Azilsartan/Amlodipine (Zacras) Combination Tablets LD & HD Specified Drug-use Survey "Long-term Use Survey"
Conditions: Hypertension
Sponsor: Takeda

 
 
Title: Specified Drug-Use Survey (“Long-Term Use Survey”) on Zacras Combination 
Tablets LD & HD 
 
NCT Number: NCT02181816 
Protocol Approve Date: 02-Jun-2017 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
 
 
 
 
Protocol for Specified Drug-Use Survey 
Specified Drug-Use Survey (“Long-Term Use Survey”) 
on Zacras Combination Tablets LD & HD 
 
 
 
 
 
 
 
Version number 
4th version 
Date of 
preparation 
2 June 2017 
Sponsor 
Takeda Pharmaceutical Company Limited 
 

 
Table of Contents 
1.0 
Background ................................................................................................................................................ 4 
2.0 
Objectives ................................................................................................................................................... 4 
3.0 
Planned Sample Size and Rationale ........................................................................................................... 4 
3.1 
Planned Sample Size .................................................................................................................................. 4 
3.2 
Rationale..................................................................................................................................................... 4 
4.0 
Survey Population ...................................................................................................................................... 5 
4.1 
Exclusion Criteria ....................................................................................................................................... 5 
5.0 
Dosage and Administration ........................................................................................................................ 5 
6.0 
Planned Number of Medical Institutions by Department ........................................................................... 6 
7.0 
Methods ...................................................................................................................................................... 6 
7.1 
Observation Period ..................................................................................................................................... 6 
7.2 
Request to and Contract with the Study Site .............................................................................................. 6 
7.3 
Method of Patient Registration ................................................................................................................... 6 
7.4 
Completion and Submission of Case Report Form .................................................................................... 7 
7.5 
Actions to be Taken in Case of Serious Adverse Events ............................................................................ 7 
8.0 
Planned Period ............................................................................................................................................ 7 
9.0 
Survey Items ............................................................................................................................................... 7 
9.1 
Entries into the Patient Registration Form ................................................................................................. 7 
9.2 
Entries into the Case Report Form ............................................................................................................. 8 
 
Cover of the Case Report Form .......................................................................................................... 8 
9.2.1
 
Patient Demographics and Baseline Characteristics .......................................................................... 8 
9.2.2
 
Treatment Given ................................................................................................................................. 8 
9.2.3
 
Tests/Observations .............................................................................................................................. 8 
9.2.4
 
Vital Signs .......................................................................................................................................... 8 
9.2.4.1
 
Laboratory Tests ................................................................................................................................. 9 
9.2.4.2
 
Other Observations ............................................................................................................................... 9 
9.2.4.3
 
Adverse Events (AEs) ........................................................................................................................ 9 
9.2.5
10.0 
Analysis Items and Methods .................................................................................................................... 11 
10.1 
Matters on Patient Composition ............................................................................................................... 11 
10.2 
Patient Demographics and Baseline Characteristics ................................................................................ 11 
10.3 
Treatment Given ....................................................................................................................................... 11 
10.4 
Matters on Safety ..................................................................................................................................... 11 
 
Occurrence of Adverse Events ......................................................................................................... 12 
10.4.1
 
Factors that May Affect the Safety ................................................................................................... 12 
10.4.2
10.5 
Matters on Efficacy .................................................................................................................................. 12 
 
Office Blood Pressure....................................................................................................................... 12 
10.5.1
 
Factors that May Affect the Efficacy ................................................................................................ 12 
10.5.2
11.0 
Posting of Survey Information ................................................................................................................. 12 
12.0 
Organization ............................................................................................................................................. 12 

 
12.1 
Administrative Manager ........................................................................................................................... 12 
12.2 
Central Registration Center ...................................................................................................................... 12 
13.0 
Contract Research Organization ............................................................................................................... 13 
14.0 
Other Necessary Matters .......................................................................................................................... 13 
14.1 
Revision of the Protocol ........................................................................................................................... 13 
14.2 
Actions to be Taken for Problems and Questions ..................................................................................... 13 
 
Appendix Observation schedule.................................................................................................................14 

 
4 
 
 
 
1.0 
Background 
Since drugs for hypertension are generally used for a long period of time, the safety of 
long-term use must be established. While the safety of long-term use of Zacras Combination 
Tablets LD & HD (hereinafter referred to as Zacras Combination Tablets) was already 
evaluated in a Japanese Phase III long-term clinical study (duration of treatment: 52 weeks, 
number of evaluated subjects: 368), it is necessary to evaluate the safety in more patients in 
clinical settings after marketing, a population that, unlike the study population, receive the drug 
in diverse situations. 
Accordingly, a specified drug-use survey (hereinafter referred to as the survey) is planned to 
evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice. This survey will be conducted in compliance 
with Good Post-marketing Study Practice (GPSP) ordinance and related requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
1,000 patients 
 
3.2 Rationale 
Patient populations identified as important missing information from Japanese clinical studies 
of Zacras Combination Tablets are patients with renal impairment, patients with hepatic 
impairment, and elderly patients (≥75 years old). The sample size required to evaluate the 
safety and efficacy of long-term use of Zacras Combination Tablets in these patient populations 
was calculated by reference to previous results. More specifically, according to final tabulation 
(number of patients included in safety evaluation: 3,300) in a previous specified drug-use 
survey (long-term use survey in hypertension) of a fixed-dose combination (UNISIA 
Combination Tablets) of an angiotensin receptor blocker (ARB) (candesartan) and a Ca 
antagonist (amlodipine), which belongs to the pharmacologically same class as Zacras 
Combination Tablets, patients with renal impairment, patients with hepatic impairment, and 
elderly patients (and those ≥75 years old) accounted for 6.9%, 11.5%, and 65.2% (36.8%) of all 
patients, respectively. According to final tabulation (number of patients included in safety 
evaluation: 4,152) in a drug use-results survey of candesartan alone (BLOPRESS Tablets), 
patients with renal impairment, patients with hepatic impairment, and elderly patients (and 
those ≥75 years old) accounted for 9.5%, 10.6%, and 53.2% (22.1%), respectively. With a 
target sample size of 1,000 patients for the present survey, 70 patients with renal impairment, 
100 patients with hepatic impairment, and 500 elderly patients (and 200 patients ≥75 years old) 

 
5 
 
 
 
are expected to be collected, probably allowing the safety and efficacy evaluation in these 
populations. This calculation is not based on statistical estimation. 
 
4.0 
Survey Population 
The survey population consists of hypertensive patients who do not meet any of the exclusion 
criteria listed in Section 4.1. Refer to the “Precautions for Indication” (presented below) and 
“Precautions” sections in the package insert. 
<Precautions for Indication> 
Zacras Combination Tablets should not be used as the first-line treatment of hypertension. An 
excessive drop in blood pressure may occur. 
4.1 Exclusion Criteria 
Patients who meet any of the following criteria should be excluded from the survey: 
(1) Patients with a history of hypersensitivity to any of the ingredients of Zacras Combination 
Tablets or other dihydropyridines 
(2) Patients who are or may be pregnant 
(3) Diabetic patients taking aliskiren fumarate (excluding those with markedly poor blood 
pressure control despite other antihypertensive treatments) 
 
5.0 
Dosage and Administration 
For adults, one Zacras Combination Tablet (20 mg/2.5 mg or 20 mg/5 mg of 
azilsartan/amlodipine) will be administered orally once daily. Zacras Combination Tablets 
should not be used as the first-line treatment of hypertension. Refer to the “Precautions for 
Dosage and Administration” (presented below) and “Precautions” sections in the package 
insert. 
<Precautions for Dosage and Administration> 
(1) It should be determined whether Zacras Combination Tablets are indicated for each patient 
individually based on the following Dosage and Administration and Precautions for Dosage 
and Administration of azilsartan and amlodipine besilate, as well as other relevant 
information:  
Azilsartan 
Dosage and Administration 
For adults, azilsartan 20 mg should usually be administered orally once daily. The dose 
may be increased or reduced as appropriate based on age and symptoms, with the 
maximum daily dose being 40 mg. 
Precautions for Dosage and Administration 
It should be carefully determined whether or not azilsartan is indicated while keeping the 
hypotensive effect of azilsartan in mind. Initiation of treatment at a low dose below 20 mg 
should also be considered. 
 

 
6 
 
 
 
   Amlodipine besilate 
 •Hypertension 
 Dosage and Administration 
  For adults, amlodipine 2.5 to 5 mg should usually be administered orally once daily. The 
dose may be increased or reduced as appropriate based on symptoms. In the case of 
insufficient response, the dose may be increased up to 10 mg given once daily. 
 
(2) As a general rule, switching to Zacras Combination Tablets should be considered for 
patients receiving azilsartan 20 mg with amlodipine 2.5 to 5 mg or patients with poor blood 
pressure control despite treatment with either one of these treatments. 
 
6.0 
Planned Number of Medical Institutions by Department 
Internal medicine and other departments 
Approximately 250 medical institutions 
 
7.0 
Methods 
7.1  Observation Period 
12 months 
 
7.2 Request to and Contract with the Study Site 
Request and contract for participation in the survey will be made using a paper case report form 
(CRF). A representative of Takeda Pharmaceutical Company Limited (hereinafter referred to as 
Takeda’s representative) will explain the objectives, contents, and methods of the survey to the 
investigator based on “Request for cooperation for specified drug-use survey,” 
“Implementation outline,” “Patient registration form (sample),” and “Case report form (sample)” 
to enter into a written contract with the study site and request the study site to conduct a survey 
within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration system via fax. After the start of the 
contract with the study site, the investigator shall register each patient for whom Zacras 
Combination Tablets are prescribed by faxing a patient registration form containing patient 
registration information (refer to Section 9.1) to the central registration center (refer to Section 
12.2) within 14 days after prescription of Zacras Combination Tablets (day of prescription 
designated as day 0 and day following the day of prescription designated as 1 day after 
prescription). No patient can be registered before Zacras Combination Tablets are actually 
prescribed. Patients determined by the central registration center to be ineligible for any reason 
cannot be registered. The investigator shall register a new patient using a new patient 
registration form supplied by Takeda’s representative. 
Takeda’s representative will supply a CRF, which will be issued after the central registration 

 
7 
 
 
 
center decides to register the relevant patient, to the investigator. 
 
