Hypertension (HTN) is an important modifiable risk factor for kidney disease progression in children, and cardiovascular (CV) disease remains a leading cause of death among those with end-stage renal disease (ESRD). Despite widespread use of antihypertensive drugs, blood pressure (BP) often remains uncontrolled in this particularly vulnerable population. Pediatric HTN trials have been limited primarily to small, industry-sponsored, placebo-controlled drug trials, and large-scale comparative effectiveness trials are not anticipated given sample size limitations in pediatric CKD. While renin-angiotensin-aldosterone system (RAAS) blockade is recommended as first line HTN therapy in CKD, the specific choice of drug from multiple available options within this category is neither standardized nor supported by evidence.
It is likely that individual patients may exhibit an unpredictable heterogeneity of treatment effects, with better BP reduction with one drug over other choices. N-of-1 trials are single-patient cross-over randomized clinical trials that can be used in certain circumstances to meet a goal not possible in traditional randomized clinical trials (RCTs): to optimize the treatment of the individual patient. We conducted a series of n-of-1 trials with repeated ABPM in 42 children with primary HTN, and showed them to be useful to differentiate drug response. Since 2018 we have enrolled 49 hypertensive children in an ongoing single center parallel group RCT comparing n-of-1 trials to usual care.
Pending pilot data, we will conduct a multi-center RCT to verify whether n-of-1 trials are generalizable outside our center and assess if n-of-1 trial-guided decision-making improves CV outcomes in children with CKD. Aim 1: Assess whether the use of n-of-1 trials is safe and feasible in pediatric patients with CKD and ESRD. Describe the% of eligible patients who agree to participate, and% that start but do not complete the protocol as planned (and reasons cited). Describe any harms from participation, including HTN-related complications. Aim 2: Assess whether the use of n-of-1 trials to modify antihypertensive drug regimen improves blood pressure (BP)control. Primary outcome: change in 24-hr MAP from baseline (prior to n-of-1 trial) to 6 months after starting n-of-1 trial. We will also assess the % of participants who achieve target BP (24-hr MAP to <50th%ile) as recommended by the 2017 AAP Clinical Practice Guidelines for treatment of HTN with CKD. Aim 3: Observational study to describe current national prescribing practices of HTN drugs in CKD patients in major pediatric centers. The CHOP/PCEN LHS Core EHR database will be queried to describe frequency of use of particular HTN drugs, and describe demographic and clinical factors associated with drug choice.
Central hypothesis: Using n-of-1 trials to select antihypertensive drug regimen will improve BP control compared to baseline. Rationale: Given the complex interaction of many environmental or genomic factors, n-of-1 trials may be the best strategy to individualize treatment for chronic disorders like HTN. It is important to determine whether, when, and how n-of-1 trials can be used optimize BP control of individual children with CKD. Research Approach: We propose a series of n-of-1 trials in hypertensive children with CKD and ESRD to assess within patient variation in BP response, and to ultimately inform which RAAS drug is preferred for the individual. Clinicians will select one ACE-inhibitor and one ARB for testing in each patient. The two drugs will be assessed at clinician-selected dosing in a randomized treatment order for two weeks per regimen (ex ABAB), with increasing doses assessed if BP remains elevated. Additional treatment cycles may be needed to add an adjunctive drug (hydrochlorothiazide or amlodipine, per clinician choice) if BP remains uncontrolled on maximum RAAS drug dose.
Treatment response for each regimen will be measured with side effect survey and 24 hour ABPM during the final 24 hours of each 2-week treatment period. When the patient, caregivers, and clinician jointly conclude that there is a sufficiently high probability that the preferred treatment has been identified, it will be prescribed for long-term use, and the n-of-1 trial will be considered complete. A final ABPM will be performed at 6 months after enrollment to assess the primary outcome. Implications: This project will provide a better understanding of the feasibility and generalizability of n-of-1 trials, which could contribute to improved BP control, slowed progression of kidney disease, and reduced CV morbidity and mortality.