Special Drug Use Surveillance; AZILVA Tablets and AZILVA Granules 1% in Pediatric Use
Conditions: Hypertension
Sponsor: Takeda

 
 
Clinical Study Protocol 
 
NCT Number: NCT05107960 
Title: Special Drug Use Surveillance; AZILVA Tablets and AZILVA Granules 1% in 
Pediatric Use 
Study Number: TAK-536-4001 
Document Version and Date: Version 4 / 14-MAY-2024 
 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
Special Drug Use Surveillance Protocol 
Azilva Tablets, Azilva Granules 1% 
<Pediatric Use> 
Special Drug Use Surveillance 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol Number
TAK-536-4001 
Version
Ver. 4 
Prepared on 
May 14, 2024
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

 
 
 
 
Table of Contents 
 
IMPLEMENTATION BACKGROUND ............................................................................................ 1 
 
OBJECTIVE ....................................................................................................................................... 1 
 
SAFETY SPECIFICATION AND EFFICACY CONSIDERATIONS .............................................. 1 
 
PLANNED SAMPLE SIZE AND RATIONALE .............................................................................. 2 
 PLANNED SAMPLE SIZE ..................................................................................................................... 2 
 RATIONALE ....................................................................................................................................... 2 
 
SUBJECTS ....................................................................................................................................... . 2 
 INCLUSION CRITERIA................................................................................................................... ..... 2 
 EXCLUSION CRITERIA ....................................................................................................... .............. 2 
 
DOSAGE AND ADMINISTRATION ............................................................................ .................. 2 
 
PLANNED NUMBER OF SITES BY DEPARTMENT .................................................................... 2 
 
METHOD ....................................................................................................... ................................... 2 
 OBSERVATION PERIOD AND RATIONALE ........................................................................................... 2 
 CLINICAL SITE CONTRACTS .............................................................................................................. 3 
 PATIENT ENROLLMENT METHOD ......................................... .. ......................................................... 3 
 PREPARATION AND SUBMISSION OF CRFS........................... ............................................................. 3 
 
PLANNED DURATION OF SURVEILLANCE .......... .. ................................................................. 3 
 
SURVEILLANCE PARAMETERS .......................... ........................................................................ 4 
 PATIENT ENROLLMENT ................................ ..................................................................................... 4 
 PATIENT CHARACTERISTICS ................. ........................................................................................... 4 
 TREATMENT ...................................................................................................................................... 4 
 TEST/OBSERVATION PARAMETERS ................................................................................................... 4 
10.4.1 Vital Signs/Body Weight .............................................................................................. 4 
10.4.2 Laboratory Tests ........................................................................................................... 5 
10.4.3 Other Observation Parameters ..................................................................................... 5 
 ADVERSE EVENTS ............................................................................................................................. 5 
 
ANALYTIC PARAMETERS AND METHODS ............................................................................... 7 
 PATIENT DISPOSITION-RELATED MATTERS ....................................................................................... 7 
 PATIENT CHARACTERISTICS .............................................................................................................. 7 
 TREATMENT ...................................................................................................................................... 7 
 SAFETY INFORMATION ...................................................................................................................... 7 
11.4.1 Incidence of Adverse Events ........................................................................................ 7 
11.4.2 Factors Potentially Affecting Safety ............................................................................ 7 
 EFFICACY INFORMATION ................................................................................................................... 7 
11.5.1 Changes in Blood Pressure Over Time ........................................................................ 7 
11.5.2 Factors Potentially Affecting Efficacy ......................................................................... 7 
 
REGISTRATION OF SURVEILLANCE INFORMATION ............................................................. 7 
 
ORGANIZATIONAL STRUCTURE................................................................................................. 8 
 CHART OF ORGANIZATIONAL STRUCTURE FOR POST-MARKETING SURVEILLANCE ........................... 8 
 
CONTRACT RESEARCH ORGANIZATIONS ................................................................................ 8 
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SCHEDULE AND RATIONALE FOR MILESTONES FOR CONDUCT OF SURVEILLANCE 
AND ASSESSMENT OF RESULTS OR REPORTS TO THE PHARMACEUTICALS AND 
MEDICAL DEVICES AGENCY ....................................................................................................... 8 
 
