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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Losartan; Drug: Placebo for Azilsartan Medoxomil; Drug: Placebo for Losartan; Drug: Azilsartan Medoxomil Low-dose; Drug: Azilsartan Medoxomil Medium-dose (20 mg); Drug: Azilsartan Medoxomil High-dose (40 mg)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 377
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Santa Fe, Argentina, S3000EPV
    • Clinica de Nefrologia, Urologia y Enf. Cardiovasculares S A
  • Buenos Aires
    • Ciudad Autonoma, Buenos Aires, Argentina, 1181
      • Hospital Italiano
    • Ciudad Autonoma, Buenos Aires, Argentina, C1425EFD
      • Hospital de Niños
• Brazil
  • Curitiba, Brazil, 80240-060
    • Clínica Nefrokids Ltda
  • Porto Alegre, Brazil, 90610-000
    • Hospital Sao Lucas Da Pucrs
  • Porto Alegre, Brazil, 90620-001
    • Instituto de Cardiologia do Rio Grande do Sul
  • São Paulo, Brazil, 01232-010
    • Hospital Samaritano
  • São Paulo, Brazil, 01227-200
    • Fundacao Jose Luiz Egydio Setubal
  • Uberlândia, Brazil, 38411-186
    • Eurolatino Pesquisas Médicas Ltda.
• Bulgaria
  • Ruse, Bulgaria, 7002
    • SHATPPD-Ruse EOOD
• Colombia
  • Bucaramanga, Colombia
    • Fundacion Oftalmologica de Santander - FOSCAL
  • Cali, Colombia
    • Fundación Valle Del Lili
  • Medellin, Colombia
    • Hospital Pablo Tobon Uribe
  • Medellin, Colombia
    • Fundación Hospitalaria San Vicente de Paul
  • Medellin, Colombia
    • Institucion Prestadora de Servicios de Salud de la Universidad de Antioquia "IPS UNIVERSITARIA"
• Hungary
  • Baja, Hungary, 6500
    • Principal SMO Kft.
  • Budapest, Hungary, 1037
    • Svabhegy Plusz Gyermekegeszsegugyi Kozpont
  • Dombovar, Hungary, 7200
    • Szent Lukacs Korhaz Dombovar
  • Miskolc, Hungary, 3526
    • Prehospital Med Kft.
  • Szeged, Hungary, 6720
    • Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin. Kozp.
• Italy
  • Bari, Italy, 70125
    • Ospedale Pediatrico Giovanni XXIII
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Palermo, Italy
    • A.R.N.A.S. Ospedale Civico e Benfratelli, G. Cristina e M.Ascoli
• Mexico
  • Durango, Mexico, 34000
    • Instituto de Investigaciones Aplicadas a la Neurociencia A.C.
  • Mexico City, Mexico
    • Hospital General de Mexico
  • Monterrey, Mexico, 6400
    • Accelerium S. de R.L. de C.V.
  • Morelia, Mexico, 58260
    • Centro de Investigación Clínica Chapultepec S.A. de C.V.
• Poland
  • Bialystok, Poland, 15-274
    • SPZOZ Uniwersytecki Dzieciecy Szpital Kliniczny im. L. Zamenhofa
  • Krakow, Poland, 30-663
    • Uniwersytecki Szpital Dzieciecy w Krakowie
  • Lodz, Poland, 93-338
    • NZOZ TRI-medica
  • Wroclaw, Poland, 50-072
    • Praktyka Lekarzy Rodzinnych R.Jadach, M.Domanski NZOZ
• South Africa
  • Germiston, South Africa
    • CRISMO Bertha Gxowa Research Centre
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2021
      • LCS Clinical Research Unit
    • Soweto, Gauteng, South Africa, 1818
      • Soweto Clinical Trial Centre
  • KwaZulu-Natal
    • Pietermaritzburg, KwaZulu-Natal, South Africa, 3201
      • Netcare St. Anne's Hospital
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Groote Schuur Hospital E13 Renal Unit
    • Worcester, Western Cape, South Africa, 6850
      • Clinical Projects Research SA (PTY) LTD
• Turkey
  • Adana, Turkey, 01330
    • Cukurova University Medical Faculty
  • Ankara, Turkey, 06500
    • Gazi University Medical Faculty
  • Istanbul, Turkey, 34093
    • Istanbul University Istanbul Medical Faculty
  • Izmir, Turkey, 35100
    • Dokuz Eylul University Medicine Faculty
  • Kayseri, Turkey, 38039
    • Erciyes University Medical Faculty
  • Manisa, Turkey, 45040
