An Efficacy and Safety Study in Children 6 to Less Than 18 Years of Age With Hypertension

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy and safety of the study drug relative to an active comparator losartan which is in the same class of drug and is approved for use in the pediatric population aged 6 years and older. Approximately 260 subjects will participate in a 6-week, double-blind, randomized, treatment phase, followed by a 2-week, double-blind, randomized, placebo-controlled withdrawal phase. A 44-week, open-label extension in which all subjects will receive azilsartan and other antihypertensive medications (if needed). Blood pressure will be assessed throughout the study.

Detailed Description
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The purpose of the study is to evaluate the efficacy and safety of the study drug relative to an active comparator losartan which the same class of drug and is approved for use in the pediatric population aged 6 years and older. Approximately 260 subjects will participate in a 6-week, double-blind, randomized, treatment phase, followed by a 2-week, double-blind, randomized, placebo-controlled withdrawal phase. This study also includes a 44-week, open-label extension Phase in which all subjects will receive azilsartan and other antihypertensive medications (if needed) in order to reach an optimal blood pressure. Blood pressure will be assessed in the clinic throughout the study, and subjects may also participate in a 24-hour ambulatory blood pressure monitoring procedure at baseline, at the end of the double-blind Phase and at the end of the open-label Phase.

Official Title
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A Randomized, Double-Blind, Efficacy and Safety Study of AR 14 (AZILSARTAN MEDOXOMIL) Treatment and Withdrawal, Followed by an Open-Label Extension, in Children 6 to Less Than 18 Years of Age With Hypertension

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Azilsartan Medoxomil Low-dose
* Drug: Losartan
* Drug: Placebo for Azilsartan Medoxomil
* Drug: Placebo for Losartan
* Drug: antihypertension medication - Add-on Therapy
* Drug: Azilsartan Medoxomil Medium-dose
* Drug: Azilsartan Medoxomil High-dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has hypertension (primary or secondary) defined as clinic Seated Diastolic BP ≥95th percentile (by age, gender, and height) or ≥90th percentile (by age, gender, height) if chronic renal disease, diabetes, heart failure or hypertensive target organ damage is present If currently treated: The subject has a documented historical diagnosis of hypertension AND a post-washout clinic Seated Diastolic BP meeting the above criteria on Day -1 (or Day 1 for subjects not participating in Ambulatory Blood Pressure Monitoring) If currently untreated: The subject has elevated Seated Diastolic BP meeting the above criteria on 3 separate occasions before Randomization, including on Day -1 (or Day 1 for subjects not participating in Ambulatory Blood Pressure Monitoring) The subject is male or female and aged 6 to <18 years at Baseline and weighs at least 25 kg The subject agrees to continue their previously implemented nonpharmacological life style modifications if begun prior to Screening. Note: For subjects participating in a weight loss program, the weight maintenance Exclusion Criteria: The subject has a clinic Seated Diastolic BP greater than 15 mm Hg and/or Seated Diastolic BP greater than 10 mm Hg above the 99th percentile for age, gender, and height as confirmed by the average (arithmetic mean) of 3 serial clinic seated BP measurements at Screening/Visit 1 The subject has a diagnosis of malignant or accelerated hypertension The subject is currently treated with more than 2 antihypertensive agents The subject or parent/legal guardian is not willing for the subject's previous antihypertensive medications to be stopped The subject has participated in the intensive, active weight-loss phase of a weight-loss program within 30 days prior to Screening/Visit 1 The subject has any of the following: severe renal impairment (eGFR <30 mL/min/1.73 m2 by the Schwartz formula); is currently undergoing dialysis treatment; renovascular disease affecting both kidneys or a solitary kidney; severe nephrotic syndrome not in remission; or serum albumin <2.5 g/dL The subject has a history or clinical manifestations of severe cardiovascular, hepato-biliary, gastrointestinal, endocrine-metabolic (e.g., hyperthyroidism, Cushing's syndrome), hematologic, immunologic, genito-urinary, or psychiatric disease, cancer, and/or any conditions that would interfere with the health status of the subject through study participation, or would jeopardize study integrity in the opinion of the investigator The subject is suffering from uncorrected coarctation of the aorta, or hemodynamically significant left ventricular outflow tract obstruction due to eg, aortic valvular disease, or is likely to undergo a procedure known to affect blood pressure (eg, repair of arterial anomalies) during the course of the study The subject is poorly controlled diabetic defined as having a glycosylated hemoglobin value >8.5% at Screening/Visit 1 The subject has hyperkalemia as defined by the central laboratory's normal reference range or any pertinent electrolyte disorders at Screening/Visit