ADDITIONAL ACTION THAT MAY BE TAKEN BASED ON SURVEILLANCE RESULTS, 
AND CRITERIA FOR INITIATING SUCH ACTION ..................................................................... 8 
 
OTHER REQUIREMENTS ............................................................................................................... 9 
 PROTOCOL AMENDMENT ................................................................................................................... 9 
 ACTIONS TO BE TAKEN WHEN PROBLEMS OR QUESTIONS ARE IDENTIFIED ....................................... 9 
APPENDIX 1 OBSERVATION SCHEDULE NOTE) .................................................................................... 10 
 
 
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IMPLEMENTATION BACKGROUND 
In pediatric hypertensive patients, appropriate blood pressure management in the early stages 
is important because hypertension that persists from childhood may lead to organ damage, 
such as cardiovascular disease and renal disorders, which may have a serious impact on 
patient quality of life and prognosis, during childhood as well as in the future. 
When Azilva (azilsartan) was being developed, many antihypertensives were available for 
adults, but only a limited number of antihypertensives had been approved for pediatric 
hypertension in Japan, only two of which were angiotensin II receptor antagonists (ARBs) 
at that point in time. Also, none of the pediatric formulations for which there is strong 
demand in the clinical setting were being developed, and it could not be said that a suitable 
therapeutic setting for pediatric hypertension had yet been achieved. Furthermore, all of the 
drugs had been publicly filed based on information in the literature or drug use surveillance, 
for example, without documentation of any clinical study data on pediatric hypertensive 
patients in Japan. 
In light of the therapeutic setting for pediatric hypertension, it would make sense to collect 
clinical trial data in Japanese pediatric hypertensive patients during treatment with azilsartan, 
which has been shown to be safe and effective for adult hypertensive patients, so as to 
develop a pediatric formulation as a new treatment option for pediatric hypertension. 
A special drug use surveillance (referred to as the present surveillance) to investigate the 
efficacy and safety of azilsartan in pediatric patients was planned for the following reasons: 
in the Japanese Phase 3 long-term treatment study on azilsartan in pediatric hypertensive 
patients 6 to less than 16 years of age (TAK-536/OCT-101) (referred to below as the study), 
the number of patients was relatively small (27 patients); no children were enrolled in the 
special drug use surveillance of Azilva tablets in adults ("long-term use" and "hypertension 
with diabetes mellitus"); and there is limited experience with the use of azilsartan in pediatric 
patients 6 to less than 16 years of age. 
The present surveillance will be conducted in compliance with the GPSP Ministerial 
Ordinance and other relevant regulatory requirements. 
 
 
OBJECTIVE 
The objective is to study the safety and efficacy of routine clinical use of azilsartan in 
pediatric hypertensive patients 6 to less than 16 years of age. 
 
 
SAFETY SPECIFICATION AND EFFICACY CONSIDERATIONS 
Important identified risk: hypotension-related events 
No efficacy considerations were identified. 
 
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PLANNED SAMPLE SIZE AND RATIONALE 
 
PLANNED SAMPLE SIZE 
Five pediatric hypertensive patients (number of patients in safety analysis set) 
 
 
RATIONALE 
In view of the feasibility of enrollment and pediatric prescription of azilsartan, the planned 
sample size in the present surveillance was established as five patients in the safety analysis 
set. 
 
 
SUBJECTS 
Pediatric hypertensive patients 6 to less than 16 years of age will be included as subjects. 
However, subjects must meet the following inclusion criteria and cannot conflict with any of 
the exclusion criteria. In addition, please refer to the current package insert . 
 