    • Celal Bayar University Medical Faculty
• Ukraine
  • Chernivtsi, Ukraine
    • CMI Chernivtsi City Children Clinical Hospital
  • Kharkiv, Ukraine
    • Regional Children CH Cardiology Department Kharkiv NMU
  • Kyiv, Ukraine
    • SI National Research Center of Radiation Medicine of NAMSU
  • Kyiv, Ukraine
    • USPC of ES EO&T Transplantation of MHU
  • Poltava, Ukraine
    • HSEI of Ukraine UMSA
  • Sumy, Ukraine
    • SSU Division MU Ch of pediatrics
  • Vinnytsia, Ukraine
    • Vynnitsa Regional Children CH pediatric department № 1 M.I. Pyrogov NMU
  • Zaporizhzhia, Ukraine
    • CI Zaporizhzhia City Multibranch Children Hospital #5
  • Zaporizhzhia, Ukraine
    • CI Zaporizhzhia Regional Clinical Children Hospital of ZRC
• United States
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center, Inc
  • Florida
    • Hialeah, Florida, United States, 33012
      • Direct Helpers Research Center
    • Miami, Florida, United States, 33125
      • JDH Medical Group LLC
    • Miami, Florida, United States, 33136
      • University of Miami/Jackson Memorial Hospital
    • Miami, Florida, United States, 33144
      • Medical Research Center of Miami II, Inc.
    • North Miami, Florida, United States, 33162
      • Pioneer Clinical Research
  • Georgia
    • Snellville, Georgia, United States, 30078
      • Georgia Clinical Research
    • Thomaston, Georgia, United States, 30286
      • Zoe Center for Pediatrics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Mississippi
    • Port Gibson, Mississippi, United States, 39150
      • David M. Headley, MD PA
  • New York
    • Lake Success, New York, United States, 10029
      • Mount Sinai PRIME
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC)
  • Tennessee
    • Memphis, Tennessee, United States, 38116
      • Memphis and Shelby County Pediatric Group
  • Texas
    • Beaumont, Texas, United States, 77701
      • Southeast Texas Clinical Research Center
    • Houston, Texas, United States, 77030
      • Texas Children's Heart Center
  • Utah
    • Clinton, Utah, United States, 84015
      • Ericksen Research & Development, LLC
  • Washington
    • Richland, Washington, United States, 99352
      • Mid-Columbia Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open Label Phase: Azilsartan Medoxomil; 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; Azilsartan medoxomil low-dose (AZM-L) 10 mg; Other Names: AR14; AZM-L
Placebo Comparator: Withdrawal Phase: Placebo to Losartan; 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; Other Names: sugar pill
Active Comparator: Double blind phase: Losartan; 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; Other Names: Cozaar
Active Comparator: Withdrawal Phase: Losartan 50 mg; Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment or to be switched to placebo.	Drug: Losartan; Other Names: Cozaar
Experimental: Double-blind: Azilsartan Medoxomil - Medium dose; 6-week, double-blind (DB), randomized, treatment phase (DB Phase), Azilsartan medoxomil Medium-dose (AZM-M), 20 mg once daily at Week 2.	Drug: Placebo for Losartan; Other Names: sugar pill; Drug: Azilsartan Medoxomil Low-dose; Azilsartan medoxomil low-dose (AZM-L) 10 mg; Other Names: AR14; AZM-L; Drug: Azilsartan Medoxomil Medium-dose (20 mg); Azilsartan medoxomil medium-dose (AZM-M) 20 mg; Other Names: AR14; AZM-M
Experimental: Double-blind: Azilsartan Medoxomil - Low dose; 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; Azilsartan medoxomil low-dose (AZM-L) 10 mg; Other Names: AR14; AZM-L
Active Comparator: Withdrawal Phase: Azilsartan medoxomil low-dose (AZM-L); Experimental Arm in the Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment (AZM-L) that was taken in Double blind OR to be switched to placebo.	Drug: Azilsartan Medoxomil Low-dose; Azilsartan medoxomil low-dose (AZM-L) 10 mg; Other Names: AR14; AZM-L