7.4 Completion and Submission of Case Report Form 
For each of all registered patients, the investigator shall complete and submit a CRF to Takeda 
Pharmaceutical within approximately 1 month after the end of the observation period. Any 
failure to confirm the intake of Zacras Combination Tablets shall be specified (no further 
information is required). 
For patients discontinued from treatment with Zacras Combination Tablets for any reason 
during the observation period, the investigator shall complete and submit a CRF to Takeda 
Pharmaceutical within approximately 1 month after the end of required observation. For any 
patient discontinued from treatment with Zacras Combination Tablets due to an adverse event, 
the investigator shall complete and submit a CRF to Takeda Pharmaceutical after monitoring 
the patient as long after discontinuation of treatment as possible until the adverse event is 
confirmed to have resolved or be resolving. 
 
7.5 Actions to be Taken in Case of Serious Adverse Events 
The investigator shall immediately communicate any serious adverse event in the observation 
period to Takeda’s representative. In addition, the investigator shall provide detailed 
information at the request of Takeda’s representative. 
 
8.0 
Planned Period 
Survey period: From June 2014 to 31 January 2017 
Patient enrollment period: From June 2014 to 31 January 2016Note) 
 
Note) Patient registration (receipt of a patient registration form via fax) will not be accepted on 1 
February 2016 onwards even if Zacras Combination Tablets are prescribed by 31 January 
2016. 
If the number of patients enrolled in the survey reaches the planned sample size before 31 
January 2016, acceptance of registration will be terminated before the end of the patient 
enrollment period. If the patient enrollment period is shortened, the survey period will be 
changed accordingly. 
 
9.0 
Survey Items 
The investigator shall enter the items listed below into the patient registration form and the CRF. 
The survey schedule is presented in Appendix. 
9.1 Entries into the Patient Registration Form 
1) Survey items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of prescription of Zacras Combination Tablets, patient identification number, 
patient initials, sex, date of birth, assessment based on the inclusion criteria, assessment 

 
8 
 
 
 
based on the exclusion criteria, presence or absence of breast-feeding (only females) 
2) Time points of survey 
At patient registration 
 
9.2 Entries into the Case Report Form 
 Cover of the Case Report Form 
9.2.1
Date of final entry into the CRF, name of a physician who completes the CRF 
 
 Patient Demographics and Baseline Characteristics 
9.2.2
1) Survey items 
Time of diagnosis of hypertension, diagnostic category (at the start of treatment with Zacras 
Combination Tablets), predisposition to hypersensitivity (presence or absence and details), 
concurrent illness (presence or absence and details), medical history (presence or absence 
and details), height, body weight, smoking history, drinking history, presence or absence of 
breast-feeding (at the start of treatment with Zacras Combination Tablets) [only females] 
2) Time points of survey 
At the start of treatment with Zacras Combination Tablets 
 
 Treatment Given 
9.2.3
1) Survey items 
Details on the use of Zacras Combination Tablets (daily dose, duration of treatment, and 
reason for discontinuation of treatment), details on the use of other antihypertensive* 
(presence or absence, name of the drug, daily dose, and duration of treatment), details on the 
use of concomitant non-antihypertensive drug (presence or absence, name of the drug, and 
purpose of use) 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
* Period from 2 months before the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) for details on the use of other 
antihypertensive 
 
 Tests/Observations 
9.2.4
 Vital Signs 
9.2.4.1
1) Tests/observations 
Office blood pressure (systolic/diastolic), pulse rate 
2) Time points of survey 
Time points of measurement at the start of treatment with Zacras Combination Tablets and 
after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 months of treatment (or discontinuation of 

 
9 
 
 
 
treatment) 
 
 Laboratory Tests 
9.2.4.2
1) Test parameters 
White blood cell count, platelet count, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), serum creatinine, blood urea 
nitrogen (BUN), serum potassium 
2) Time points of survey 
Time points of test from the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) 
 
 Other Observations 
9.2.4.3
1) Observations 
Presence or absence of pregnancy in the observation period (only females) 
If pregnancy is detected during the observation period, treatment with Zacras Combination 
Tablets should be discontinued immediately, and Takeda’s representative should be 
informed. The investigator shall provide detailed information (including information up to 
delivery such as premature delivery, wherever possible) using a pregnancy sheet at the 
request of Takeda’s representative. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
 
 Adverse Events (AEs) 
9.2.5
1) Survey items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and 
reason for seriousness (refer to Table 2), presence or absence of discontinuation of 
treatment with Zacras Combination Tablets, date of outcome assessment, outcome, causal 
relationship to Zacras Combination Tablets* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 
* For the causal relationship to Zacras Combination Tablets, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected natural course 
of the disease, will be handled as an AE, but expected worsening of target disease should not be 
handled as an AE. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 

 
10 
 
 
 
treatment (or discontinuation of treatment) 
 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a 
drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
•Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with a drug 
•Symptoms and so forth that occur in children treated with a drug 
•Symptoms and so forth that occur as a result of occupational exposure to a drug 
•Symptoms and so forth that occur after administration of counterfeit medicines of our ethical drugs 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
•Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
•Anaphylactic shock 
•Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
•Acute renal failure 
•Malignant hypertension 
•Pulmonary hypertension 
•Convulsive seizures (including convulsion and epilepsy) 
•Pulmonary fibrosis (including interstitial 
pneumonia) 
•Agranulocytosis 
•Neuroleptic malignant syndrome / 
malignant hyperthermia 
•Aplastic anemia 
•Spontaneous abortion / stillbirth and fetal 
death 
•Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
•Confirmed or suspected transmission of 
infectious agent by a medicinal product 
•Hepatic necrosis 
•Confirmed or suspected endotoxin shock 
•Acute liver failure 
 

 
11 
 
 
 
 
Table 3 Criteria for assessing the relationship of each adverse event to Zacras Combination 
Tablets 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of the 
drug), or for which possible involvement of the drug can be argued, 
although factors other than the drug, such as underlying diseases, 
concurrent illnesses, concomitant drugs, and concomitant treatments, 
may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by 
other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal sequence 
from administration of a drug (including the course after withdrawal 
of the drug), underlying diseases, concurrent illnesses, concomitant 
drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients from whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics, including sex, age, duration of disease, 
predisposition to hypersensitivity, and concurrent illness, will be tabulated. 
 
10.3 Treatment Given 
Details on the use of Zacras Combination Tablets, details on the use of other antihypertensive, 
and details on the use of concomitant non-antihypertensive drug will be tabulated. 
 
10.4 Matters on Safety 
For the safety analysis set, data will be tabulated as described below. AEs will be coded 
according to the MedDRA/J and summarized using preferred term (PT) and system organ class 
(SOC). 
 

 
12 
 
 
 
 Occurrence of Adverse Events 
10.4.1
For AEs reported during the observation period, the incidence will be tabulated by type, time 
of onset, seriousness, and causal relationship to Zacras Combination Tablets. 
 
 Factors that May Affect the Safety 
10.4.2
For AEs reported during the observation period, the incidence will be tabulated by patient 
background factors (e.g., sex, age, presence or absence of concurrent renal impairment, 
presence or absence of concurrent hepatic impairment) and treatment given (e.g., details on 
the use of Zacras Combination Tablets, details on the use of concomitant drug). 
 
10.5 Matters on Efficacy 
For the efficacy analysis set, data will be tabulated as described below. 
 Office Blood Pressure 
10.5.1
For office blood pressure, measured value, change (measured value at each post-baseline 
time point of measurement - measured value at the start of treatment with Zacras 
Combination Tablets), and percentage change [(measured value at each time point of 
measurement - measured value at the start of treatment with Zacras Combination Tablets) ÷ 
measured value at the start of treatment with Zacras Combination Tablets × 100] at each 
time point of test will be tabulated. 
 
 Factors that May Affect the Efficacy 
10.5.2
Office blood pressure will be tabulated by patient background factors (e.g., sex, age) and 
treatment given (e.g., details on the use of Zacras Combination Tablets, details on the use of 
other antihypertensive). 
 
11.0 
Posting of Survey Information 
Takeda Pharmaceutical Company Limited will post survey information on Clinical Trials.gov 
and an open website (JAPIC-CTI*) before starting the survey.  
* Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization 
12.1 Administrative Manager 
 
Takeda Pharmaceutical Company Limited 
 
12.2 Central Registration Center 
 
PPD
PPD

 
13 
 
 
 
13.0 
Contract Research Organization 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the survey, attention will be paid to comprehend the status of progression of the survey, 
presence or absence of unexpected adverse drug reactions (ADRs)/serious ADRs (based on 
precautions), presence or absence of increased incidence of certain ADRs, and appropriateness 
of survey items, and this protocol will be reviewed and revised if necessary. If partial change to 
dosage and administration or indications is approved during the survey, the necessity of 
revising the protocol will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety or efficacy problem is detected, data will be carefully examined to discuss 
measures. 
 
