseases
Sponsor: The University of Texas Health Science Center, Houston

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessing the feasibility of n-of-1 trials in children with hypertension and chronic kidney 
disease 
 
 
NCT04591171 
 
Version Date: 10/02/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

tion, whose
Assessing the feasibility of n-of-1 trials in children with hypertension and chronic kidney 
disease: a pilot study 
 
PI: Joyce P. Samuel MD MS 
Co-investigators: Cynthia Bell PhD, Rita Swinford MD, Joshua Samuels MD MPH, Sonal Bhatnagar MD 
Funding Period: October 1, 2020 to September 30, 2021 
Funding Agency: CHOP PCEN Pilot and Feasibility Program for Clinical Trials in Pediatric Kidney Disease 
 
Background 
Hypertension (HTN) and kidney disease are closely linked disease states, in that uncontrolled blood 
pressure (BP) contributes to acceleration of kidney disease, and as kidney function worsens, BP becomes 
more difficult to control.1,2 Despite the widespread use of antihypertensive medication in children with chronic 
kidney disease (CKD) and end-stage renal disease (ESRD), BP often remains uncontrolled in this particularly 
vulnerable population.3 Cardiovascular (CV) disease is a leading cause of morbidity and mortality among 
patients with ESRD,4 yet robust evidence to guide therapeutic decisions is lacking. Pediatric HTN treatment 
studies have been limited primarily to small, industry-sponsored drug trials and large-scale comparative 
effectiveness trials are not anticipated given sample size limitations.5 National pediatric guidelines recommend 
renin-angiotensin-aldosterone system (RAAS) inhibition as the preferred first-line therapy for hypertensive 
patients with CKD, but it is unknown whether individuals will exhibit heterogeneity of treatment effects to the 
various widely used and commonly available options within this drug class.6 The drug that works best overall in 
a traditional parallel group trial may not be best for the individual patient, depending on a variety of factors that 
can affect treatment response, including etiology of renal disease, concurrent medication use, age, ethnicity, 
obesity status, and genomic factors. To address this problem, we will investigate whether n-of-1 trials to 
personalize treatment decisions result in improved clinical outcomes compared to usual practice. 
N-of-1 trials are single patient randomized controlled trials (RCTs) that systematically compare various 
therapeutic options in the patient in a crossover fashion, applying techniques borrowed from traditional trials to 
minimize confounding and bias.7 The results are used to inform treatment decisions for the individual patient 
and in some circumstances can also be aggregated across participants to produce population-level estimates.8 
Although n-of- trials were first proposed decades ago, their potential value is now being more widely 
recognized.9-11 However it is unclear whether their potential benefits would justify the effort required to use 
them in clinical practice.12 We propose a series of n-of-1 trials in hypertensive children with CKD and ESRD to 
determine if ambulatory BP control is improved after the antihypertensive regimen is modified based on the 
results of an n-of-1 trial. 
With KL-2 funding we previously conducted a series of n-of-1 trials with repeated ambulatory BP 
monitoring (ABPM) in 42 children with primary HTN, and found them to be useful to differentiate drug 
response. In that study, n-of-1 trials were designed to identify which of three commonly used medications 
(amlodipine, hydrochlorothiazide (HCTZ), and lisinopril) when prescribed as monotherapy produced the 
greatest ambulatory BP reduction for the individual patient without unacceptable side effects. This study, HSC- 
MS-13-0287: “Individualizing the treatment of essential hypertension in adolescents using n-of-1 trials”, was 
determined to be a QI activity by the UTH IRB. We recruited patients from our pediatric hypertension clinic 
from June 2013 to July 2016. Among 55 patients meeting inclusion criteria, 42 (76%) agreed to participate in 
an n-of-1 trial with little urging. In this sample (N=42) no single drug emerged as the preferred therapy for the 
majority of patients, with amlodipine selected for 19%, lisinopril 38%, HCTZ 10%.13 The n-of-1 trial resulted in 
drug discontinuation in 17% and BP remained uncontrolled on a single drug in 10%. 
These results prompted our consideration of whether n-of-1 trials should be incorporated into routine 
clinical practice. To test whether n-of-1 trials produce improved clinical outcomes compared to usual care, we 
were awarded the UTHealth Learning Healthcare Scholars award to conduct a single center parallel group 
RCT comparing n-of-1 trials to usual care in our pediatric HTN clinics. We have randomized 49 participants 
since 2018 and enrollment is ongoing. For this study, HSC-MS-17-1014: “N-of-1 Trials in Children with 
Hypertension (NICHE): A Randomized Clinical Trial of the N-of-1 Trial Approach”, verbal informed consent is 
obtained with waiver of documentation of consent. 
Our previous work has been limited to patients without significant comorbidities, whose BP is likely to 
be well-controlled with one or two antihypertensive drugs. We have not yet studied what role n-of-1 trials can 
play in the care of children with CKD, ESRD or after kidney transplanta 
HIRTBNNmUM
anBaEgRe:mHeSnCt-MstSra-2t0e-g1y005 
differs greatly from children with primary HTN. 
IRB APPROVAL DATE: 10/02/2020 