 
INCLUSION CRITERIA 
Patients must meet all of the following criteria: 
① 6 to less than 16 years of age 
② Have hypertension 
 
 
EXCLUSION CRITERIA 
Patients who meet the following criteria are not eligible. 
Azilsartan is contraindicated 
 
 
DOSAGE AND ADMINISTRATION 
Usually, the initial once-daily oral dose in children 6 years of age or older is 2.5 mg azilsartan 
for children weighing less than 50 kg and is 5 mg azilsartan for children weighing 50 kg or 
more. The dose may be adjusted, depending on age, body weight, and symptoms, but the 
maximum daily dose will be 20 mg for children weighing less than 50 kg and will be 40 mg 
for children weighing 50 kg or more. In addition, please refer to the current package insert . 
 
 
PLANNED NUMBER OF SITES BY DEPARTMENT 
Pediatrics, etc.:   Approximately 5 sites 
 
 
METHOD 
 
OBSERVATION PERIOD AND RATIONALE 
Up to 12 months 
 
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<Rationale for Observation Period> 
As the duration of treatment was 52 weeks in the clinical study, an observation period of up 
to 12 months was established for comparison with the clinical study data. It is believed that 
an observation period of up to 12 months will allow comparison with the "long-term use" 
data from the special drug use surveillance in which the safety of azilsartan was assessed in 
adult hypertensive patients. 
For patients who discontinue treatment during the observation period, the reason for 
discontinuation will be documented, and the details leading to discontinuation will be 
checked. 
 
 
CLINICAL SITE CONTRACTS 
Takeda Pharmaceutical Company Limited will conclude a written agreement with study sites 
to conduct the present surveillance. 
 
 
PATIENT ENROLLMENT METHOD 
The surveillance will be conducted via "centralized enrollment" using a web-based electronic 
data capture (EDC) system. 
For patients prescribed azilsartan after the start of the contract period, investigators will enter 
patient enrollment-related information into the EDC no later than 14 days after the initial 
azilsartan prescription date (where "day 0" indicates the prescription date, and "day 1 after" 
indicates the day after the prescription date). Retrospective enrollment will be allowed for 
patients who started treatment prior to the conclusion of the contract if treatment had been 
initiated on or after December 16, 2021, when the granule dosage form was first marketed. 
 
 
PREPARATION AND SUBMISSION OF CRFS 
Information will be collected using the EDC. 
Investigators will promptly enter data into the EDC system after necessary observations for 
all enrolled patients. Cases where treatment compliance could not be confirmed should be 
entered (subsequent entries do not need to be completed). 
Patients who discontinue azilsartan treatment during the observation period due to the 
occurrence of an adverse event will continue to be observed after discontinuation, if possible, 
until the adverse event resolves, and the data will be entered into the EDC. 
Investigators will electronically sign the EDC to ensure the accuracy and reliability of the 
data recorded in the EDC. 
 
 
PLANNED DURATION OF SURVEILLANCE 
Surveillance period: After start of granule dosage form marketing to August 31, 2024  
Patient enrollment period: After start of granule dosage form marketing to May 31, 2024 
 
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SURVEILLANCE PARAMETERS 
Investigators will enter the following parameters into the EDC: The schedule for the present 
surveillance is shown in Appendix 1. 
 
 PATIENT ENROLLMENT 
1) Surveillance parameters 
Azilsartan prescription date, patient identification number, patient initials, sex, date of 
birth or age (at the time that Azilsartan is prescribed), inclusion criteria, exclusion 
criteria 
2) Time point 
At patient enrollment 
 
 PATIENT CHARACTERISTICS 
1) Surveillance parameters 
Time of hypertension diagnosis, inpatient/outpatient status (at start of azilsartan 
treatment), comorbidities (details, if any), medical history (details, if any), height, and 
predisposition to hypersensitivity (details, if any). 
2) Time point 
At start of azilsartan treatment 
 
 TREATMENT 
1) Surveillance parameters 
Azilsartan treatment status (dosage form, daily dose, start date, end date, and reason for 
discontinuation), concomitant medication (antihypertensives other than azilsartan)* 
treatment status (name of drug(s) if used, route of administration, daily dose, and 
treatment duration), and concomitant medication (other than antihypertensive) treatment 
status (name of drug(s) if used, route of administration, and purpose of treatment). 
*Including antihypertensives discontinued within 3 months prior to starting of azilsartan 
treatment 
2) Time points 
From start of azilsartan treatment up to 12 months later (or at discontinuation) 
 
