Series of N-of-1 Crossover Trials of Antihypertensive Therapy in Adolescents With Essential Hypertension

Study Overview
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Brief Summary
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Children are increasingly being diagnosed with essential hypertension and the absence of comparative effectiveness research in antihypertensive therapies has contributed to considerable differences in prescribing practices among physicians treating children with essential hypertension. This study will consist of a series of systematically-administered n-of-1 trials among children to verify the need for ongoing antihypertensive treatment and if so, to identify the preferred single drug therapy.

Detailed Description
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This is a series of systematically-administered n-of-1 trials among children with essential hypertension to verify the need for ongoing antihypertensive treatment and if so, to identify the preferred single drug therapy from among the three major classes of drugs commonly used for essential hypertension (angiotensin converting enzyme inhibitors, calcium channel blockers, and diuretics). The investigators will determine whether there is one that is preferred for the great majority of patients. The preferred therapy will be defined as the drug which produces normal ambulatory blood pressure, with the greatest reduction in awake mean systolic blood pressure without unacceptable side effects. For each patient, the order of the 3 drugs will be assigned randomly and each drug will be taken for 2 weeks. The effectiveness of each drug will be measured with 24-hour ambulatory blood pressure monitoring, and tolerability will be assessed using a side effect questionnaire. Participants will rotate through treatment periods, repeating drugs and adjusting doses until the preferred therapy is identified. In assessing whether one the medications is most effective for the great majority of subjects, the primary outcome will be the percentage of participants for whom each drug is selected as the preferred therapy. Primary hypothesis: no drug will be selected for the majority of the subjects, a finding that would support consideration of clinical use of n-of-1 trials. Secondary analyses will explore whether patient characteristics predict which medication will be selected as a preferred drug.

Official Title
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Series of N-of-1 Crossover Trials of Antihypertensive Therapy in Adolescents With Essential Hypertension

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: Lisinopril
* Drug: Amlodipine
* Drug: Hydrochlorothiazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of essential hypertension Treating physician has determined that pharmacologic therapy is necessary Exclusion Criteria: Compelling indication to select one particular medication Specific contraindication for any of the 3 therapies