PPD

 
14 
 
 
 
Appendix Observation schedule 
   Time point of survey 
 
 
Survey item 
Observation period 
At patient registration 
Start of treatment 
After 1 month of 
treatment 
After 2 months of 
treatment 
After 3 months of 
treatment 
After 4 months of 
treatment 
After 5 months of 
treatment 
After 6 months of 
treatment 
After 7 months of 
treatment 
After 8 months of 
treatment 
After 9 months of 
treatment 
After 10 months of 
treatment 
After 11 months of 
treatment 
After 12 months of 
treatment 
At discontinuation of 
treatment 
Patient registration 
Date of prescription of Zacras 
Combination Tablets 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient initials 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demographics and baseline characteristics 
Time of diagnosis of 
hypertension 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic category 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predisposition to hypersensitivity 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent illness 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment given, etc. 
Details on the use of Zacras 
Combination Tablets 
 
○ 
○ 
Details on the use of other 
antihypertensive 
 
○ 
○ 
Details on the use of concomitant 
non-antihypertensive drug 
 
○ 
○ 
Tests/observations, etc. 
Office blood pressure 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pulse rate 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
White blood cell count 
 
○ 
○ 
Platelet count 
 
○ 
○ 
AST 
 
○ 
○ 
ALT 
 
○ 
○ 

 
15 
 
 
 
γ-GTP 
 
○ 
○ 
Serum creatinine 
 
○ 
○ 
BUN 
 
○ 
○ 
Serum potassium 
 
○ 
○ 
Presence or absence of 
pregnancy (only females) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○   : Performed 
○   : Performed throughout the period 
 
 

 
 
 
 
 
Protocol for Specified Drug-Use Survey 
Specified Drug-Use Survey (“Long-Term Use Survey”) 
on Zacras Combination Tablets LD & HD 
 
 
 
 
 
 
 
Version number 
3rd version 
Date of 
preparation 
1 April 2015 
Sponsor 
Takeda Pharmaceutical Company Limited 
 

 
Table of Contents 
1.0 
Background ................................................................................................................................................ 4 
2.0 
Objectives ................................................................................................................................................... 4 
3.0 
Planned Sample Size and Rationale ........................................................................................................... 4 
3.1 
Planned Sample Size .................................................................................................................................. 4 
3.2 
Rationale..................................................................................................................................................... 4 
4.0 
Survey Population ...................................................................................................................................... 5 
4.1 
Exclusion Criteria ....................................................................................................................................... 5 
5.0 
Dosage and Administration ........................................................................................................................ 5 
6.0 
Planned Number of Medical Institutions by Department ........................................................................... 6 
7.0 
Methods ...................................................................................................................................................... 6 
7.1 
Observation Period ..................................................................................................................................... 6 
7.2 
Request to and Contract with the Study Site .............................................................................................. 6 
7.3 
Method of Patient Registration ................................................................................................................... 6 
7.4 
Completion and Submission of Case Report Form .................................................................................... 7 
7.5 
Actions to be Taken in Case of Serious Adverse Events ............................................................................ 7 
8.0 
Planned Period ............................................................................................................................................ 7 
9.0 
Survey Items ............................................................................................................................................... 7 
9.1 
Entries into the Patient Registration Form ................................................................................................. 7 
9.2 
Entries into the Case Report Form ............................................................................................................. 8 
 
Cover of the Case Report Form .......................................................................................................... 8 
9.2.1
 
Patient Demographics and Baseline Characteristics .......................................................................... 8 
9.2.2
 
Treatment Given ................................................................................................................................. 8 
9.2.3
 
Tests/Observations .............................................................................................................................. 8 
9.2.4
 
Vital Signs .......................................................................................................................................... 8 
9.2.4.1
 
Laboratory Tests ................................................................................................................................. 9 
9.2.4.2
 
Other Observations ............................................................................................................................... 9 
9.2.4.3
 
Adverse Events (AEs) ........................................................................................................................ 9 
9.2.5
10.0 
Analysis Items and Methods .................................................................................................................... 11 
10.1 
Matters on Patient Composition ............................................................................................................... 11 
10.2 
Patient Demographics and Baseline Characteristics ................................................................................ 11 
10.3 
Treatment Given ....................................................................................................................................... 11 
10.4 
Matters on Safety ..................................................................................................................................... 11 
 
Occurrence of Adverse Events ......................................................................................................... 11 
10.4.1
 
Factors that May Affect the Safety ................................................................................................... 12 
10.4.2
10.5 
Matters on Efficacy .................................................................................................................................. 12 
 
Office Blood Pressure....................................................................................................................... 12 
10.5.1
 
Factors that May Affect the Efficacy ................................................................................................ 12 
10.5.2
11.0 
Posting of Survey Information ................................................................................................................. 12 
12.0 
Organization ............................................................................................................................................. 12 

 
12.1 
Administrative Manager ........................................................................................................................... 12 
12.2 
Central Registration Center ...................................................................................................................... 12 
13.0 
Contract Research Organizations ............................................................................................................. 12 
14.0 
Other Necessary Matters .......................................................................................................................... 13 
14.1 
Revision of the Protocol ........................................................................................................................... 13 
14.2 
Actions to be Taken for Problems and Questions ..................................................................................... 13 
 
Appendix Observation schedule.................................................................................................................14 

 
4 
 
 
 
1.0 
Background 
Since drugs for hypertension are generally used for a long period of time, the safety of 
long-term use must be established. While the safety of long-term use of Zacras Combination 
Tablets LD & HD (hereinafter referred to as Zacras Combination Tablets) was already 
evaluated in a Japanese Phase III long-term clinical study (duration of treatment: 52 weeks, 
number of evaluated subjects: 368), it is necessary to evaluate the safety in more patients in 
clinical settings after marketing, a population that, unlike the study population, receive the drug 
in diverse situations. 
Accordingly, a specified drug-use survey (hereinafter referred to as the survey) is planned to 
evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice. This survey will be conducted in compliance 
with Good Post-marketing Study Practice (GPSP) ordinance and related requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
1,000 patients 
 
3.2 Rationale 
Patient populations identified as important missing information from Japanese clinical studies 
of Zacras Combination Tablets are patients with renal impairment, patients with hepatic 
impairment, and elderly patients (≥75 years old). The sample size required to evaluate the 
safety and efficacy of long-term use of Zacras Combination Tablets in these patient populations 
was calculated by reference to previous results. More specifically, according to final tabulation 
(number of patients included in safety evaluation: 3,300) in a previous specified drug-use 
survey (long-term use survey in hypertension) of a fixed-dose combination (UNISIA 
Combination Tablets) of an angiotensin receptor blocker (ARB) (candesartan) and a Ca 
antagonist (amlodipine), which belongs to the pharmacologically same class as Zacras 
Combination Tablets, patients with renal impairment, patients with hepatic impairment, and 
elderly patients (and those ≥75 years old) accounted for 6.9%, 11.5%, and 65.2% (36.8%) of all 
patients, respectively. According to final tabulation (number of patients included in safety 
evaluation: 4,152) in a drug use-results survey of candesartan alone (BLOPRESS Tablets), 
patients with renal impairment, patients with hepatic impairment, and elderly patients (and 
those ≥75 years old) accounted for 9.5%, 10.6%, and 53.2% (22.1%), respectively. With a 
target sample size of 1,000 patients for the present survey, 70 patients with renal impairment, 
100 patients with hepatic impairment, and 500 elderly patients (and 200 patients ≥75 years old) 

 
5 
 
 
 
are expected to be collected, probably allowing the safety and efficacy evaluation in these 
populations. This calculation is not based on statistical estimation. 
 
4.0 
Survey Population 
The survey population consists of hypertensive patients who do not meet any of the exclusion 
criteria listed in Section 4.1. Refer to the “Precautions for Indication” (presented below) and 
“Precautions” sections in the package insert. 
<Precautions for Indication> 
Zacras Combination Tablets should not be used as the first-line treatment of hypertension. An 
excessive drop in blood pressure may occur. 
4.1 Exclusion Criteria 
Patients who meet any of the following criteria should be excluded from the survey: 
(1) Patients with a history of hypersensitivity to any of the ingredients of Zacras Combination 
Tablets or other dihydropyridines 
(2) Patients who are or may be pregnant 
(3) Diabetic patients taking aliskiren fumarate (excluding those with markedly poor blood 
pressure control despite other antihypertensive treatments) 
 
5.0 
Dosage and Administration 
For adults, one Zacras Combination Tablet (20 mg/2.5 mg or 20 mg/5 mg of 
azilsartan/amlodipine) will be administered orally once daily. Zacras Combination Tablets 
should not be used as the first-line treatment of hypertension. Refer to the “Precautions for 
Dosage and Administration” (presented below) and “Precautions” sections in the package 
insert. 
<Precautions for Dosage and Administration> 
(1) It should be determined whether Zacras Combination Tablets are indicated for each patient 
individually based on the following Dosage and Administration and Precautions for Dosage 
and Administration of azilsartan and amlodipine besilate, as well as other relevant 
information:  
Azilsartan 
Dosage and Administration 
For adults, azilsartan 20 mg should usually be administered orally once daily. The dose 
may be increased or reduced as appropriate based on age and symptoms, with the 
maximum daily dose being 40 mg. 
Precautions for Dosage and Administration 
It should be carefully determined whether or not azilsartan is indicated while keeping the 
hypotensive effect of azilsartan in mind. Initiation of treatment at a low dose below 20 mg 
should also be considered. 
 

 
6 
 
 
 
   Amlodipine besilate 
   •Hypertension 
   Dosage and Administration 
    For adults, amlodipine 2.5 to 5 mg should usually be administered orally once daily. The 
dose may be increased or reduced as appropriate based on symptoms. In the case of 
insufficient response, the dose may be increased up to 10 mg given once daily. 
 