anagement
Specific Aims 
HTN contributes to progression of renal failure and is an important modifiable risk factor for CV 
morbidity/mortality. Little is known about whether any specific medications are more effective than others in 
reducing BP for children with kidney disease, or whether group-level treatment recommendations would be 
appropriate at all. Limited work has been done to characterize national practice variation of pharmacologic 
management of HTN in pediatric CKD/ESRD.14 Given the complex interaction of many factors in the 
pathophysiology of HTN in CKD, including sodium retention, volume expansion, RAAS activation, sympathetic 
nervous system over-activity, and endothelial dysfunction, n-of-1 trials may be the best strategy to 
systematically individualize the HTN management approach in this high risk, yet understudied population. In 
view of the high baseline risk for CV morbidity in children with kidney disease, it is especially important to 
determine whether n-of-1 trials should be used to optimize BP control for these individuals, which could slow 
the decline of kidney function and reduce CV morbidity and mortality. 
The funding requested will allow our team to capitalize on our unique expertise in n-of-1 trials and 
advance the field by assessing their feasibility in children with CKD/ESRD at our center. We propose a series 
of customizable n-of-1 trials to individualize the antihypertensive drug regimen prescribed to pediatric patients 
in our outpatient nephrology clinics and dialysis unit. The experience and data from the proposed pilot study 
will be an indispensable preliminary step towards our next goal: to design and conduct a multi-center RCT 
among children with CKD/ESRD to test whether n-of-1 trial guided decision-making improves BP control 
compared to current usual practice. Central hypothesis: BP control will be improved for the individual patient 
after the antihypertensive drug regimen is modified based on the results of an n-of-1 trial. Rationale: In the 
absence of robust evidence, prescribing decisions are often informed by clinician preferences, anecdotal 
experience, and trial-and-error. Instead, n-of-1 trials can provide patient-derived data to inform management 
decisions and reduce the guesswork inherent in usual practice. Our prior work showed that n-of-1 trials were 
well accepted in children with primary HTN, and led to a change from pre-trial antihypertensive therapy in 75% 
of participants.15 We are currently testing whether the antihypertensive drug regimen that is informed by an n- 
of-1 trial produces improved BP control compared to usual practice in an ongoing RCT among children with 
primary hypertension at our institution. The proposed project will allow us to assess whether n-of-1 trials are 
feasible in the management of HTN associated with kidney disease, and could directly lead to a future funding 
proposal for a larger multicenter RCT assessing generalizability to other centers and whether this approach 
results in improved patient outcomes. Qualifications: This pilot funding proposal builds on the productivity, 
infrastructure, and investment by our team in the design and implementation of n-of-1 trials.15-19 
 
Aim 1: To assess the safety and feasibility of n-of-1 trials in children with CKD/ESRD. After offering an n- 
of-1 trial to all patients at our center who meet eligibility criteria, we will report the % of eligible patients who 
agree to participate, and % that start but do not complete the protocol as planned. We will explore reasons 
cited by patients or clinicians for declining to participate or deviation from n-of-1 protocol. Upon completion, 
perceived harms from participation, including HTN-related complications will be described. 
Hypothesis: N-of-1 trials will be well-accepted in this population and will not be associated with significant 
adverse effects. 
 
Aim 2: Investigate whether the use of n-of-1 trials to modify antihypertensive treatment strategy 
improves BP in children with kidney disease. 24-hour ABPM will be conducted at enrollment and at 6 
months to compare BP (24-hr MAP) before and after the drug regimen is modified based on n-of-1 trial. We will 
also assess the % of participants who achieve target BP (24-hr MAP to <50th %ile) as recommended for this 
population.6 
Hypothesis: When antihypertensive medications are prescribed based on the results of an n-of-1 trial, the 
resulting drug regimen will be more effective in BP reduction for the individual patient, compared to the pre-n- 
of-1 regimen. 
 