Placebo Comparator: Withdrawal Phase: Placebo to match azilsartan medoxomil low dose (AZM-L); Placebo Arm in the Withdrawal Phase for subjects who were on AZM-L in double blind then randomized (1:1) to placebo for withdrawal phase	Drug: Losartan; Other Names: Cozaar
Experimental: Double-blind: Azilsartan Medoxomil - High dose (AZM-H); 6-week, double-blind (DB), randomized, treatment phase (DB Phase): Azilsartan medoxomil High-dose (AZM-H), 40 mg AZM-M	Drug: Azilsartan Medoxomil High-dose (40 mg); Azilsartan medoxomil high-dose (AZM-L) 40 mg; Other Names: AR14; AZM-H
Experimental: Withdrawal: Azilsartan Medoxomil - Medium dose; Experimental Arm in the Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment (AZM-M) that was taken in Double blind OR to be switched to placebo.	Drug: Azilsartan Medoxomil Low-dose; Azilsartan medoxomil low-dose (AZM-L) 10 mg; Other Names: AR14; AZM-L; Drug: Azilsartan Medoxomil Medium-dose (20 mg); Azilsartan medoxomil medium-dose (AZM-M) 20 mg; Other Names: AR14; AZM-M
Experimental: Withdrawal: Azilsartan Medoxomil - High dose; Experimental Arm in the Withdrawal Phase, subjects will be randomized (1:1) to continue taking their previously assigned active treatment (AZM-H) that was taken in double blind OR to be switched to placebo.	Drug: Azilsartan Medoxomil High-dose (40 mg); Azilsartan medoxomil high-dose (AZM-L) 40 mg; Other Names: AR14; AZM-H
Experimental: Withdrawal Phase: Placebo to match azilsartan medoxomil medium dose (AZM-M); Placebo arm in the Withdrawal Phase for subjects who were on AZM-M in double blind then randomized (1:1) to matching placebo for withdrawal phase	Drug: Placebo for Azilsartan Medoxomil; Other Names: sugar pill
Experimental: Withdrawal Phase: Placebo to match azilsartan medoxomil high dose (AZM-H); Placebo arm in the Withdrawal Phase for subjects who were on AZM-H in Double blind then randomized (1:1) to matching placebo for withdrawal phase	Drug: Placebo for Azilsartan Medoxomil; Other Names: sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Seated Diastolic Blood Pressure Between AZM and Placebo	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	From Week 6/Final Visit of DB Phase to Week 8/Final Visit of Withdrawal Phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Trough Seated Systolic Blood Pressure	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	From Week 6/Final Visit of the Double-Blind Phase to Week 8/Final Visit of the Withdrawal Phase
Change in Mean Arterial Pressure	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	From Week 6 of the Double-Blind Phase to Week 8 of the Withdrawal Phase

Collaborators and Investigators

• Sponsor: Arbor Pharmaceuticals, Inc.
• Investigators: Study Director: Steve Caras, MD, Arbor Pharmaceuticals, LLC

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2015
• Primary Completion (Actual): November 11, 2019
• Study Completion (Actual): November 11, 2019

Study Registration Dates

• First Submitted: September 8, 2014
• First Submitted That Met QC Criteria: September 9, 2014
• First Posted (Estimated): September 10, 2014

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 5, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Hypertension; Pediatric; High Blood Pressure; Pediatric Hypertension; Primary Hypertension; Secondary Hypertension
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypertension; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan; Azilsartan medoxomil
• Other Study ID Numbers: AR14.001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No