(2) As a general rule, switching to Zacras Combination Tablets should be considered for 
patients receiving azilsartan 20 mg with amlodipine 2.5 to 5 mg or patients with poor blood 
pressure control despite treatment with either one of these treatments. 
 
6.0 
Planned Number of Medical Institutions by Department 
Internal medicine and other departments 
Approximately 250 medical institutions 
 
7.0 
Methods 
7.1  Observation Period 
12 months 
 
7.2 Request to and Contract with the Study Site 
Request and contract for participation in the survey will be made using a paper case report form 
(CRF). A representative of Takeda Pharmaceutical Company Limited (hereinafter referred to as 
Takeda’s representative) will explain the objectives, contents, and methods of the survey to the 
investigator based on “Request for cooperation for specified drug-use survey,” 
“Implementation outline,” “Patient registration form (sample),” and “Case report form (sample)” 
to enter into a written contract with the study site and request the study site to conduct a survey 
within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration system via fax. After the start of the 
contract with the study site, the investigator shall register each patient for whom Zacras 
Combination Tablets are prescribed by faxing a patient registration form containing patient 
registration information (refer to Section 9.1) to the central registration center (refer to Section 
12.2) within 14 days after prescription of Zacras Combination Tablets (day of prescription 
designated as day 0 and day following the day of prescription designated as 1 day after 
prescription). No patient can be registered before Zacras Combination Tablets are actually 
prescribed. Patients determined by the central registration center to be ineligible for any reason 
cannot be registered. The investigator shall register a new patient using a new patient 
registration form supplied by Takeda’s representative. 
Takeda’s representative will supply a CRF, which will be issued after the central registration 

 
7 
 
 
 
center decides to register the relevant patient, to the investigator. 
 
7.4 Completion and Submission of Case Report Form 
For each of all registered patients, the investigator shall complete and submit a CRF to Takeda 
Pharmaceutical within approximately 1 month after the end of the observation period. Any 
failure to confirm the intake of Zacras Combination Tablets shall be specified (no further 
information is required). 
For patients discontinued from treatment with Zacras Combination Tablets for any reason 
during the observation period, the investigator shall complete and submit a CRF to Takeda 
Pharmaceutical within approximately 1 month after the end of required observation. For any 
patient discontinued from treatment with Zacras Combination Tablets due to an adverse event, 
the investigator shall complete and submit a CRF to Takeda Pharmaceutical after monitoring 
the patient as long after discontinuation of treatment as possible until the adverse event is 
confirmed to have resolved or be resolving. 
 
7.5 Actions to be Taken in Case of Serious Adverse Events 
The investigator shall immediately communicate any serious adverse event in the observation 
period to Takeda’s representative. In addition, the investigator shall provide detailed 
information at the request of Takeda’s representative. 
 
8.0 
Planned Period 
Survey period: From June 2014 to 31 January 2017 
Patient enrollment period: From June 2014 to 31 January 2016Note) 
 
Note) Patient registration (receipt of a patient registration form via fax) will not be accepted on 1 
February 2016 onwards even if Zacras Combination Tablets are prescribed by 31 January 
2016. 
If the number of patients enrolled in the survey reaches the planned sample size before 31 
January 2016, acceptance of registration will be terminated before the end of the patient 
enrollment period. If the patient enrollment period is shortened, the survey period will be 
changed accordingly. 
 
9.0 
Survey Items 
The investigator shall enter the items listed below into the patient registration form and the CRF. 
The survey schedule is presented in Appendix. 
9.1 Entries into the Patient Registration Form 
1) Survey items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of prescription of Zacras Combination Tablets, patient identification number, 
patient initials, sex, date of birth, assessment based on the inclusion criteria, assessment 

 
8 
 
 
 
based on the exclusion criteria, presence or absence of breast-feeding (only females) 
2) Time points of survey 
At patient registration 
 
9.2 Entries into the Case Report Form 
 Cover of the Case Report Form 
9.2.1
Date of final entry into the CRF, name of a physician who completes the CRF 
 
 Patient Demographics and Baseline Characteristics 
9.2.2
1) Survey items 
Time of diagnosis of hypertension, diagnostic category (at the start of treatment with Zacras 
Combination Tablets), predisposition to hypersensitivity (presence or absence and details), 
concurrent illness (presence or absence and details), medical history (presence or absence 
and details), height, body weight, smoking history, drinking history, presence or absence of 
breast-feeding (at the start of treatment with Zacras Combination Tablets) [only females] 
2) Time points of survey 
At the start of treatment with Zacras Combination Tablets 
 
 Treatment Given 
9.2.3
1) Survey items 
Details on the use of Zacras Combination Tablets (daily dose, duration of treatment, and 
reason for discontinuation of treatment), details on the use of other antihypertensive* 
(presence or absence, name of the drug, daily dose, and duration of treatment), details on the 
use of concomitant non-antihypertensive drug (presence or absence, name of the drug, and 
purpose of use) 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
* Period from 2 months before the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) for details on the use of other 
antihypertensive 
 
 Tests/Observations 
9.2.4
 Vital Signs 
9.2.4.1
1) Tests/observations 
Office blood pressure (systolic/diastolic), pulse rate 
2) Time points of survey 
Time points of measurement at the start of treatment with Zacras Combination Tablets and 
after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 months of treatment (or discontinuation of 

 
9 
 
 
 
treatment) 
 
 Laboratory Tests 
9.2.4.2
1) Test parameters 
White blood cell count, platelet count, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), serum creatinine, blood urea 
nitrogen (BUN), serum potassium 
2) Time points of survey 
Time points of test from the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) 
 
 Other Observations 
9.2.4.3
1) Observations 
Presence or absence of pregnancy in the observation period (only females) 
If pregnancy is detected during the observation period, treatment with Zacras Combination 
Tablets should be discontinued immediately, and Takeda’s representative should be 
informed. The investigator shall provide detailed information (including information up to 
delivery such as premature delivery, wherever possible) using a pregnancy sheet at the 
request of Takeda’s representative. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
 
 Adverse Events (AEs) 
9.2.5
1) Survey items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and 
reason for seriousness (refer to Table 2), presence or absence of discontinuation of 
treatment with Zacras Combination Tablets, date of outcome assessment, outcome, causal 
relationship to Zacras Combination Tablets* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 
* For the causal relationship to Zacras Combination Tablets, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected natural course 
of the disease, will be handled as an AE, but expected worsening of target disease should not be 
handled as an AE. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 

 
10 
 
 
 
treatment (or discontinuation of treatment) 
 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a 
drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
•Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with a drug 
•Symptoms and so forth that occur in children treated with a drug 
•Symptoms and so forth that occur as a result of occupational exposure to a drug 
•Symptoms and so forth that occur after administration of counterfeit medicines of our ethical drugs 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
•Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
•Anaphylactic shock 
•Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
•Acute renal failure 
•Malignant hypertension 
•Pulmonary hypertension 
•Convulsive seizures (including convulsion and epilepsy) 
•Pulmonary fibrosis (including interstitial 
pneumonia) 
•Agranulocytosis 
•Neuroleptic malignant syndrome / 
malignant hyperthermia 
•Aplastic anemia 
•Spontaneous abortion / stillbirth and fetal 
death 
•Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
•Confirmed or suspected transmission of 
infectious agent by a medicinal product 
•Hepatic necrosis 
•Confirmed or suspected endotoxin shock 
•Acute liver failure 
 

 
11 
 
 
 
Table 3 Criteria for assessing the relationship of each adverse event to Zacras Combination 
Tablets 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of the 
drug), or for which possible involvement of the drug can be argued, 
although factors other than the drug, such as underlying diseases, 
concurrent illnesses, concomitant drugs, and concomitant treatments, 
may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by 
other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal sequence 
from administration of a drug (including the course after withdrawal 
of the drug), underlying diseases, concurrent illnesses, concomitant 
drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients from whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics, including sex, age, duration of disease, 
predisposition to hypersensitivity, and concurrent illness, will be tabulated. 
 
10.3 Treatment Given 
Details on the use of Zacras Combination Tablets, details on the use of other antihypertensive, 
and details on the use of concomitant non-antihypertensive drug will be tabulated. 
 
10.4 Matters on Safety 
For the safety analysis set, data will be tabulated as described below. AEs will be coded 
according to the MedDRA/J and summarized using preferred term (PT) and system organ class 
(SOC). 
 
 Occurrence of Adverse Events 
10.4.1
For AEs reported during the observation period, the incidence will be tabulated by type, time 

 
12 
 
 
 
of onset, seriousness, and causal relationship to Zacras Combination Tablets. 
 
 Factors that May Affect the Safety 
10.4.2
For AEs reported during the observation period, the incidence will be tabulated by patient 
background factors (e.g., sex, age, presence or absence of concurrent renal impairment, 
presence or absence of concurrent hepatic impairment) and treatment given (e.g., details on 
the use of Zacras Combination Tablets, details on the use of concomitant drug). 
 
10.5 Matters on Efficacy 
For the efficacy analysis set, data will be tabulated as described below. 
 Office Blood Pressure 
10.5.1
For office blood pressure, measured value, change (measured value at each post-baseline 
time point of measurement - measured value at the start of treatment with Zacras 
Combination Tablets), and percentage change [(measured value at each time point of 
measurement - measured value at the start of treatment with Zacras Combination Tablets) ÷ 
measured value at the start of treatment with Zacras Combination Tablets × 100] at each 
time point of test will be tabulated. 
 
 Factors that May Affect the Efficacy 
10.5.2
Office blood pressure will be tabulated by patient background factors (e.g., sex, age) and 
treatment given (e.g., details on the use of Zacras Combination Tablets, details on the use of 
other antihypertensive). 
 