Aim 3: Describe treatment strategies in the management of hypertension in children with chronic 
kidney disease at major pediatric centers nationally. The PEDSnet database will be queried to provide a 
description of treatment strategies including frequency of use of particular HTN drugs, number of drugs 
prescribed per patient, and longitudinal description of changes in BP m 
oIRveBrNtiUmMeB. ER: HSC-MS-20-1005 
Hypothesis: Prescribing practices vary greatly by center. 
IRB APPROVAL DATE: 10/02/2020 

ed to patien
will record 
The overarching goal of this proposal, which addresses key knowledge gaps in the management of 
hypertension in pediatric kidney disease and in the design and conduct of n-of-1 trials, is to develop a deeper 
understanding of the feasibility and generalizability of n-of-1 trials to children with kidney disease. If we find that 
BP control is improved when the drug regimen is modified based on an n-of-1 trial, this approach should be 
tested more rigorously in a multicenter RCT. Our next step also may include the development of a decision 
support tool informed by the results of previous n-of-1 trials to provide Bayesian probabilities of treatment 
success with various treatment strategies based on patient characteristics. If shown to improve the 
management of HTN in patients with CKD/ESRD, this could result in improved long-term BP control and 
intermediate CV outcomes, and holds potential to slow the progression of renal disease in children. 
 
Research Approach 
We propose a series of n-of-1 trials in hypertensive children with CKD/ESRD to assess within patient variation 
in BP response, and to ultimately inform the treatment strategy for the individual patient. 
Population/setting: We will recruit from the clinical practices affiliated with the UTH Division of Pediatric 
Nephrology & Hypertension, including outpatient nephrology clinic at UTPhysicians, the nephrology clinic at the 
Pediatric Transplant Center and the chronic dialysis unit at Children’s Memorial Hermann Hospital (CMHH). 
Eligibility: Inclusion criteria: children and adolescents 5-22 yrs old, with hypertension and CKD stage 2-5, and 
requiring antihypertensive medication per clinician judgement. BP control at enrollment (whether well- 
controlled or uncontrolled on current regimen) will not affect eligibility status. Exclusion criteria: renal 
transplant anticipated or occurred within 6 months of screening, transfer out of our practice setting anticipated 
within 6 months, unable to complete 24 hr ABPM due to developmental or behavioral limitations. 
Screening: Electronic health record data will be pre-screened with a one-time structured data query by the 
UTH School of Biomedical Informatics to identify patients within 5-22 yo, with relevant ICD10-CM codes (HTN: 
I10-I16, CKD: N18*, dialysis-dependent: Z99.2, or kidney transplant status: Z94), and seen by a pediatric 
nephrologist within 12 months. These records will be reviewed to exclude those who do not meet eligibility 
criteria. The remaining patients will be considered eligible and will be entered into a REDCap database. 
Recruitment: For clinic CKD patients, recruitment will take place during a routine nephrology clinic visit. 
Clinicians will be emailed once weekly with a list of all eligible patients scheduled to be seen that week. For 
dialysis-dependent ESRD patients, recruitment will take place during a routine dialysis visit in September 2020. 
A brief recruitment video (online) will be viewed by patient and caretaker from clinic room computer and 
followed by face to face discussion with nephrologist (all of whom are co-investigators). The video will 
introduce the concept of therapeutic uncertainty and will delineate the n-of-1 trial protocol and the procedures 
for the baseline and 6 month assessments. 
Consent: Patient verbal assent and caretaker verbal consent will be obtained before enrollment. This consent 
procedure was previously approved by the UTH IRB committee for a similar protocol in children without CKD. 
N-of-1 trial protocol: 
The n-of-1 trial will be customized for the individual patient to test which treatment strategy produces superior 
BP reduction without unacceptable side effects. After discussion with the patient/caregiver to identify whether 
they have specific concerns about particular medications, the nephrologist will decide which two drugs and 
dosages will be tested in the n-of-1 trial. Drugs from the α-blocker and β-blocker drug classes will not be 
eligible for testing due to the risk of withdrawal syndrome associated with abrupt cessation. These and all other 
previously prescribed antihypertensive drugs not being tested will be continued at unchanged doses during the 
n-of-1 trial. 
The two drugs will be assessed at clinician-selected dosing in a randomized treatment order (ex ABAB), for 
two weeks per treatment period and two treatment periods per drug with increasing doses assessed for 
additional treatment periods if BP remains elevated with initial dosing of both regimeIRnBs.NTUreMaBtmERe:nHt SreCs-MpoSn-2s0e-1005 
for each regimen will be measured with a side effect survey administer 
t/IcRaBreAgPivPeRrOaVnAdL2D4AhToEu: r10/02/2020 
ABPM (Spacelabs) on day 14 of each 2-week treatment period. ABPM 
readings every 20 min for 

