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

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.

• Azilsartan Medoxomil Low-dose (Drug), also known as AR14, AZM-L: Azilsartan medoxomil low-dose (AZM-L) 10 mg
• Losartan (Drug), also known as Cozaar
• Placebo for Azilsartan Medoxomil (Drug)
• Placebo for Losartan (Drug)
• Azilsartan Medoxomil Medium-dose (20 mg) (Drug), also known as AR14, AZM-M: Azilsartan medoxomil medium-dose (AZM-M) 20 mg
• Azilsartan Medoxomil High-dose (40 mg) (Drug), also known as AR14, AZM-H: Azilsartan medoxomil high-dose (AZM-L) 40 mg

Primary outcomes

• Change in Seated Diastolic Blood Pressure Between AZM and Placebo [From Week 6/Final Visit of DB Phase to Week 8/Final Visit of Withdrawal Phase]: Change in Seated Diastolic Blood Pressure from Week 6/Final visit of DB Phase to Week 8/Final Visit of the Withdrawal Phase, analysis of study subjects randomized to receiving placebo at Week 6 of treatment versus those who remained on treatment

Secondary outcomes

• Change in Trough Seated Systolic Blood Pressure [From Week 6/Final Visit of the Double-Blind Phase to Week 8/Final Visit of the Withdrawal Phase]: Change in Trough Seated Systolic Blood Pressure from Week 6 of the Double-Blind Phase to Week 8 of the Withdrawal Phase Between AZM and Placebo, analysis of study subjects randomized to receiving placebo at Week 6 of treatment versus those who remained on treatment
• Change in Mean Arterial Pressure [From Week 6 of the Double-Blind Phase to Week 8 of the Withdrawal Phase]: Change in Mean Arterial Pressure from Week 6 of the Double-Blind Phase to Week 8 of the Withdrawal Phase Between AZM and Placebo, analysis of study subjects randomized to receiving placebo at Week 6 of treatment versus those who remained on treatment

Sex: All, ages: 6 Years to 18 Years

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

  1. 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)
  2. 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

Participant flow

Outcome results

• Change in Seated Diastolic Blood Pressure Between AZM and Placebo (Primary), Mean, mmHg: Pooled Placebo 3.9 +/- 8; Pooled AZM -1.6 +/- 6.69
• Change in Trough Seated Systolic Blood Pressure (Secondary), Mean, mmHg: Pooled Placebo 4.4 +/- 9.96; Pooled AZM -2.3 +/- 8.72
• Change in Mean Arterial Pressure (Secondary), Mean, mmHg: Pooled Placebo 4.1 +/- 7.43; Pooled AZM -1.8 +/- 6.63

Adverse events

Time frame: 54 weeks

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2018-12-12)
• Statistical Analysis Plan (PDF, 2020-01-13)

• Steve Caras, MD, Study director, Arbor Pharmaceuticals, LLC