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 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
Interventional Model Description: There are 3 phases in this study. Double-blind, withdrawal phase, and open-label phase.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-blind: Azilsartan Medoxomil - Low dose<br>6-week, double-blind (DB), randomized, treatment phase (DB Phase): Azilsartan medoxomil Low-dose (AZM-L), 10 mg once daily. | Drug: Azilsartan Medoxomil Low-dose<br> <br> * Other names: AZM-L;|
| Active Comparator: Double blind phase: Losartan<br>6-week, double-blind (DB), randomized, treatment phase (DB Phase): Starting at Losartan 25/50 and force titrated to 50/100 mg daily at Week 2. | Drug: Losartan<br> <br> * Other names: Cozaar;|
| Active Comparator: WITHDRAWAL Phase: Azilsartan medoxomil LOW-dose<br>Experimental Arm in the Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment ( Azilsartan medoxomil low dose) that was taken in Double blind OR to be switched to placebo. | Drug: Azilsartan Medoxomil Low-dose<br> <br> * Other names: AZM-L;|
| Placebo Comparator: WITHDRAWAL Phase: PLACEBO to match azilsartan medoxomil LOW DOSE<br>PLACEBO Arm in the Withdrawal Phase for subjects who were on Azilsartan medoxomil LOW dose) in Double blind then randomized (1:1) to placebo for withdrawal phase | Drug: Losartan<br> <br> * Other names: Cozaar;|
| Experimental: Open Label Phase: Azilsartan Medoxomil<br>Azilsartan Medoxomil 10 mg which can be titrated to higher dose(s) (up to 40 mg for subjects <50 kg or up to 80 mg for subjects ≥50 kg) | Drug: Azilsartan Medoxomil Low-dose<br> <br> * Other names: AZM-L;|
| Other: Open Label Phase: Other<br>If add-on therapy is needed, a calcium channel blocker, such as amlodipine; a diuretic, such as hydrochlorothiazide; or a beta-blocker such as metoprolol will be determined per the investigator's clinical judgment. | Drug: Azilsartan Medoxomil Low-dose<br> <br> * Other names: AZM-L;Drug: antihypertension medication - Add-on Therapy<br>* add-on therapy (e.g., a calcium channel blocker, such as amlodipine, a diuretic, such as hydrochlorothiazide, or a beta-blocker such as metoprolol) per PI's clinical judgment.<br>|
| Active Comparator: Withdrawal Phase: Losartan 50 mg<br>Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment or to be switched to placebo. | Drug: Losartan<br> <br> * Other names: Cozaar;|
| Placebo Comparator: Withdrawal Phase: PLACEBO to Losartan<br>Placebo Arm In the Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment or to be switched to placebo. | Drug: Placebo for Losartan<br> <br> * Other names: sugar pill;|
| Experimental: Double-blind: Azilsartan Medoxomil - Medium dose<br>6-week, double-blind (DB), randomized, treatment phase (DB Phase), Azilsartan medoxomil Medium-dose (AZM-M), 20 mg once daily at Week 2. | Drug: Azilsartan Medoxomil Low-dose<br> <br> * Other names: AZM-L;Drug: Azilsartan Medoxomil Medium-dose<br> <br> * Other names: AZM-M;|
| Experimental: Double-blind: Azilsartan Medoxomil - High dose<br>6-week, double-blind (DB), randomized, treatment phase (DB Phase): Azilsartan medoxomil High-dose (AZM-H), 40 mg AZM-M | Drug: Azilsartan Medoxomil Low-dose<br> <br> * Other names: AZM-L;Drug: Azilsartan Medoxomil High-dose<br> <br> * Other names: AZM-H;|
| Experimental: WITHDRAWAL Azilsartan Medoxomil - Medium dose<br>Experimental Arm in the Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment ( Azilsartan medoxomil MEDIUM dose) that was taken in Double blind OR to be switched to placebo. | Drug: Azilsartan Medoxomil Medium-dose<br> <br> * Other names: AZM-M;|
| Experimental: WITHDRAWAL Azilsartan Medoxomil - High dose<br>Experimental Arm in the Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment ( Azilsartan medoxomil HIGH dose) that was taken in Double blind OR to be switched to placebo. | Drug: Azilsartan Medoxomil High-dose<br> <br> * Other names: AZM-H;|
| Experimental: WITHDRAWAL Phase: PLACEBO to match azilsartan medoxomil MEDIUM DOSE<br>PLACEBO Arm in the Withdrawal Phase for subjects who were on Azilsartan medoxomil MEDIUM dose) in Double blind then randomized (1:1) to matching placebofor withdrawal phase | Drug: Placebo for Azilsartan Medoxomil<br> <br> * Other names: sugar pill;|
| Experimental: WITHDRAWAL Phase: PLACEBO to match azilsartan medoxomil HIGH DOSE<br>PLACEBO Arm in the Withdrawal Phase for subjects who were on Azilsartan medoxomil HIGH dose) in Double blind then randomized (1:1) to matching placebofor withdrawal phase | Drug: Placebo for Azilsartan Medoxomil<br> <br> * Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Blood Pressure | Change from Week 6/Final Visit of the double-blindPhase to Week 8/Final Visit of the WD Phase in trough clinic seated diastolic blood pressure between azilsartan medoxomil and placebo | Double-Blind and Withdrawal Phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood Pressure relative to the comparator | Change from Week 6/Final Visit of the double-blind Phase to Week 8/Final Visit of the withdrawal phase in trough clinic seated systolic blood pressure and mean arterial pressure (MAP) between azilsartan medoxomil and placebo. | Double Blind and Withdrawal Phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric Hypertension, High Blood Pressure, Hypertension, Pediatric, Primary Hypertension, Secondary Hypertension