A Study of TAK-536 in Children From 2 to Less Than 6 Years Old With High Blood Pressure

Study Overview
=================
Brief Summary
-----------------
The main aim of this study is to check the safety of TAK-536. This study will take place in Japan. At the first visit, the study doctor will check if each child can take part. For those who can take part, each participant will have a check-up by the study doctor. This might take 2 weeks or longer. After this, parents or the caregivers of each participant will be given sachets that contain granules of TAK-536 to give to that participant. The participants will take the TAK-536 granules once a day for 52 weeks. After treatment has finished, participants will visit the study clinic for a final check-up.

Detailed Description
-----------------
The drug being tested in this study is called TAK-536. TAK-536 is being tested in pediatric participants with hypertension aged 2 to less than 6 years. This study will look at the safety, efficacy, and pharmacokinetics of long-term administration of TAK-536. The study will enroll 10 participants. Participants will receive the study drug (TAK-536) orally once daily before or after breakfast. The initial dose of TAK-536 will be 0.1 mg/kg (not exceeding 2.5 mg/day). After the initial dose, TAK-536 will be titrated to 0.2 mg/kg (not exceeding 5 mg/day), 0.4 mg/kg (not exceeding 10 mg/day), and 0.8 mg/kg (not exceeding 20 mg/day) if the participants do not achieve the target blood pressure and no concerns are found in safety and tolerability. This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 56 weeks. Participants will make multiple visits to the clinic.

Official Title
-----------------
A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, Efficacy and Pharmacokinetics of TAK-536 in Pediatric Subjects From 2 to Less Than 6 Years of Age With Hypertension

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: TAK-536


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In the opinion of the investigator or subinvestigator, the participant's parent or 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. A 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 >=95th percentile for essential hypertension without concomitant hypertensive organ damage, and >=90th percentile for secondary hypertension with concomitant CKD, diabetes mellitus, heart failure or 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 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 meets the above criteria for hypertension on 3 separate time points including screening and the end of the Run-in Period (Week 0). In addition, for a participant with essential hypertension without hypertensive organ damage, the participant does not respond to non-pharmacological therapy such as diet modification or exercises for at least 3 months within 1 year prior to the start of screening. The participant is male or female and aged 2 to less than 6 years at the time of informed consent. At screening, the participant has not less than minus 2 standard deviations from mean weight for age of reference population shown in the table of pediatric body weight by the Japanese Society for Pediatric Endocrinology. The participant is able to swallow the study drug. A participant who has undergone kidney transplantation is eligible if he/she underwent the transplantation, 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, CT [computed tomography] scan or MRI [magnetic resonance imaging]) excluding dose at least 30 days prior to screening is eligible. The participant, judged by the investigator or subinvestigator, who can safely discontinue the therapy with RAS inhibitors for 2 weeks prior to the Treatment Period. This period may change to between 1 and 4 weeks depending on the participant's duration of Run-in 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 surgical therapy. The participant previously received therapy with azilsartan. The participant has poorly controlled hypertension indicated by an office sitting systolic blood pressure higher by at least 22 mmHg and/or an office sitting diastolic blood pressure higher by at least 17 mmHg than the 95th 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 (compliance: <70% or >130%) with the study drug during the Run-in Period. The proportion of the number of the received the study drug to the number of the study drug which the participants should receive. 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, urogenital, 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 uncorrected aortic valvular disease, or is scheduled to undergo a medical procedure affecting blood pressure during the study (eg, correction of arterial anomaly). Note: This does not apply to participants who received medical procedure(s) (eg, surgery for aortic coarctation) before the study and investigator or subinvestigator assess that participant's condition is stable at screening. The participant has a history of or concurrent clinically significant abnormality of 12-lead 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 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 ARBs. The participant needs treatment with any of the excluded medication.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 5 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-536<br>TAK-536 granule formulation, orally once daily before or after breakfast. The initial dose of TAK-536 will be 0.1 mg/kg (not exceeding 2.5 mg/day). After the initial dose, TAK-536 will be titrated to 0.2 mg/kg (not exceeding 5 mg/day), 0.4 mg/kg (not exceeding 10 mg/day), and 0.8 mg/kg (not exceeding 20 mg/day) if the subjects do not achieve the target blood pressure and no concerns are found in safety and tolerability. | Drug: TAK-536<br>* TAK-536 granule formulation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced at Least One Treatment-Emergent Adverse Event (TEAE) |  | 54 Weeks | 
| Number of Participants with TEAE Related to 12-lead Electrocardiograms |  | 54 Weeks | 
| Number of Participants with TEAE Related to Anthropometric Measurement (Weight, Height and Body Mass Index (BMI)) |  | 54 Weeks | 
| Number of Participants with TEAE Related to Clinical Laboratory Tests |  | 54 Weeks | 
| Number of Participants with TEAE Related to Vital Sign (Office Sitting Pulse Rate and Home Sitting Blood Pressure) |  | 54 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in office trough sitting diastolic blood pressure at Week 12 and 52 (last observation carried forward [LOCF]) |  | Baseline, up to Week 12 and 52 | 
| Change from baseline in office trough sitting systolic blood pressure at Week 12 and 52 (last observation carried forward [LOCF]) |  | Baseline, up to Week 12 and 52 | 
| Percentage of participants who achieve the target blood pressure at Week 12 and 52 (LOCF) | The target blood pressure is defined as the normal reference range for blood pressure by age according to Guidelines on the Clinical Examination for Decision Making of Diagnosis and Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the Japanese Circulation Society JCS 2018 (JCS 2018). | Baseline, up to Week 12 and 52 | 
| Cmax: Maximum Observed Plasma Concentration for TAK-536 |  | Pre-dose and 2 hours post-dose | 
| AUC: Area Under the Concentration-Time Curve for TAK-536 |  | Pre-dose and 2 hours post-dose |