IRB APPROVAL DATE: 10/02/2020 
 
24 hours. For patients unwilling or unable to undergo repeated ABPM, home BP monitoring (Qardioarm) will be 
used, (mean of 3 readings, 1 minute apart) twice daily on days 13 and 14 of each 2-week treatment period. 
Blinding can be employed in n-of-1 trials to minimize biased assessments of treatment effects. In our past 
studies, we have not made any attempt to mask patients/caregivers to the current treatment. In the present 
study, we will offer blinding to each patient/caregiver to assess the acceptability of blinding. If the family 
declines blinding, then the reasons will be recorded. If they agree to be blinded, patients will be advised to fill 
both prescriptions at the start of the trial. Medication will be dispensed by the patient’s usual retail pharmacy 
with costs covered through usual insurance coverage. Caregivers who opt in to blinding will provide the 
research team with the dispensed medications, who will sort out the pills into a 31 day pill organizer according 
to the randomized treatment order and refill as needed once monthly. While a patient could theoretically 
decipher their treatment based on pill appearance, those who opt in to blinding are less likely to attempt to 
unblind themselves. Additionally, costly pharmacy fees would make other blinding approaches less feasible 
within the funding limitations of the current pilot award. 
At the conclusion of all treatment periods, the clinician will review the BP and side effect survey findings with 
the family via either an in person or telemedicine visit. When the patient, caregiver, and clinician jointly 
conclude that there is a sufficiently high probability that the preferred treatment has been identified (defined as 
that which produces superior BP reduction without unacceptable side effects), it will be prescribed for long- 
term use along with all other previously prescribed antihypertensive medications, and the n-of-1 trial will 
conclude. 
Aim 1: Assess the safety and feasibility of n-of-1 trials in children with CKD/ESRD. 
Hypothesis: N-of-1 trials will be well-accepted and will not be associated with any significant adverse effects. 
Acceptance rate will be tracked for all eligible patients who were offered enrollment. The nephrologist may 
decline without discussing first with the patient, and the patient/caretaker may decline after discussing 
participation with the nephrologist. Reasons for declining (by both clinician and patient/caregiver) will be 
collected in free text format in REDCap. Upon review of reasons for declining, emergent themes will be 
reported. 
Completion rate will be tracked for all enrolled patients. Participants may withdraw at any time. At 6 months, all 
enrolled participants will be categorized according to their level of adherence to the n-of-1 trial protocol. 
Reasons for variance from the protocol will be recorded. We will explore whether any patient or clinical 
characteristics are associated with increased likelihood of deviation from the protocol. 
Safety of participants will be carefully monitored. Clinicians will be encouraged to continue their usual practice 
of checking bloodwork within 1-2 weeks of starting certain medications (RAAS inhibitors, diuretics) to assess 
for clinically important changes in electrolytes or serum creatinine, which will be recorded along with adverse 
events or side effects which lead to early termination of a treatment period. At 6 months, the clinician will 
complete a safety form to report any additional harms which might have been linked to participation. 
Data on acceptance, completion, and harms is critical in understanding the feasibility of this approach in this 
population, and will be of broad interest in the field of n-of-1 trials. This information will help us in future studies 
to adapt our approach and protocol to better meet patient and clinician preferences. 
Aim 2: Investigate whether the use of n-of-1 trials to modify antihypertensive treatment strategy 
improves BP in children with kidney disease 
Hypothesis: When antihypertensive medications are prescribed based on the results of an n-of-1 trial, the 
resulting treatment strategy will be more effective in BP reduction for the individual patient when compared to 
the BP with the pre-n-of-1 drug regimen. 
Outcome measurement: 24-hr average of mean arterial pressure (MAP) on ABPM will be assessed before and 
after treatment strategy is informed by the n-of-1 trial. 
IRB NUMBER: HSC-MS-20-1005 