 TEST/OBSERVATION PARAMETERS 
Data will be entered into the EDC whenever tests/observations are conducted at the various 
surveillance time points during routine clinical use. 
10.4.1 Vital Signs/Body Weight 
1) Test/observation parameters 
Pulse rate, office blood pressure (systolic/diastolic), body weight 
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2) Time points 
Measurement time points at baseline, 1 month, 2 months, 3 months, 4 months, 5 
months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, and 12 months 
(or at treatment discontinuation) 
 
10.4.2 Laboratory Tests 
1) Test parameters 
Serum creatinine, BUN, serum potassium 
2) Time points 
Test time points at baseline, 1 month, 2 months, 3 months, 4 months, 5 months, 6 
months, 7 months, 8 months, 9 months, 10 months, 11 months, and 12 months (or at 
treatment discontinuation) 
 
10.4.3 Other Observation Parameters 
1) Observation parameters 
Pregnancy status during the observation period (women only) 
2) Time points 
From start of azilsartan treatment up to 12 months later (or at discontinuation) 
 
 ADVERSE EVENTS 
1) Surveillance parameters 
Adverse events (see Table 1), adverse event terms, date of onset, seriousness and 
rationale for seriousness (see Table 2), reason for discontinuation of azilsartan, date 
outcome assessed, outcome, causal relationship to azilsartan* (see Table 3), and changes 
over time in clinically significant laboratory values related to adverse events** 
Follow-up should be performed, if possible, whenever the outcome is determined to be 
unresolved or unknown. 
Hypotension-related event, renal impairment-related events, and hyperkalaemia-related 
events should also be followed, if possible. 
*The rationale for determining no causal relationship to azilsartan should be documented. 
**Laboratory test values at the start of azilsartan treatment (before the start of azilsartan treatment), 
when adverse events occur, and when the outcome of adverse events is determined will be 
documented, if possible. 
2) Time points 
From start of azilsartan treatment up to 12 months later (or at discontinuation) 
 
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ANALYTIC PARAMETERS AND METHODS 
 PATIENT DISPOSITION-RELATED MATTERS 
The number of enrolled patients, the number of patients for whom CRFs were collected, the 
number of patients in the safety and efficacy analysis sets, the number of patients excluded 
from analysis, and the reasons for exclusion will be tabulated. 
 
 PATIENT CHARACTERISTICS 
Patient characteristics such as sex, age, disease duration, and comorbidities will be tabulated. 
 
 TREATMENT 
Azilsartan and concomitant medication (antihypertensive and non-antihypertensive) 
treatment status will be tabulated. 
 
 SAFETY INFORMATION 
 The following will be tabulated in the safety analysis set. AEs will be coded using 
MedDRA/J, and will be summarized by preferred term (PT) and system organ class (SOC). 
11.4.1 Incidence of Adverse Events 
The frequency of adverse events occurring during the observation period will be tabulated 
by type, time of onset, seriousness, and causal relationship to azilsartan, for example. 
 
11.4.2 Factors Potentially Affecting Safety 
Adverse reactions occurring during the observation period, patient characteristics (such as 
sex, age, and comorbidity), and azilsartan treatment status, for example, will be listed. 
 
 EFFICACY INFORMATION 
The following will be tabulated in the efficacy analysis set. 
11.5.1 Changes in Blood Pressure Over Time 
Blood pressure values and changes at each time point (laboratory values at each time point 
after the start of azilsartan treatment - laboratory values at the start of azilsartan treatment) 
will be tabulated. Listings will be provided when there are 2 or fewer patients in the 
efficacy analysis set. 
 
11.5.2 Factors Potentially Affecting Efficacy 
Blood pressure values, patient characteristics (such as age, sex, and comorbidity), and 
treatment (such as azilsartan treatment status, and concomitant medication 
(antihypertensive) treatment status) will be listed. 
 
