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

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

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. After this, each participant will take placebo. This might take 2 weeks.

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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: TAK-536

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Hiroshima, Japan
    • Hiroshima Prefectural Hospital
  • Saitama, Japan
    • Local Independent Administrative Institution Saitama prefectural hospital organization Saitama Children's Medical Center
  • Shizuoka, Japan
    • Shizuoka Childrens Hospital
  • Wakayama, Japan
    • Wakayama Medical University Hospital
  • Aichi
    • Nagoya, Aichi, Japan
      • Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital
    • Obu, Aichi, Japan
      • Aichi Children's Health and Medical Center
  • Hyogo
    • Kobe, Hyogo, Japan
      • Hyogo Prefectural Kobe Children's Hospital
  • Ishikawa
    • Kanazawa, Ishikawa, Japan
      • National Hospital Organization Kanazawa Medical Center
  • Kanagawa
    • Sagamihara, Kanagawa, Japan
      • Kitasato University Hospital
  • Miyagi
    • Sendai, Miyagi, Japan
      • Tohoku University Hospital
    • Sendai, Miyagi, Japan
      • Miyagi Children's Hospital
  • Okinawa
    • Nakagami-gun, Okinawa, Japan
      • University of the Ryukyus Hospital
    • Shimajiri-gun, Okinawa, Japan
      • Okinawa Prefectural Nanbu Medical Center & Children's Medical Center
  • Osaka
    • Suita, Osaka, Japan
      • Osaka University Hospital
  • Shiga
    • Otsu, Shiga, Japan
      • Shiga University of Medical Science Hospital
  • Tochigi
    • Shimotsuke, Tochigi, Japan
      • Jichi Medical University Hospital
  • Tokyo
    • Fuchu, Tokyo, Japan
      • Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Children's Medical Center
    • Setagaya-ku, Tokyo, Japan
      • National Center for Child Health and Development
    • Shinjuku-ku, Tokyo, Japan
      • Tokyo Women's Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 5 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. In the opinion of the investigator or subinvestigator, the participant's parent or legal guardian is capable of understanding and complying with protocol requirements.
2. 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.

3. 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.

4. The participant is male or female and aged 2 to less than 6 years at the time of informed consent.
5. 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.
6. The participant is able to swallow the study drug.
7. 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.
8. 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:

1. 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.

2. The participant previously received therapy with azilsartan.
3. 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.
4. The participant has a diagnosis of malignant or accelerated hypertension.
5. 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.
6. 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.
7. 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.

8. 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.

9. 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.
10. The participant has poorly controlled diabetes mellitus indicated by HbA1c >9.0% at screening.
11. 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.
12. The participant has hyperkalemia exceeding ULN at screening.
13. The participant has a history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at screening.
14. The participant has a known hypersensitivity or allergy to any ARBs.
15. The participant needs treatment with any of the excluded medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TAK-536; 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; TAK-536 granule formulation

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)	An Adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant whose parent or legal guardian had signed informed consent form to participate in a study; it did not necessarily have to have a causal relationship with this treatment or study participation. An AE could therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study participation whether or not it was considered related to the drug or study procedures. A TEAE was defined as any AE occurring after the start of TAK-536 administration, and until the end of follow-up period of 2 weeks.	From first dose of study drug up to end of follow-up period (Week 54)
Number of Participants With TEAE Related to Resting 12-lead Electrocardiogram (ECG)	The relatedness of TEAEs with resting 12-lead ECG was based upon investigator discretion.	From first dose of study drug up to Week 52
Number of Participants With TEAE Related to Anthropometric Measurement	The anthropometric measurements included weight, height and body mass index (BMI). The relatedness of TEAEs to anthropometric measurements was based upon investigator discretion.	From first dose of study drug up to Week 52
Number of Participants With TEAE Related to Clinical Laboratory Parameters	The laboratory values outside the range (triglycerides greater than [>] 2.5*upper limit of normal [ULN], blood urea nitrogen [BUN] >30 milligram per deciliter [mg/dL], estimated glomerular filtration rate [eGFR] less than [<] 30 milliliter per minute per 1.73 square meter [mL/min/1.73m^2], and glucose <50 mg/dL were considered markedly abnormal for TEAEs. The relatedness of TEAEs to clinical laboratory parameters was based upon investigator discretion.	From first dose of study drug up to Week 52
Number of Participants With TEAE Related to Vital Sign Values	Vital signs included home sitting blood pressure (diastolic and systolic) and office sitting pulse rate (pulse rate per 1 minute). The pulse rate measured at the last measurement of the sitting blood pressure was used as the sitting pulse rate value. The relatedness of TEAEs to vital signs was based upon investigator discretion.	From first dose of study drug up to end of follow-up period (Week 54)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Office Trough Sitting Diastolic Blood Pressure at Weeks 12 (Last Observation Carried Forward [LOCF]) and 52 (LOCF)	Office trough sitting diastolic blood pressure were measured in a sitting position. LOCF method was used to impute missing values.	Baseline, Weeks 12 (LOCF) and 52 (LOCF)
Change From Baseline in Office Trough Sitting Systolic Blood Pressure at Weeks 12 (LOCF) and 52 (LOCF)	Office trough sitting systolic blood pressure were measured in a sitting position. LOCF method was used to impute missing values.	Baseline, Weeks 12 (LOCF) and 52 (LOCF)
Percentage of Participants Who Achieved the Target Blood Pressure at Weeks 12 (LOCF) and 52 (LOCF)	The target blood pressure was 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 participants with cardiovascular diseases by the Japanese Circulation Society 2018 (JCS 2018). LOCF method was used to impute missing values.	At Weeks 12 (LOCF) and 52 (LOCF)
Plasma Concentration of TAK-536	Plasma concentration of TAK-536 were reported.	Weeks 2, 4, 8 and 12: Pre-dose and at 2 hours post-dose; Week 16: 2 hours post-dose

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Study Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2021
• Primary Completion (Actual): December 28, 2023
• Study Completion (Actual): December 28, 2023

Study Registration Dates

• First Submitted: December 10, 2020
• First Submitted That Met QC Criteria: December 10, 2020
• First Posted (Actual): December 16, 2020

Study Record Updates

• Last Update Posted (Actual): December 9, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypertension; Molecular Mechanisms of Pharmacological Action; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Azilsartan medoxomil
• Other Study ID Numbers: Azilsartan-3004; U1111-1259-9316 (Other Identifier: WHO); jRCT2041200083 (Registry Identifier: jRCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants/study sites).

Drug and device information, study documents

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