N-of-1 Trials In Children With Hypertension

Study Overview
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Brief Summary
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The single patient (n-of-1) randomized trial is an underused approach to resolving therapeutic uncertainty by using a patient's own data to inform an individualized treatment plan. The proposed research is designed to assess whether the n-of-1 trial approach improves blood pressure control compared to usual care. This trial aims to advance learning about not only the treatment of pediatric hypertension but also the use of a neglected type of randomized trial to optimize the care of each patient.

Detailed Description
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Pediatric hypertension, a growing problem, often requires prescription of antihypertensive medication. Pediatric hypertension specialists lack an evidentiary base on which to establish definitive clinical practice guidelines for first-line therapy. Significant practice variation is an unsurprising consequence. Routine choice of the same first-line therapy for most patients with hypertension, absent testing other options, may delay correction of blood pressure for months or years. Failure to incorporate patient preferences in medical decision-making may also contribute to decreased patient satisfaction and adherence. Large parallel-group, comparative effectiveness trials are likely not on the horizon for this population. Moreover, heterogeneity of treatment effects would minimize the generalizability of such a trial to all patients. This is a parallel-group, randomized clinical trial to compare the n-of-1 trial approach to usual care in normalizing blood pressure while minimizing exposure to compliance-reducing side effects.

Official Title
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A Randomized Clinical Trial of the N-of-1 Approach in Children With Hypertension

Conditions
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Pediatric Hypertension

Intervention / Treatment
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* Other: NICHE method
* Other: Usual care
* Drug: Amlodipine
* Drug: Lisinopril
* Drug: Hydrochlorothiazide
* Drug: Losartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: treating physician determines that pharmacologic therapy is indicated for treatment of hypertension ambulatory hypertension has been confirmed (off meds) within 12 months of enrollment Exclusion Criteria: age < 10 years resistant hypertension (requiring ≥ 3 drug therapy) absolute contraindication or allergy to any of the tested drugs.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NICHE method<br>In the NICHE method, antihypertensive therapy will be chosen using an n-of-1 trial to identify the preferred therapy. Preferred therapy is defined a priori as that which produces the greatest reduction in ambulatory BP without intolerable side effects. Tested drugs will include amlodipine or losartan, lisinopril, and hydrochlorothiazide. | Other: NICHE method<br>* Based on underlying comorbidities at enrollment, patients will be assigned to either an unrestricted protocol (amlodipine versus lisinopril) or a restricted protocol (losartan versus lisinopril). Two drugs are tested in randomized order. Failure to achieve BP control at maximum doses of the first two drugs will result in augmentation with a diuretic (hydrochlorothiazide). BP control is assessed with 24 hour ambulatory monitoring at the end of each 2 week treatment period. Side effect tolerability is assessed with a questionnaire.<br>Drug: Amlodipine<br>* Calcium-channel blocker; antihypertensive<br>Drug: Lisinopril<br>* Angiotensin-converting-enzyme (ACE) inhibitor; antihypertensive<br>Drug: Hydrochlorothiazide<br>* Thiazide diuretic; antihypertensive<br>Drug: Losartan<br>* Angiotensin II receptor blocker (ARB); antihypertensive<br>|
| Active Comparator: Usual Care<br>No protocol will be introduced to standardize BP management in the control arm. | Other: Usual care<br>* Physician preference will dictate choice and adjustment of antihypertensive medication, BP measurement modality, interval between visits, and assessment of side effects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Ambulatory Blood Pressure (BP) Control at 6 Months | Blood pressure control is when ambulatory blood pressure is normal, with normal as defined by the American Heart Association (AHA) criteria [the AHA criteria are systolic blood pressure and diastolic blood pressure (throughout wake and sleep) less than the 95th percentile based on the patient's gender and height]. To assess ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24-hour period. | 6 months from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean 24-hour Ambulatory Systolic Blood Pressure | To assess 24-hour mean ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24-hour period, while awake and while asleep. The mean of all recordings over the 24-hour period is calculated per participant for both baseline and 6 months, and then the mean 24-hour systolic blood pressure at 6 months minus the mean 24-hour systolic blood pressure at baseline is calculated per participant. The average difference is reported, with a negative value indicating a reduction in blood pressure over time. | baseline, 6 months | 
| Change in Mean Wake Ambulatory Systolic Blood Pressure | To assess mean wake ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24 hour period, throughout wake and sleep. The mean of all recordings that occur while the participant is awake during the 24-hour period is calculated for both baseline and 6 months, and then the mean wake systolic blood pressure at 6 months minus the mean wake systolic blood pressure at baseline is calculated per participant. The average difference is reported, with a negative value indicating a reduction in blood pressure over time. | baseline, 6 months | 
| Number of Participants Who Reported That Side Effects From Medication Led Them to Discontinue Medication |  | from baseline to 6 months | 
| Number of Participants Who Self-reported Adherence to Intervention | Adherence is reported as the number of participants who self-reported at the 6-month visit that they had not missed any doses of their medication in the preceding month. | from month 5 to month 6 | 
| Patient Satisfaction With Intervention as Assessed by a Survey | Patient satisfaction is scored from 0 to 10, where 0 is the worst health care possible and 10 is the best health care possible. | 6 months |