 
REGISTRATION OF SURVEILLANCE INFORMATION 
Information about the present surveillance will be registered on the following public websites 
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before the start of the surveillance. 
· 
Japan Registry of Clinical Trials (jRCT) 
· 
ClinicalTrials.gov (National Institutes of Health registry of clinical trials) 
 
 
ORGANIZATIONAL STRUCTURE 
 CHART OF ORGANIZATIONAL STRUCTURE FOR POST-MARKETING SURVEILLANCE 
See attachment 
 
 
CONTRACT RESEARCH ORGANIZATIONS 
(1) 
 
 
Responsibilities: Data management, archiving of records, and post-marketing 
surveillance support 
(2) 
  
 
Responsibilities: EDC installation and management 
(3) 
 
 
Responsibilities: Statistical analysis 
(4) 
 
 
Responsibilities: Monitoring tasks 
 
 
SCHEDULE AND RATIONALE FOR MILESTONES FOR CONDUCT OF 
SURVEILLANCE AND ASSESSMENT OF RESULTS OR REPORTS TO THE 
PHARMACEUTICALS AND MEDICAL DEVICES AGENCY 
Periodic Safety Reports: for comprehensive review of safety information. 
Final tabulation: for final tabulation when data is locked after the completion of the 
observation period for all patients 
 
 
 
 
ADDITIONAL ACTION THAT MAY BE TAKEN BASED ON SURVEILLANCE 
RESULTS, AND CRITERIA FOR INITIATING SUCH ACTION 
The Risk Management Plan will be reviewed at each milestone time point based on the 
following: 
Whenever any new findings regarding the Safety Specification come to light, we will 
review whether there is any need to modify the RMP, including revisions of the package 
insert. 
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We will review whether there is any need to supplement or modify pharmacovigilance 
activities or the establishment of the RMP, including new Safety Specifications. 
 
 
OTHER REQUIREMENTS 
 PROTOCOL AMENDMENT 
In the course of the surveillance, we will assess, for example, the progress of the surveillance, 
the emergence of adverse reactions and serious adverse reactions that are unexpected based 
on the Precautions, whether there are any increases in the incidence of specific adverse 
reactions, and the appropriateness of surveillance parameters, and the protocol will be 
reviewed and amended as needed. If partial changes in the dosage and administration or 
indications are approved during the surveillance, the need for revising the protocol will be 
reviewed as necessary, and the protocol will be revised as necessary. 
 
 ACTIONS TO BE TAKEN WHEN PROBLEMS OR QUESTIONS ARE IDENTIFIED 
Whenever any safety or efficacy problems are identified, the response will be assessed upon 
a detailed examination of the data. 
 
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(b): Document antihypertensives other than azilsartan that are administered for 3 months prior to the start 
of azilsartan treatment (including antihypertensives discontinued within 3 months prior to the start of 
azilsartan treatment). 
(c): At the surveillance time points noted in 10.4.2 2), if possible. 
 
 
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Document History 
 
Version 
Date 
Comments 
original version 
September 14, 2021 
New document 
Version 2 
May 10, 2022 
13.0 
ORGANIZATIONAL STRUCTURE 
Version 3 
May 9, 2023 
1.0 
IMPLEMENTATION BACKGROUND 
4.1 
PLANNED SAMPLE SIZE 
4.2 
RATIONALE 
7.0 
PLANNED NUMBER OF SITES BY 
DEPARTMENT 
8.1 
OBSERVATION 
PERIOD 
AND 
RATIONALE 
8.3 
PATIENT ENROLLMENT METHOD 
8.4 
PREPARATION AND SUBMISSION OF 
CRFS 
9.0 
PLANNED 
DURATION 
OF 
SURVEILLANCE 
10.3 
TREATMENT 
10.4 
TEST/OBSERVATION PARAMETERS 
10.5 
ADVERSE EVENTS 
11.4 
SAFETY INFORMATION 
11.5 
EFFICACY INFORMATION 
Version 4 
May 14, 2024 
8.1 
OBSERVATION 
PERIOD 
AND 
RATIONALE 
 
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