ithin site. 
Potential
• 
Baseline BP assessment: Shortly after enrollment, 24 hr ABPM will be performed to assess BP control 
on current (pre-n-of-1) antihypertensive treatment strategy. 
• 
Final BP assessment: At 6 months after enrollment, regardless of when n-of-1 trial was completed, 24 
hr ABPM will be performed to assess BP control on current treatment strategy (post- n-of-1). 
1o outcome: Change in 24-hr MAP (from baseline to final) 
2o outcome: Proportion of participants with target BP (24-hr MAP to <50th %ile)6 (from baseline to final) 
Sample size: We plan to enroll as many patients as feasible during the funding period. Based on our estimates 
of number of potentially eligible patients and our previous acceptance rate, we anticipate enrolling 20 patients. 
Analytic approach: The primary outcome of 24-hr MAP will be analyzed by generalized linear mixed model 
(GLMM) accounting for repeated ABPMs over the study period including the pre-n-of-1 ABPM assessment. 
The mixed model will contain a random intercept for each patient and appropriate link function based on the 
distribution of the 24-hr mean MAP. From this model, we will report the average difference between 24-hr MAP 
at 6 months and baseline ABPM. Success for the n-of-1 trial will be defined as any decrease in mean 24-hr 
MAP at 6 months compared to pre-n-of-1 ABPM. Bayesian models with uninformative, neutral priors for 
regression coefficients and error variances will be used to determine the probability of decrease in 24-hr MAP 
after the n-of-1 trial. All analyses will be conducted on an intention-to-treat basis with the GLMM allowing 
inclusion of patients with missing BP measurements at some time points. Secondary binary outcome of 24-hr 
MAP to <50th %ile will be similarly analyzed over the study period to determine if the proportion of patients with 
24-hr MAP to <50th %ile is greater after the n-of-1 trial. If the sample size allows, exploratory analysis will 
examine strata specific effects for sex, age group, race, BMI, CKD stage, medication class, and number of 
anti-hypertensive medications. 
Aim 3: Describe treatment strategies in the management of hypertension in children with chronic 
kidney disease at major pediatric centers nationally (retrospective cohort study of de-identified 
multicenter dataset that does not include patients from our institution). 
Our current and previous n-of-1 trial protocols were designed based on our local prescribing preferences in 
HTN management. As we prepare to design a future multicenter RCT, it will be essential to better understand 
national prescribing patterns to inform the design of n-of-1 trial protocols that are generalizable and broadly 
appealing to pediatric nephrologists at other centers. Previous large studies describing antihypertensive 
medication prescribing patterns in childhood kidney disease have been limited to cross-sectional design,14 but 
the proposed observational study would allow longitudinal descriptions of treatment patterns within an 
individual over time. 
Working with a data science team at CHOP, we will explore PEDSnet data to characterize BP phenotype in 
children with CKD/ESRD and describe common treatment strategies. Our search will be restricted to patients 
<18 years old who have been seen by a nephrologist, diagnosed with CKD or with an estimated GFR <90 
ml/min per 1.73 m2 on 2 occurrences separated by 90 days. 
In addition to demographic factors (age, gender, race/ethnicity), we will describe other clinical factors (obesity, 
etiology and staging of CKD) and blood pressure phenotype, including modality of BP measurement, degree of 
elevation, frequency of repeated readings in a single visit, and number of visits until HTN is diagnosed. 
We will describe what % of patients with CKD are diagnosed with HTN, and what % are prescribed 
antihypertensive medications. We will describe frequency of use of particular HTN drugs and drug classes, 
number of HTN drugs prescribed per patient, and longitudinal description of changes in management over time 
(ex. typical first/second line choices, and interval between dose and drug changes). 
Analytic approach: To describe longitudinal hypertensive treatment patterns in children with CKD across 
multiple pediatric centers we will use generalized multilevel mixed models with appropriate link functions and 
two-level random effects for correlated observations within patient and w 
TIhReBaNnUaMlyBsiEsRw: HillSbCe-MtaSi-lo20re-1d005 
to the available data once the PEDSnet variable set has been identified. 
pIrRimBaAryPPoRuOtcVoAmLeDsAinTcEl:u1d0e/02/2020 

IRB NUMBER: HSC-MS-20-1005 
IRB APPROVAL DATE: 10/02/2020 
 
antihypertensive medication as binary (yes/no) or count (number of medications) stratified by medication class 
if available. Treatment patterns for these primary outcomes will be examined over time and across strata (BP 
level, severity of hypertension, CKD etiology, gender, age) as available. 

IRB NUMBER: HSC-MS-20-1005 
IRB APPROVAL DATE: 10/02/2020 
 
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