A Phase 3 Long-term Study of TAK-536 in Pediatric Patients 6 to Less Than 16 Years With Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of administration of azilsartan in pediatric patients aged 6 to less than 16 years with hypertension.

Detailed Description
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The drug being tested in this study is called azilsartan. Azilsartan is being tested to treat pediatric participants with hypertension. The study enrolled 27 participants. Following a 2-week Placebo Run-in Period, participants were assigned to one of the two treatment groups based on weight: Azilsartan 2.5 - 20 mg (Participants < 50 kg) Azilsartan 5 - 40 mg (Participants ≥ 50 kg) Participants weighing < 50 kg were asked to take an initial dose azilsartan 2.5 mg (titrated as needed to the highest dose of 20 mg) and participants weighing ≥ 50 kg were asked to take an initial dose of 5 mg azilsartan (titrated as needed to the highest dose of 40 mg). This multi-centre trial was conducted in Japan. The overall time to participate in this study is 56 weeks. The study consisted of a Run-in Period (Week -2 to Week 0), a 52-week Treatment Period, and a 2-week Follow-up Period (up to Week 54). Participants made multiple visits to the clinic and a final visit 2 weeks after the last dose of study drug for follow-up assessment.

Official Title
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A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, Efficacy and Pharmacokinetics of TAK-536 in Pediatric Patients 6 to Less Than 16 Years of Age With Hypertension

Conditions
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Pediatric Hypertension

Intervention / Treatment
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* Drug: Azilsartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In the opinion of the investigator or subinvestigator, the participant's parent or the participant's legal guardian is capable of understanding and complying with protocol requirements. The participant's parent or the participant's legal guardian is capable of signing and dating a written, informed consent form on behalf of the participant prior to the initiation of any study procedures. Written informed assent is also obtained from the participant as much as possible. The Japanese participant who has a diagnosis of hypertension. A participant is eligible if he/she is deemed hypertensive according to the Reference Blood Pressure Values of Children by Gender and Age; office sitting diastolic or systolic blood pressure ≥ 95 percentile for essential hypertension without concomitant hypertensive organ damage, and ≥ 90 percentile for secondary hypertension with concomitant chronic kidney disease (CKD), diabetes mellitus, heart failure or any hypertensive organ damage. In addition, participants need to meet the following criteria: - If currently treated with any antihypertensive drugs at the start of the Run-in Period: Participant has a documented historical diagnosis of hypertension and an office sitting diastolic or systolic blood pressure meeting the above criteria at the end of the Run-in Period (Week 0). - If currently untreated with any antihypertensive drugs at the start of the Run-in Period: Participant who meets the above criteria on 3 separate time points including screening and the end of the Run-in Period (Week 0). In addition, participant with essential hypertension without concomitant hypertensive organ damage still maintains hypertension with non-pharmacotherapy including foods or exercises for at least 3 months within 1 year prior to the start of screening. The participant is male or female and aged 6 to less than 16 years at the time of informed consent. The participant weighs at least 20 kg at screening. The participant is capable of taking the tablets or granules supplied as the study drug. A participant who has undergone kidney transplantation is eligible if he/she underwent the transplantation at least 6 months earlier at screening, and the graft has been functionally stable (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2) for at least 6 months with evidence (eg, Doppler echography, computed tomography (CT) scan or magnetic resonance imaging (MRI) excluding grafted kidney arterial stenosis. A participant on immunosuppressive therapy with a stable dose at least 30 days prior to screening is eligible. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent through 1 month after the completion of the study, and proves negative in the pregnancy test at screening. The participants judged by the investigator or subinvestigator that he/she can discontinue the therapy with renin-angiotensin-system (RAS) inhibitors for 2 weeks (acceptable range, 1 to 4 weeks) in safe prior to the Treatment Period. Exclusion Criteria: The participant has received any investigational compound within 30 days prior to screening or is participating in another clinical study or a post-marketing clinical study. Note: This does not apply to participants participating in observational studies without interventional or invasive therapy. The participant previously received therapy with azilsartan. Note: This does not apply to participants participating in single dose pharmacokinetic studies of TAK-536. The participant has poorly controlled hypertension indicated by an office sitting systolic blood pressure higher by at least 15 mmHg and/or an office sitting diastolic blood pressure higher by at least 10 mmHg than the 99 percentiles of the Reference Blood Pressure Values of Children by Gender and Age. The participant has a diagnosis of malignant or accelerated hypertension. The participant was noncompliant (< 70% or > 130%) with the study drug during the Run-in Period. The participant has severe renal dysfunction (eGFR < 30 mL/min/1.73 m^2), is receiving dialysis, has a renovascular disease affecting one or both kidneys, severe nephrotic syndrome not in remission, or a serum albumin level < 2.5 g/dL. The participant has a history of, or the signs/symptoms of serious cardiovascular, hepatobiliary, gastrointestinal, endocrine (eg, hyperthyroidism, Cushing's syndrome), hematological, immunological, urinogenital, psychiatric disease, cancer, or any other disease that adversely affects participant's health, or, in the opinion of the investigator or subinvestigator, potentially confounds the study results. The participant has hemodynamically significant left ventricular outflow obstruction due to aortic stenosis or aortic valvular disease, or is scheduled to undergo a medical procedure affecting blood pressure during the study (eg, correction of arterial anomaly). The participant has a history of or concurrent clinically significant abnormality of 12-lead electrocardiogram (ECG) that, in the opinion of the investigator or subinvestigator, disqualifies the participant for participation in the study. The participant has poorly controlled diabetes mellitus indicated by hemoglobin A1c (HbA1c) > 9.0% at screening. The participant has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 2.5 × the upper limit of normal (ULN), or a total bilirubin level ≥ 1.5 × ULN at screening, severely impaired hepatic function, any active liver disease (regardless of the cause), or jaundice. The participant has hyperkalemia exceeding ULN at screening. The participant has a history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at screening. The participant has a known hypersensitivity or allergy to any angiotensin II receptor blocker (ARBs). The participant needs treatment with any of the excluded medication. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after the completion of this study.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 15 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azilsartan 2.5 - 20 mg (Weight < 50 kg)<br>Following a 2-week placebo run-in period, azilsartan 2.5 mg (titrated as needed to the highest dose of 20 mg) was administered orally once daily before or after breakfast, for the participants weighing < 50 kg. | Drug: Azilsartan<br>* Azilsartan granules and tablets<br>* Other names: AZILVA ®;Drug: Placebo<br>* Placebo-matching azilsartan granules and tablets<br>|
| Experimental: Azilsartan 5 - 40 mg (Weight ≥ 50 kg)<br>Following a 2-week placebo run-in period, azilsartan 5 mg (titrated as needed to the highest dose of 40 mg) was administered orally once daily before or after breakfast, for the participants weighing ≥ 50 kg. | Drug: Azilsartan<br>* Azilsartan granules and tablets<br>* Other names: AZILVA ®;Drug: Placebo<br>* Placebo-matching azilsartan granules and tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs or worsens after receiving study drug. | Up to Week 54 | 
| Number of Participants With TEAEs Related to Anthropometric Measurement (Weight, Height and Body Mass Index (BMI)) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs or worsens after receiving study drug. | Up to Week 54 | 
| Number Of Participants With Markedly Abnormal Values of Laboratory Parameters | The laboratory values outside the range (Blood Urea Nitrogen (BUN) (mg/dL) >30, Creatinine (mg/dL) >2.0, eGFR (mL/min/1.73m^2) <30, Creatine Kinase (U/L) >5×ULN) are considered markedly abnormal. | Up to Week 54 | 