11.0 
Posting of Survey Information 
Takeda Pharmaceutical Company Limited will post survey information on Clinical Trials.gov 
and an open website (JAPIC-CTI*) before starting the survey.  
* Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization 
12.1 Administrative Manager 
 
Takeda Pharmaceutical Company Limited 
 
12.2 Central Registration Center 
 
13.0 
Contract Research Organization 
 
PPD
PPD
PPD

 
13 
 
 
 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the survey, attention will be paid to comprehend the status of progression of the survey, 
presence or absence of unexpected adverse drug reactions (ADRs)/serious ADRs (based on 
precautions), presence or absence of increased incidence of certain ADRs, and appropriateness 
of survey items, and this protocol will be reviewed and revised if necessary. If partial change to 
dosage and administration or indications is approved during the survey, the necessity of 
revising the protocol will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety or efficacy problem is detected, data will be carefully examined to discuss 
measures. 
 
PPD

 
14 
 
 
 
Appendix Observation schedule 
   Time point of survey 
 
 
Survey item 
Observation period 
At patient registration 
Start of treatment 
After 1 month of 
treatment 
After 2 months of 
treatment 
After 3 months of 
treatment 
After 4 months of 
treatment 
After 5 months of 
treatment 
After 6 months of 
treatment 
After 7 months of 
treatment 
After 8 months of 
treatment 
After 9 months of 
treatment 
After 10 months of 
treatment 
After 11 months of 
treatment 
After 12 months of 
treatment 
At discontinuation of 
treatment 
Patient registration 
Date of prescription of Zacras 
Combination Tablets 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient initials 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demographics and baseline characteristics 
Time of diagnosis of 
hypertension 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic category 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predisposition to hypersensitivity 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent illness 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment given, etc. 
Details on the use of Zacras 
Combination Tablets 
 
○ 
○ 
Details on the use of other 
antihypertensive 
 
○ 
○ 
Details on the use of concomitant 
non-antihypertensive drug 
 
○ 
○ 
Tests/observations, etc. 
Office blood pressure 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pulse rate 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
White blood cell count 
 
○ 
○ 
Platelet count 
 
○ 
○ 
AST 
 
○ 
○ 
ALT 
 
○ 
○ 

 
15 
 
 
 
γ-GTP 
 
○ 
○ 
Serum creatinine 
 
○ 
○ 
BUN 
 
○ 
○ 
Serum potassium 
 
○ 
○ 
Presence or absence of 
pregnancy (only females) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○   : Performed 
○   : Performed throughout the period 
 
 

 
 
 
 
 
Protocol for Specified Drug-Use Survey 
Specified Drug-Use Survey (“Long-Term Use Survey”) 
on Zacras Combination Tablets LD & HD 
 
 
 
 
 
 
 
Version number 
2nd version 
Date of 
preparation 
15 May 2014 
Sponsor 
Takeda Pharmaceutical Company Limited 
 

 
Table of Contents 
1.0 
Background ................................................................................................................................................ 4 
2.0 
Objectives ................................................................................................................................................... 4 
3.0 
Planned Sample Size and Rationale ........................................................................................................... 4 
3.1 
Planned Sample Size .................................................................................................................................. 4 
3.2 
Rationale..................................................................................................................................................... 4 
4.0 
Survey Population ...................................................................................................................................... 5 
4.1 
Exclusion Criteria ....................................................................................................................................... 5 
5.0 
Dosage and Administration ........................................................................................................................ 5 
6.0 
Planned Number of Medical Institutions by Department ........................................................................... 6 
7.0 
Methods ...................................................................................................................................................... 6 
7.1 
Observation Period ..................................................................................................................................... 6 
7.2 
Request to and Contract with the Study Site .............................................................................................. 6 
7.3 
Method of Patient Registration ................................................................................................................... 6 
7.4 
Completion and Submission of Case Report Form .................................................................................... 7 
7.5 
Actions to be Taken in Case of Serious Adverse Events ............................................................................ 7 
8.0 
Planned Period ............................................................................................................................................ 7 
9.0 
Survey Items ............................................................................................................................................... 7 
9.1 
Entries into the Patient Registration Form ................................................................................................. 7 
9.2 
Entries into the Case Report Form ............................................................................................................. 8 
 
Cover of the Case Report Form .......................................................................................................... 8 
9.2.1
 
Patient Demographics and Baseline Characteristics .......................................................................... 8 
9.2.2
 
Treatment Given ................................................................................................................................. 8 
9.2.3
 
Tests/Observations .............................................................................................................................. 8 
9.2.4
 
Vital Signs .......................................................................................................................................... 8 
9.2.4.1
 
Laboratory Tests ................................................................................................................................. 9 
9.2.4.2
 
Other Observations ............................................................................................................................... 9 
9.2.4.3
 
Adverse Events (AEs) ........................................................................................................................ 9 
9.2.5
10.0 
Analysis Items and Methods .................................................................................................................... 11 
10.1 
Matters on Patient Composition ............................................................................................................... 11 
10.2 
Patient Demographics and Baseline Characteristics ................................................................................ 11 
10.3 
Treatment Given ....................................................................................................................................... 11 
10.4 
Matters on Safety ..................................................................................................................................... 11 
 
Occurrence of Adverse Events ......................................................................................................... 12 
10.4.1
 
Factors that May Affect the Safety ................................................................................................... 12 
10.4.2
10.5 
Matters on Efficacy .................................................................................................................................. 12 
 
Office Blood Pressure....................................................................................................................... 12 
10.5.1
 
Factors that May Affect the Efficacy ................................................................................................ 12 
10.5.2
11.0 
Posting of Survey Information ................................................................................................................. 12 
12.0 
Organization ............................................................................................................................................. 12 

 
12.1 
Administrative Manager ........................................................................................................................... 12 
12.2 
Central Registration Center ...................................................................................................................... 12 
13.0 
Contract Research Organization ............................................................................................................... 13 
14.0 
Other Necessary Matters .......................................................................................................................... 13 
14.1 
Revision of the Protocol ........................................................................................................................... 13 
14.2 
Actions to be Taken for Problems and Questions ..................................................................................... 13 
 
Appendix Observation schedule.................................................................................................................14 

 
4 
 
 
 
1.0 
Background 
Since drugs for hypertension are generally used for a long period of time, the safety of 
long-term use must be established. While the safety of long-term use of Zacras Combination 
Tablets LD & HD (hereinafter referred to as Zacras Combination Tablets) was already 
evaluated in a Japanese Phase III long-term clinical study (duration of treatment: 52 weeks, 
number of evaluated subjects: 368), it is necessary to evaluate the safety in more patients in 
clinical settings after marketing, a population that, unlike the study population, receive the drug 
in diverse situations. 
Accordingly, a specified drug-use survey (hereinafter referred to as the survey) is planned to 
evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice. This survey will be conducted in compliance 
with Good Post-marketing Study Practice (GPSP) ordinance and related requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
1,000 patients 
 
3.2 Rationale 
Patient populations identified as important missing information from Japanese clinical studies 
of Zacras Combination Tablets are patients with renal impairment, patients with hepatic 
impairment, and elderly patients (≥75 years old). The sample size required to evaluate the 
safety and efficacy of long-term use of Zacras Combination Tablets in these patient populations 
was calculated by reference to previous results. More specifically, according to final tabulation 
(number of patients included in safety evaluation: 3,300) in a previous specified drug-use 
survey (long-term use survey in hypertension) of a fixed-dose combination (UNISIA 
Combination Tablets) of an angiotensin receptor blocker (ARB) (candesartan) and a Ca 
antagonist (amlodipine), which belongs to the pharmacologically same class as Zacras 
Combination Tablets, patients with renal impairment, patients with hepatic impairment, and 
elderly patients (and those ≥75 years old) accounted for 6.9%, 11.5%, and 65.2% (36.8%) of all 
patients, respectively. According to final tabulation (number of patients included in safety 
evaluation: 4,152) in a drug use-results survey of candesartan alone (BLOPRESS Tablets), 
patients with renal impairment, patients with hepatic impairment, and elderly patients (and 
those ≥75 years old) accounted for 9.5%, 10.6%, and 53.2% (22.1%), respectively. With a 
target sample size of 1,000 patients for the present survey, 70 patients with renal impairment, 
100 patients with hepatic impairment, and 500 elderly patients (and 200 patients ≥75 years old) 

 
5 
 
 
 
are expected to be collected, probably allowing the safety and efficacy evaluation in these 
populations. This calculation is not based on statistical estimation. 
 
4.0 
Survey Population 
The survey population consists of hypertensive patients who do not meet any of the exclusion 
criteria listed in Section 4.1. Refer to the “Precautions for Indication” (presented below) and 
“Precautions” sections in the package insert. 
<Precautions for Indication> 
Zacras Combination Tablets should not be used as the first-line treatment of hypertension. An 
excessive drop in blood pressure may occur. 
4.1 Exclusion Criteria 
Patients who meet any of the following criteria should be excluded from the survey: 
(1) Patients with a history of hypersensitivity to any of the ingredients of Zacras Combination 
Tablets or other dihydropyridines 
(2) Patients who are or may be pregnant 
(3) Diabetic patients taking aliskiren fumarate (excluding those with markedly poor blood 
pressure control despite other antihypertensive treatments) 
 
5.0 
Dosage and Administration 
For adults, one Zacras Combination Tablet (20 mg/2.5 mg or 20 mg/5 mg of 
azilsartan/amlodipine) will be administered orally once daily. Zacras Combination Tablets 
should not be used as the first-line treatment of hypertension. Refer to the “Precautions for 
Dosage and Administration” (presented below) and “Precautions” sections in the package 
insert. 
<Precautions for Dosage and Administration> 
(1) It should be determined whether Zacras Combination Tablets are indicated for each patient 
individually based on the following Dosage and Administration and Precautions for Dosage 
and Administration of azilsartan and amlodipine besilate, as well as other relevant 
information:  
Azilsartan 
Dosage and Administration 
For adults, azilsartan 20 mg should usually be administered orally once daily. The dose 
may be increased or reduced as appropriate based on age and symptoms, with the 
maximum daily dose being 40 mg. 
Precautions for Dosage and Administration 
It should be carefully determined whether or not azilsartan is indicated while keeping the 
hypotensive effect of azilsartan in mind. Initiation of treatment at a low dose below 20 mg 
should also be considered. 
 