Ages Eligible for Study
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Minimum Age: 9 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: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Amlodipine, then HCTZ, then Lisinopril<br>Participants first received amlodipine once daily for 2 weeks, then crossed over to hydrochlorothiazide (HCTZ) once daily for 2 weeks, then lisinopril once daily for 2 weeks. Subsequent treatments varied depending on individual patient response. | Drug: Lisinopril<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 10 mg/dose). Maximum final dose: 40 mg/dose or 0.6 mg/kg/dose.<br>* Other names: Angiotensin-converting enzyme inhibitor;Drug: Amlodipine<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 5 mg/dose). Maximum final dose: 10 mg/dose<br>* Other names: Dihydropyridine calcium channel blocker;Drug: Hydrochlorothiazide<br>* Initial dose: 1 mg/kg/dose orally, once daily (maximum initial dose 25 mg/dose). Maximum final dose: 50 mg/dose or 3 mg/kg/dose<br>* Other names: Thiazide diuretic;|
| Active Comparator: Amlodipine, then Lisinopril, then HCTZ<br>Participants first received amlodipine once daily for 2 weeks, then crossed over to lisinopril once daily for 2 weeks, then hydrochlorothiazide (HCTZ) once daily for 2 weeks. Subsequent treatments varied depending on individual patient response. | Drug: Lisinopril<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 10 mg/dose). Maximum final dose: 40 mg/dose or 0.6 mg/kg/dose.<br>* Other names: Angiotensin-converting enzyme inhibitor;Drug: Amlodipine<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 5 mg/dose). Maximum final dose: 10 mg/dose<br>* Other names: Dihydropyridine calcium channel blocker;Drug: Hydrochlorothiazide<br>* Initial dose: 1 mg/kg/dose orally, once daily (maximum initial dose 25 mg/dose). Maximum final dose: 50 mg/dose or 3 mg/kg/dose<br>* Other names: Thiazide diuretic;|
| Active Comparator: HCTZ, then Amlodipine, then Lisinopril<br>Participants first received hydrochlorothiazide (HCTZ) once daily for 2 weeks, then crossed over to amlodipine once daily for 2 weeks, then lisinopril once daily for 2 weeks. Subsequent treatments varied depending on individual patient response. | Drug: Lisinopril<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 10 mg/dose). Maximum final dose: 40 mg/dose or 0.6 mg/kg/dose.<br>* Other names: Angiotensin-converting enzyme inhibitor;Drug: Amlodipine<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 5 mg/dose). Maximum final dose: 10 mg/dose<br>* Other names: Dihydropyridine calcium channel blocker;Drug: Hydrochlorothiazide<br>* Initial dose: 1 mg/kg/dose orally, once daily (maximum initial dose 25 mg/dose). Maximum final dose: 50 mg/dose or 3 mg/kg/dose<br>* Other names: Thiazide diuretic;|
| Active Comparator: HCTZ, then Lisinopril, then Amlodipine<br>Participants first received hydrochlorothiazide (HCTZ) once daily for 2 weeks, then crossed over to lisinopril once daily for 2 weeks, then amlodipine once daily for 2 weeks. Subsequent treatments varied depending on individual patient response. | Drug: Lisinopril<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 10 mg/dose). Maximum final dose: 40 mg/dose or 0.6 mg/kg/dose.<br>* Other names: Angiotensin-converting enzyme inhibitor;Drug: Amlodipine<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 5 mg/dose). Maximum final dose: 10 mg/dose<br>* Other names: Dihydropyridine calcium channel blocker;Drug: Hydrochlorothiazide<br>* Initial dose: 1 mg/kg/dose orally, once daily (maximum initial dose 25 mg/dose). Maximum final dose: 50 mg/dose or 3 mg/kg/dose<br>* Other names: Thiazide diuretic;|
| Active Comparator: Lisinopril, then Amlodipine, then HCTZ<br>Participants first received lisinopril once daily for 2 weeks, then crossed over to amlodipine once daily for 2 weeks, then hydrochlorothiazide (HCTZ) once daily for 2 weeks. Subsequent treatments varied depending on individual patient response. | Drug: Lisinopril<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 10 mg/dose). Maximum final dose: 40 mg/dose or 0.6 mg/kg/dose.<br>* Other names: Angiotensin-converting enzyme inhibitor;Drug: Amlodipine<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 5 mg/dose). Maximum final dose: 10 mg/dose<br>* Other names: Dihydropyridine calcium channel blocker;Drug: Hydrochlorothiazide<br>* Initial dose: 1 mg/kg/dose orally, once daily (maximum initial dose 25 mg/dose). Maximum final dose: 50 mg/dose or 3 mg/kg/dose<br>* Other names: Thiazide diuretic;|
| Active Comparator: Lisinopril, then HCTZ, then Amlodipine<br>Participants first received lisinopril once daily for 2 weeks, then crossed over to hydrochlorothiazide (HCTZ) once daily for 2 weeks, then amlodipine once daily for 2 weeks. Subsequent treatments varied depending on individual patient response. | Drug: Lisinopril<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 10 mg/dose). Maximum final dose: 40 mg/dose or 0.6 mg/kg/dose.<br>* Other names: Angiotensin-converting enzyme inhibitor;Drug: Amlodipine<br>* Initial dose: 0.1 mg/kg/dose orally, once daily (maximum initial dose 5 mg/dose). Maximum final dose: 10 mg/dose<br>* Other names: Dihydropyridine calcium channel blocker;Drug: Hydrochlorothiazide<br>* Initial dose: 1 mg/kg/dose orally, once daily (maximum initial dose 25 mg/dose). Maximum final dose: 50 mg/dose or 3 mg/kg/dose<br>* Other names: Thiazide diuretic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients for Whom Each Drug is Selected as the Preferred Therapy | For each n-of-1 trial, the preferred drug is defined as that which produces normal ambulatory blood pressure (by pediatric Ambulatory blood pressure monitoring (ABPM) standards), with the greatest magnitude of wake mean systolic BP reduction, and without unacceptable side effects. | The outcome of BP control and side effect tolerability will be assessed 2 weeks after starting each drug. Participants will be followed for an average of 10-12 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-hypertensive medications, Pediatrics, N-of-1 trial