| Number Of Participants With TEAEs Related To Resting 12-Lead Electrocardiogram (ECG) | A standard 12-lead ECG was performed while the participant was at rest. Any abnormal ECG findings determined by the investigator to be clinically significant were reported as adverse events. | Up to Week 54 | 
| Number Of Participants With TEAEs Related To Vital Signs (Hypotension) | A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Vital signs included office standing blood pressure, office sitting pulse rate, office standing pulse rate, and home sitting blood pressure. Any abnormal vital signs findings determined by the investigator to be clinically significant were reported as adverse events. | Up to Week 54 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Office Trough Sitting Systolic Blood Pressure | Office trough sitting blood pressure is defined as the blood pressure collected in the office while the participant was sitting at a time point immediately before the next dosing, when the blood drug concentration is assumed to be the lowest. A negative change from Baseline indicates improvement. The data of change from baseline to the End of Treatment Period I (EOT 1) and the End of the Treatment Period 2 (EOT 2) were calculated with the evaluable data within the acceptable time points (EOT1 was for up to Week 12 and EOT2 was for up to Week 52) with the largest Study Day was used. Meanwhile, change from baseline to Week 12 and 52 were calculated with the data of Week 12 and 52 respectively. | Baseline (Day 0), Weeks 2, 4, 8, 12,16, 20, 24, 32, 40, 52, Week 54 (Follow-up), End-of-treatment (EOT) 1 (Up to Week 12), EOT 2 (Up to Week 52) | 
| Change From Baseline in Office Trough Sitting Diastolic Blood Pressure | Office trough sitting blood pressure is defined as the blood pressure collected in the office while the participant was sitting at a time point immediately before the next dosing, when the blood drug concentration is assumed to be the lowest. A negative change from Baseline indicates improvement. The data of change from baseline to the End of Treatment Period I (EOT 1) and the End of the Treatment Period 2 (EOT 2) were calculated with the evaluable data within the acceptable time points (EOT1 was for up to Week 12 and EOT2 was for up to Week 52) with the largest Study Day was used. Meanwhile, change from baseline to Week 12 and 52 were calculated with the data of Week 12 and 52 respectively. | Baseline (Day 0), Weeks 2, 4, 8, 12,16, 20, 24, 32, 40, 52, Week 54 (Follow-up), EOT 1 (Up to Week 12), EOT 2 (Up to Week 52) | 
| Percentage Of Participants Who Achieve The Target Blood Pressure | Target blood pressure is defined as the normal reference range for blood pressure by age according to Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the Japanese Circulation Society JCS 2012 (JCS 2012). The data of change from baseline to EOT 1 and EOT 2 were calculated with the evaluable data within the acceptable time points (EOT1 was for up to Week 12 and EOT2 was for up to Week 52) with the largest Study Day was used. Meanwhile, change from baseline to Week 12 and 52 were calculated with the data of Week 12 and 52 respectively. Target blood pressure were described on Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the Japanese Circulation Society JCS 2012 (JCS 2012) (see Links on Registration Section). | Weeks 2, 4, 8, 12,16, 20, 24, 32, 40, 52, Week 54 (Follow-up), EOT 1 (Up to Week 12), EOT 2 (Up to Week 52) | 
| Observed Plasma Concentration for Azilsartan | Reported data were observed plasma concentration for Azilsartan for each arm. Dosage of the study drug after Week 2 (postdose) is different among participants. | Predose and 2 hours postdose Weeks 2, 4, 8, 12 and 2 hours postdose Week 16 | 
| Observed Plasma Concentration for Azilsartan Metabolites (M-I) | Reported data were observed plasma concentration for Azilsartan Metabolites (M-I) for each arm. Dosage of the study drug after Week 2 (postdose) is different among participants. | Predose and 2 hours postdose Weeks 2, 4, 8, 12 and 2 hours postdose Week 16 | 
| Observed Plasma Concentration for Azilsartan Metabolites (M-II) | Reported data were observed plasma concentration for Azilsartan Metabolites (M-II) for each arm. Dosage of the study drug after Week 2 (postdose) is different among participants. | Predose and 2 hours postdose Weeks 2, 4, 8, 12 and 2 hours postdose Week 16 |