 
6 
 
 
 
   Amlodipine besilate 
 •Hypertension 
  Dosage and Administration 
   For adults, amlodipine 2.5 to 5 mg should usually be administered orally once daily. The 
dose may be increased or reduced as appropriate based on symptoms. In the case of 
insufficient response, the dose may be increased up to 10 mg given once daily. 
 
(2) As a general rule, switching to Zacras Combination Tablets should be considered for 
patients receiving azilsartan 20 mg with amlodipine 2.5 to 5 mg or patients with poor blood 
pressure control despite treatment with either one of these treatments. 
 
6.0 
Planned Number of Medical Institutions by Department 
Internal medicine and other departments 
Approximately 250 medical institutions 
 
7.0 
Methods 
7.1  Observation Period 
12 months 
 
7.2 Request to and Contract with the Study Site 
Request and contract for participation in the survey will be made using a paper case report form 
(CRF). A medical representative of Takeda Pharmaceutical Company Limited (hereinafter 
referred to as Takeda’s MR) will explain the objectives, contents, and methods of the survey to 
the investigator based on “Request for cooperation for specified drug-use survey,” 
“Implementation outline,” “Patient registration form (sample),” and “Case report form (sample)” 
to enter into a written contract with the study site and request the study site to conduct a survey 
within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration system via fax. After the start of the 
contract with the study site, the investigator shall register each patient for whom Zacras 
Combination Tablets are prescribed by faxing a patient registration form containing patient 
registration information (refer to Section 9.1) to the central registration center (refer to Section 
12.2) within 14 days after prescription of Zacras Combination Tablets (day of prescription 
designated as day 0 and day following the day of prescription designated as 1 day after 
prescription). No patient can be registered before Zacras Combination Tablets are actually 
prescribed. Patients determined by the central registration center to be ineligible for any reason 
cannot be registered. The investigator shall register a new patient using a new patient 
registration form supplied by Takeda’s MR. 
Takeda’s MR will supply a CRF, which will be issued after the central registration center 

 
7 
 
 
 
decides to register the relevant patient, to the investigator. 
 
7.4 Completion and Submission of Case Report Form 
For each of all registered patients, the investigator shall complete and submit a CRF to Takeda’s 
MR within approximately 1 month after the end of the observation period. Any failure to 
confirm the intake of Zacras Combination Tablets shall be specified (no further information is 
required). 
For patients discontinued from treatment with Zacras Combination Tablets for any reason 
during the observation period, the investigator shall complete and submit a CRF to Takeda’s 
MR within approximately 1 month after the end of required observation. For any patient 
discontinued from treatment with Zacras Combination Tablets due to an adverse event, the 
investigator shall complete and submit a CRF to Takeda’s MR after monitoring the patient as 
long after discontinuation of treatment as possible until the adverse event is confirmed to have 
resolved or be resolving. 
 
7.5 Actions to be Taken in Case of Serious Adverse Events 
The investigator shall immediately communicate any serious adverse event in the observation 
period to Takeda’s MR. In addition, the investigator shall provide detailed information at the 
request of Takeda’s MR. 
 
8.0 
Planned Period 
Survey period: From June 2014 to 31 January 2017 
Patient enrollment period: From June 2014 to 31 January 2016Note) 
 
Note) Patient registration (receipt of a patient registration form via fax) will not be accepted on 1 
February 2016 onwards even if Zacras Combination Tablets are prescribed by 31 January 
2016. 
If the number of patients enrolled in the survey reaches the planned sample size before 31 
January 2016, acceptance of registration will be terminated before the end of the patient 
enrollment period. If the patient enrollment period is shortened, the survey period will be 
changed accordingly. 
 
9.0 
Survey Items 
The investigator shall enter the items listed below into the patient registration form and the CRF. 
The survey schedule is presented in Appendix. 
9.1 Entries into the Patient Registration Form 
1) Survey items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of prescription of Zacras Combination Tablets, patient identification number, 
patient initials, sex, date of birth, assessment based on the inclusion criteria, assessment 

 
8 
 
 
 
based on the exclusion criteria, presence or absence of breast-feeding (only females) 
2) Time points of survey 
At patient registration 
 
9.2 Entries into the Case Report Form 
 Cover of the Case Report Form 
9.2.1
Date of final entry into the CRF, name of a physician who completes the CRF 
 
 Patient Demographics and Baseline Characteristics 
9.2.2
1) Survey items 
Time of diagnosis of hypertension, diagnostic category (at the start of treatment with Zacras 
Combination Tablets), predisposition to hypersensitivity (presence or absence and details), 
concurrent illness (presence or absence and details), medical history (presence or absence 
and details), height, body weight, smoking history, drinking history, presence or absence of 
breast-feeding (at the start of treatment with Zacras Combination Tablets) [only females] 
2) Time points of survey 
At the start of treatment with Zacras Combination Tablets 
 
 Treatment Given 
9.2.3
1) Survey items 
Details on the use of Zacras Combination Tablets (daily dose, duration of treatment, and 
reason for discontinuation of treatment), details on the use of other antihypertensive* 
(presence or absence, name of the drug, daily dose, and duration of treatment), details on the 
use of concomitant non-antihypertensive drug (presence or absence, name of the drug, and 
purpose of use) 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
* Period from 2 months before the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) for details on the use of other 
antihypertensive 
 
 Tests/Observations 
9.2.4
 Vital Signs 
9.2.4.1
1) Tests/observations 
Office blood pressure (systolic/diastolic), pulse rate 
2) Time points of survey 
Time points of measurement at the start of treatment with Zacras Combination Tablets and 
after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 months of treatment (or discontinuation of 

 
9 
 
 
 
treatment) 
 
 Laboratory Tests 
9.2.4.2
1) Test parameters 
White blood cell count, platelet count, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), serum creatinine, blood urea 
nitrogen (BUN), serum potassium 
2) Time points of survey 
Time points of test from the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) 
 
 Other Observations 
9.2.4.3
1) Observations 
Presence or absence of pregnancy in the observation period (only females) 
If pregnancy is detected during the observation period, treatment with Zacras Combination 
Tablets should be discontinued immediately, and Takeda’s MR should be informed. The 
investigator shall provide detailed information (including information up to delivery such 
as premature delivery, wherever possible) using a pregnancy sheet at the request of 
Takeda’s MR. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
 
 Adverse Events (AEs) 
9.2.5
1) Survey items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and 
reason for seriousness (refer to Table 2), presence or absence of discontinuation of 
treatment with Zacras Combination Tablets, date of outcome assessment, outcome, causal 
relationship to Zacras Combination Tablets* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 
* For the causal relationship to Zacras Combination Tablets, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected natural course 
of the disease, will be handled as an AE, but expected worsening of target disease should not be 
handled as an AE. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 

 
10 
 
 
 
treatment (or discontinuation of treatment) 
 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a 
drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
•Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with a drug 
•Symptoms and so forth that occur in children treated with a drug 
•Symptoms and so forth that occur as a result of occupational exposure to a drug 
•Symptoms and so forth that occur after administration of counterfeit medicines of our ethical drugs 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
•Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
•Anaphylactic shock 
•Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
•Acute renal failure 
•Malignant hypertension 
•Pulmonary hypertension 
•Convulsive seizures (including convulsion and epilepsy) 
•Pulmonary fibrosis (including interstitial 
pneumonia) 
•Agranulocytosis 
•Neuroleptic malignant syndrome / 
malignant hyperthermia 
•Aplastic anemia 
•Spontaneous abortion / stillbirth and fetal 
death 
•Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
•Confirmed or suspected transmission of 
infectious agent by a medicinal product 
•Hepatic necrosis 
•Confirmed or suspected endotoxin shock 
•Acute liver failure 
 

 
11 
 
 
 
 
Table 3 Criteria for assessing the relationship of each adverse event to Zacras Combination 
Tablets 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of the 
drug), or for which possible involvement of the drug can be argued, 
although factors other than the drug, such as underlying diseases, 
concurrent illnesses, concomitant drugs, and concomitant treatments, 
may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by 
other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal sequence 
from administration of a drug (including the course after withdrawal 
of the drug), underlying diseases, concurrent illnesses, concomitant 
drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients from whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics, including sex, age, duration of disease, 
predisposition to hypersensitivity, and concurrent illness, will be tabulated. 
 
10.3 Treatment Given 
Details on the use of Zacras Combination Tablets, details on the use of other antihypertensive, 
and details on the use of concomitant non-antihypertensive drug will be tabulated. 
 
10.4 Matters on Safety 
For the safety analysis set, data will be tabulated as described below. AEs will be coded 
according to the MedDRA/J and summarized using preferred term (PT) and system organ class 
(SOC). 
 

 
12 
 
 
 
 Occurrence of Adverse Events 
10.4.1
For AEs reported during the observation period, the incidence will be tabulated by type, time 
of onset, seriousness, and causal relationship to Zacras Combination Tablets. 
 
