Hypertension
Conditions
Keywords
Pediatric Hypertension, High Blood Pressure, Hypertension, Pediatric, Primary Hypertension, Secondary Hypertension
Brief summary
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
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.
Interventions
DRUGAzilsartan Medoxomil Low-dose
Azilsartan medoxomil low-dose (AZM-L) 10 mg
DRUGLosartan
DRUGPlacebo for Azilsartan Medoxomil
DRUGAzilsartan Medoxomil Medium-dose (20 mg)
Azilsartan medoxomil medium-dose (AZM-M) 20 mg
DRUGAzilsartan Medoxomil High-dose (40 mg)
Azilsartan medoxomil high-dose (AZM-L) 40 mg
Sponsors
Arbor Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blind masking in the Double Blind Phase and Withdrawal Phase.
Intervention model description
There are 3 phases in this study. Double-blind, withdrawal phase, and open-label phase.
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Argentina, Brazil, Bulgaria, Colombia, Hungary, Italy, Mexico, Poland, South Africa, Turkey (Türkiye), Ukraine, United States
Participant flow
Pre-assignment details
If the subject was taking antihypertensive medication, the subject was required a 14-day washout. The washout coincided with the Placebo Run-in. The Run-in Period consisted of two visits: Run-in, Day-14 (Visit 2); and Run-in, Day-1 (Visit 3), which only was required for subjects participating in the Ambulatory Blood Pressure Monitoring (ABPM) procedure. Participants who were enrolled in the study may have screen failed prior to first dosing with study drug, described above.
Participants by arm
| Arm | Count |
|---|---|
| AZM-H Subjects who received AZM-H | 54 |
| AZM-M Subjects who received AZM-M | 56 |
| AZM-L Subjects who received AZM-L | 52 |
| Losartan Subjects who received Losartan | 53 |
| Total | 215 |
Baseline characteristics
| Characteristic | AZM-H | Total | Losartan | AZM-L | AZM-M |
|---|---|---|---|---|---|
| Age, Continuous | 13.5 years STANDARD_DEVIATION 2.85 | 13.4 years STANDARD_DEVIATION 3 | 13.2 years STANDARD_DEVIATION 3.18 | 13.4 years STANDARD_DEVIATION 2.92 | 13.4 years STANDARD_DEVIATION 3.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 55 Participants | 13 Participants | 13 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 37 Participants | 155 Participants | 38 Participants | 38 Participants | 42 Participants |
| Sex: Female, Male Female | 25 Participants | 118 Participants | 25 Participants | 28 Participants | 40 Participants |
| Sex: Female, Male Male | 29 Participants | 97 Participants | 28 Participants | 24 Participants | 16 Participants |
| Weight (kg) | 68.97 kilogram STANDARD_DEVIATION 24.744 | 69.23 kilogram STANDARD_DEVIATION 25.952 | 69.00 kilogram STANDARD_DEVIATION 26.235 | 72.53 kilogram STANDARD_DEVIATION 28.556 | 66.65 kilogram STANDARD_DEVIATION 24.627 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 289 | 0 / 53 | 0 / 52 | 0 / 56 | 0 / 54 | 0 / 103 | 0 / 23 | 0 / 26 | 0 / 26 | 0 / 25 | 0 / 156 | 0 / 41 |
| other Total, other adverse events | 0 / 289 | 6 / 53 | 5 / 52 | 6 / 56 | 5 / 54 | 6 / 103 | 0 / 23 | 4 / 26 | 0 / 26 | 0 / 25 | 11 / 156 | 32 / 41 |
| serious Total, serious adverse events | 0 / 289 | 2 / 53 | 1 / 52 | 1 / 56 | 0 / 54 | 0 / 103 | 0 / 23 | 1 / 26 | 0 / 26 | 0 / 25 | 7 / 156 | 2 / 41 |
Outcome results
Primary
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
Time frame: From Week 6/Final Visit of DB Phase to Week 8/Final Visit of Withdrawal Phase
Population: Analysis of study subjects randomized to receiving placebo at Week 6 of treatment versus those who remained on treatment. The data was pooled for participants who were randomized to receive placebo from Week 6 and pooled for participants who remained receiving AZM treatment from Week 6 to compare the difference in outcome between those who remained on AZM vs. those who changed to placebo. The placebo arms were pooled and the AZM arms were pooled during the DB and Withdrawal phases.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pooled Placebo | Change in Seated Diastolic Blood Pressure Between AZM and Placebo | 3.9 mmHg | Standard Deviation 8 |
| Pooled AZM | Change in Seated Diastolic Blood Pressure Between AZM and Placebo | -1.6 mmHg | Standard Deviation 6.69 |
Secondary
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
Time frame: From Week 6 of the Double-Blind Phase to Week 8 of the Withdrawal Phase
Population: Analysis of study subjects randomized to receiving placebo at Week 6 of treatment versus those who remained on treatment. The data was pooled for participants who were randomized to receive placebo from Week 6 and then pooled for participants who remained receiving AZM treatment from Week 6 to compare the difference in outcome between those who remained on AZM vs. those who changed to placebo. The placebo arms were pooled and the AZM arms were pooled during the DB and Withdrawal phases.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pooled Placebo | Change in Mean Arterial Pressure | 4.1 mmHg | Standard Deviation 7.43 |
| Pooled AZM | Change in Mean Arterial Pressure | -1.8 mmHg | Standard Deviation 6.63 |
Secondary
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
Time frame: From Week 6/Final Visit of the Double-Blind Phase to Week 8/Final Visit of the Withdrawal Phase
Population: Analysis of study subjects randomized to receiving placebo at Week 6 of treatment versus those who remained on treatment. The data was pooled for participants who were randomized to receive placebo from Week 6 and then pooled for participants who remained receiving AZM treatment from Week 6 to compare the difference in outcome between those who remained on AZM vs. those who changed to placebo. The placebo arms were pooled and the AZM arms were pooled during the DB and Withdrawal phases.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pooled Placebo | Change in Trough Seated Systolic Blood Pressure | 4.4 mmHg | Standard Deviation 9.96 |
| Pooled AZM | Change in Trough Seated Systolic Blood Pressure | -2.3 mmHg | Standard Deviation 8.72 |