 Factors that May Affect the Safety 
10.4.2
For AEs reported during the observation period, the incidence will be tabulated by patient 
background factors (e.g., sex, age, presence or absence of concurrent renal impairment, 
presence or absence of concurrent hepatic impairment) and treatment given (e.g., details on 
the use of Zacras Combination Tablets, details on the use of concomitant drug). 
 
10.5 Matters on Efficacy 
For the efficacy analysis set, data will be tabulated as described below. 
 Office Blood Pressure 
10.5.1
For office blood pressure, measured value, change (measured value at each post-baseline 
time point of measurement - measured value at the start of treatment with Zacras 
Combination Tablets), and percentage change [(measured value at each time point of 
measurement - measured value at the start of treatment with Zacras Combination Tablets) ÷ 
measured value at the start of treatment with Zacras Combination Tablets × 100] at each 
time point of test will be tabulated. 
 
 Factors that May Affect the Efficacy 
10.5.2
Office blood pressure will be tabulated by patient background factors (e.g., sex, age) and 
treatment given (e.g., details on the use of Zacras Combination Tablets, details on the use of 
other antihypertensive). 
 
11.0 
Posting of Survey Information 
Takeda Pharmaceutical Company Limited will post survey information on Clinical Trials.gov 
and an open website (JAPIC-CTI*) before starting the survey.  
* Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization 
12.1 Administrative Manager 
Takeda Pharmaceutical 
Company Limited 
 
12.2 Central Registration Center 
PPD
PPD

 
13 
 
 
 
 
13.0 
Contract Research Organization 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the survey, attention will be paid to comprehend the status of progression of the survey, 
presence or absence of unexpected adverse drug reactions (ADRs)/serious ADRs (based on 
precautions), presence or absence of increased incidence of certain ADRs, and appropriateness 
of survey items, and this protocol will be reviewed and revised if necessary. If partial change to 
dosage and administration or indications is approved during the survey, the necessity of 
revising the protocol will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety or efficacy problem is detected, data will be carefully examined to discuss 
measures. 
 
PPD

 
14 
 
 
 
Appendix Observation schedule 
   Time point of survey 
 
 
Survey item 
Observation period 
At patient registration 
Start of treatment 
After 1 month of 
treatment 
After 2 months of 
treatment 
After 3 months of 
treatment 
After 4 months of 
treatment 
After 5 months of 
treatment 
After 6 months of 
treatment 
After 7 months of 
treatment 
After 8 months of 
treatment 
After 9 months of 
treatment 
After 10 months of 
treatment 
After 11 months of 
treatment 
After 12 months of 
treatment 
At discontinuation of 
treatment 
Patient registration 
Date of prescription of Zacras 
Combination Tablets 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient initials 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demographics and baseline characteristics 
Time of diagnosis of 
hypertension 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic category 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predisposition to hypersensitivity 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent illness 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment given, etc. 
Details on the use of Zacras 
Combination Tablets 
 
○ 
○ 
Details on the use of other 
antihypertensive 
 
○ 
○ 
Details on the use of concomitant 
non-antihypertensive drug 
 
○ 
○ 
Tests/observations, etc. 
Office blood pressure 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pulse rate 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
White blood cell count 
 
○ 
○ 
Platelet count 
 
○ 
○ 
AST 
 
○ 
○ 
ALT 
 
○ 
○ 

 
15 
 
 
 
γ-GTP 
 
○ 
○ 
Serum creatinine 
 
○ 
○ 
BUN 
 
○ 
○ 
Serum potassium 
 
○ 
○ 
Presence or absence of 
pregnancy (only females) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○  : Performed 
○   : Performed throughout the period 

 
 
 
 
 
Protocol for Specified Drug-Use Survey 
Specified Drug-Use Survey (“Long-Term Use Survey”) 
on Zacras Combination Tablets LD & HD 
 
 
 
 
 
 
 
Version number 
1st version 
Date of 
preparation 
8 April 2014 
Sponsor 
Takeda Pharmaceutical Company Limited 
 

 
Table of Contents 
1.0 
Background ................................................................................................................................................ 4 
2.0 
Objectives ................................................................................................................................................... 4 
3.0 
Planned Sample Size and Rationale ........................................................................................................... 4 
3.1 
Planned Sample Size .................................................................................................................................. 4 
3.2 
Rationale..................................................................................................................................................... 4 
4.0 
Survey Population ...................................................................................................................................... 5 
4.1 
Exclusion Criteria ....................................................................................................................................... 5 
5.0 
Dosage and Administration ........................................................................................................................ 5 
6.0 
Planned Number of Medical Institutions by Department ........................................................................... 6 
7.0 
Methods ...................................................................................................................................................... 6 
7.1 
Observation Period ..................................................................................................................................... 6 
7.2 
Request to and Contract with the Study Site .............................................................................................. 6 
7.3 
Method of Patient Registration ................................................................................................................... 6 
7.4 
Completion and Submission of Case Report Form .................................................................................... 7 
7.5 
Actions to be Taken in Case of Serious Adverse Events ............................................................................ 7 
8.0 
Planned Period ............................................................................................................................................ 7 
9.0 
Survey Items ............................................................................................................................................... 7 
9.1 
Entries into the Patient Registration Form ................................................................................................. 7 
9.2 
Entries into the Case Report Form ............................................................................................................. 8 
 
Cover of the Case Report Form .......................................................................................................... 8 
9.2.1
 
Patient Demographics and Baseline Characteristics .......................................................................... 8 
9.2.2
 
Treatment Given ................................................................................................................................. 8 
9.2.3
 
Tests/Observations .............................................................................................................................. 8 
9.2.4
 
Vital Signs .......................................................................................................................................... 8 
9.2.4.1
 
Laboratory Tests ................................................................................................................................. 9 
9.2.4.2
 
Other Observations ............................................................................................................................... 9 
9.2.4.3
 
Adverse Events (AEs) ........................................................................................................................ 9 
9.2.5
10.0 
Analysis Items and Methods .................................................................................................................... 11 
10.1 
Matters on Patient Composition ............................................................................................................... 11 
10.2 
Patient Demographics and Baseline Characteristics ................................................................................ 11 
10.3 
Treatment Given ....................................................................................................................................... 11 
10.4 
Matters on Safety ..................................................................................................................................... 11 
 
Occurrence of Adverse Events ......................................................................................................... 12 
10.4.1
 
Factors that May Affect the Safety ................................................................................................... 12 
10.4.2
10.5 
Matters on Efficacy .................................................................................................................................. 12 
 
Office Blood Pressure....................................................................................................................... 12 
10.5.1
 
Factors that May Affect the Efficacy ................................................................................................ 12 
10.5.2
11.0 
Posting of Survey Information ................................................................................................................. 12 
12.0 
Organization ............................................................................................................................................. 12 

 
12.1 
Administrative Manager ........................................................................................................................... 12 
12.2 
Central Registration Center ...................................................................................................................... 12 
13.0 
Contract Research Organization ............................................................................................................... 13 
14.0 
Other Necessary Matters .......................................................................................................................... 13 
14.1 
Revision of the Protocol ........................................................................................................................... 13 
14.2 
Actions to be Taken for Problems and Questions ..................................................................................... 13 
 
Appendix Observation schedule.................................................................................................................14 

 
4 
 
 
 
1.0 
Background 
Since drugs for hypertension are generally used for a long period of time, the safety of 
long-term use must be established. While the safety of long-term use of Zacras Combination 
Tablets LD & HD (hereinafter referred to as Zacras Combination Tablets) was already 
evaluated in a Japanese Phase III long-term clinical study (duration of treatment: 52 weeks, 
number of evaluated subjects: 368), it is necessary to evaluate the safety in more patients in 
clinical settings after marketing, a population that, unlike the study population, receive the drug 
in diverse situations. 
Accordingly, a specified drug-use survey (hereinafter referred to as the survey) is planned to 
evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice. This survey will be conducted in compliance 
with Good Post-marketing Study Practice (GPSP) ordinance and related requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of long-term use of Zacras Combination Tablets in 
hypertensive patients in daily medical practice 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
1,000 patients 
 
3.2 Rationale 
Patient populations identified as important missing information from Japanese clinical studies 
of Zacras Combination Tablets are patients with renal impairment, patients with hepatic 
impairment, and elderly patients (≥75 years old). The sample size required to evaluate the 
safety and efficacy of long-term use of Zacras Combination Tablets in these patient populations 
was calculated by reference to previous results. More specifically, according to final tabulation 
(number of patients included in safety evaluation: 3,300) in a previous specified drug-use 
survey (long-term use survey in hypertension) of a fixed-dose combination (UNISIA 
Combination Tablets) of an angiotensin receptor blocker (ARB) (candesartan) and a Ca 
antagonist (amlodipine), which belongs to the pharmacologically same class as Zacras 
Combination Tablets, patients with renal impairment, patients with hepatic impairment, and 
elderly patients (and those ≥75 years old) accounted for 6.9%, 11.5%, and 65.2% (36.8%) of all 
patients, respectively. According to final tabulation (number of patients included in safety 
evaluation: 4,152) in a drug use-results survey of candesartan alone (BLOPRESS Tablets), 
patients with renal impairment, patients with hepatic impairment, and elderly patients (and 
those ≥75 years old) accounted for 9.5%, 10.6%, and 53.2% (22.1%), respectively. With a 
target sample size of 1,000 patients for the present survey, 70 patients with renal impairment, 
100 patients with hepatic impairment, and 500 elderly patients (and 200 patients ≥75 years old) 

 
5 
 
 
 
are expected to be collected, probably allowing the safety and efficacy evaluation in these 
populations. This calculation is not based on statistical estimation. 
 
4.0 
Survey Population 
The survey population consists of hypertensive patients who do not meet any of the exclusion 
criteria listed in Section 4.1. Refer to the “Precautions for Indication” (presented below) and 
“Precautions” sections in the package insert. 
<Precautions for Indication> 
Zacras Combination Tablets should not be used as the first-line treatment of hypertension. An 
excessive drop in blood pressure may occur. 
4.1 Exclusion Criteria 
Patients who meet any of the following criteria should be excluded from the survey: 
(1) Patients with a history of hypersensitivity to any of the ingredients of Zacras Combination 
Tablets or other dihydropyridines 
(2) Patients who are or may be pregnant 
(3) Diabetic patients taking aliskiren fumarate (excluding those with markedly poor blood 
pressure control despite other antihypertensive treatments) 
 
5.0 
Dosage and Administration 
For adults, one Zacras Combination Tablet (20 mg/2.5 mg or 20 mg/5 mg of 
azilsartan/amlodipine) will be administered orally once daily. Zacras Combination Tablets 
should not be used as the first-line treatment of hypertension. Refer to the “Precautions for 
Dosage and Administration” (presented below) and “Precautions” sections in the package 
insert. 
<Precautions for Dosage and Administration> 
(1) It should be determined whether Zacras Combination Tablets are indicated for each patient 
individually based on the following Dosage and Administration and Precautions for Dosage 
and Administration of azilsartan and amlodipine besilate, as well as other relevant 
information:  
Azilsartan 
Dosage and Administration 
For adults, azilsartan 20 mg should usually be administered orally once daily. The dose may 
be increased or reduced as appropriate based on age and symptoms, with the maximum 
daily dose being 40 mg. 
Precautions for Dosage and Administration 
It should be carefully determined whether or not azilsartan is indicated while keeping the 
hypotensive effect of azilsartan in mind. Initiation of treatment at a low dose below 20 mg 
should also be considered. 
 

 
6 
 
 
 
   Amlodipine besilate 
   •Hypertension 
Dosage and Administration 
   For adults, amlodipine 2.5 to 5 mg should usually be administered orally once daily. The 
dose may be increased or reduced as appropriate based on symptoms. In the case of 
insufficient response, the dose may be increased up to 10 mg given once daily. 
 
(2) As a general rule, switching to Zacras Combination Tablets should be considered for 
patients receiving azilsartan 20 mg with amlodipine 2.5 to 5 mg or patients with poor blood 
pressure control despite treatment with either one of these treatments. 
 
6.0 
Planned Number of Medical Institutions by Department 
Internal medicine and other departments 
Approximately 250 medical institutions 
 
7.0 
Methods 
7.1  Observation Period 
12 months 
 
7.2 Request to and Contract with the Study Site 
Request and contract for participation in the survey will be made using a paper case report form 
(CRF). A medical representative of Takeda Pharmaceutical Company Limited (hereinafter 
referred to as Takeda’s MR) will explain the objectives, contents, and methods of the survey to 
the investigator based on “Request for cooperation for specified drug-use survey,” 
“Implementation outline,” “Patient registration form (sample),” and “Case report form (sample)” 
to enter into a written contract with the study site and request the study site to conduct a survey 
within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration system via fax. After the start of the 
contract with the study site, the investigator shall register each patient for whom Zacras 
Combination Tablets are prescribed by faxing a patient registration form containing patient 
registration information (refer to Section 9.1) to the central registration center (refer to Section 
12.2) within 14 days after prescription of Zacras Combination Tablets (day of prescription 
designated as day 0 and day following the day of prescription designated as 1 day after 
prescription). No patient can be registered before Zacras Combination Tablets are actually 
prescribed. Patients determined by the central registration center to be ineligible for any reason 
cannot be registered. The investigator shall register a new patient using a new patient 
registration form supplied by Takeda’s MR. 
Takeda’s MR will supply a CRF, which will be issued after the central registration center 

 
7 
 
 
 
decides to register the relevant patient, to the investigator. 
 
7.4 Completion and Submission of Case Report Form 
For each of all registered patients, the investigator shall complete and submit a CRF to Takeda’s 
MR within approximately 1 month after the end of the observation period. Any failure to 
confirm the intake of Zacras Combination Tablets shall be specified (no further information is 
required). 
For patients discontinued from treatment with Zacras Combination Tablets for any reason 
during the observation period, the investigator shall complete and submit a CRF to Takeda’s 
MR within approximately 1 month after the end of required observation. For any patient 
discontinued from treatment with Zacras Combination Tablets due to an adverse event, the 
investigator shall complete and submit a CRF to Takeda’s MR after monitoring the patient as 
long after discontinuation of treatment as possible until the adverse event is confirmed to have 
resolved or be resolving. 
 
7.5 Actions to be Taken in Case of Serious Adverse Events 
The investigator shall immediately communicate any serious adverse event in the observation 
period to Takeda’s MR. In addition, the investigator shall provide detailed information at the 
request of Takeda’s MR. 
 
8.0 
Planned Period 
Survey period: From June 2014 to 31 January 2017 
Patient enrollment period: From June 2014 to 31 January 2016Note) 
 
Note) Patient registration (receipt of a patient registration form via fax) will not be accepted on 1 
February 2016 onwards even if Zacras Combination Tablets are prescribed by 31 January 
2016. 
If the number of patients enrolled in the survey reaches the planned sample size before 31 
January 2016, acceptance of registration will be terminated before the end of the patient 
enrollment period. If the patient enrollment period is shortened, the survey period will be 
changed accordingly. 
 
9.0 
Survey Items 
The investigator shall enter the items listed below into the patient registration form and the CRF. 
The survey schedule is presented in Appendix. 
9.1 Entries into the Patient Registration Form 
1) Survey items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of prescription of Zacras Combination Tablets, patient identification number, 
patient initials, sex, date of birth, assessment based on the inclusion criteria, assessment 

 
8 
 
 
 
based on the exclusion criteria, presence or absence of breast-feeding (only females) 
2) Time points of survey 
At patient registration 
 
9.2 Entries into the Case Report Form 
 Cover of the Case Report Form 
9.2.1
Date of final entry into the CRF, name of a physician who completes the CRF 
 
 Patient Demographics and Baseline Characteristics 
9.2.2
1) Survey items 
Time of diagnosis of hypertension, diagnostic category (at the start of treatment with Zacras 
Combination Tablets), predisposition to hypersensitivity (presence or absence and details), 
concurrent illness (presence or absence and details), medical history (presence or absence 
and details), height, body weight, smoking history, drinking history, presence or absence of 
breast-feeding (at the start of treatment with Zacras Combination Tablets) [only females] 
2) Time points of survey 
At the start of treatment with Zacras Combination Tablets 
 
 Treatment Given 
9.2.3
1) Survey items 
Details on the use of Zacras Combination Tablets (daily dose, duration of treatment, and 
reason for discontinuation of treatment), details on the use of other antihypertensive* 
(presence or absence, name of the drug, daily dose, and duration of treatment), details on the 
use of concomitant non-antihypertensive drug (presence or absence, name of the drug, and 
purpose of use) 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
* Period from 2 months before the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) for details on the use of other 
antihypertensive 
 
 Tests/Observations 
9.2.4
 Vital Signs 
9.2.4.1
1) Tests/observations 
Office blood pressure (systolic/diastolic), pulse rate 
2) Time points of survey 
Time points of measurement at the start of treatment with Zacras Combination Tablets and 
after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 months of treatment (or discontinuation of 

 
9 
 
 
 
treatment) 
 
 Laboratory Tests 
9.2.4.2
1) Test parameters 
White blood cell count, platelet count, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), serum creatinine, blood urea 
nitrogen (BUN), serum potassium 
2) Time points of survey 
Time points of test from the start of treatment with Zacras Combination Tablets to 12 
months of treatment (or discontinuation of treatment) 
 
 Other Observations 
9.2.4.3
1) Observations 
Presence or absence of pregnancy in the observation period (only females) 
If pregnancy is detected during the observation period, treatment with Zacras Combination 
Tablets should be discontinued immediately, and Takeda’s MR should be informed. The 
investigator shall provide detailed information (including information up to delivery such 
as premature delivery, wherever possible) using a pregnancy sheet at the request of 
Takeda’s MR. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 
treatment (or discontinuation of treatment) 
 
 Adverse Events (AEs) 
9.2.5
1) Survey items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and 
reason for seriousness (refer to Table 2), presence or absence of discontinuation of 
treatment with Zacras Combination Tablets, date of outcome assessment, outcome, causal 
relationship to Zacras Combination Tablets* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 
* For the causal relationship to Zacras Combination Tablets, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected natural course 
of the disease, will be handled as an AE, but expected worsening of target disease should not be 
handled as an AE. 
2) Time points of survey 
Period from the start of treatment with Zacras Combination Tablets to 12 months of 

 
10 
 
 
 
treatment (or discontinuation of treatment) 
 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a 
drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
•Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with a drug 
•Symptoms and so forth that occur in children treated with a drug 
•Symptoms and so forth that occur as a result of occupational exposure to a drug 
•Symptoms and so forth that occur after administration of counterfeit medicines of our ethical drugs 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
•Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
•Anaphylactic shock 
•Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
•Acute renal failure 
•Malignant hypertension 
•Pulmonary hypertension 
•Convulsive seizures (including convulsion and epilepsy) 
•Pulmonary fibrosis (including interstitial 
pneumonia) 
•Agranulocytosis 
•Neuroleptic malignant syndrome / 
malignant hyperthermia 
•Aplastic anemia 
•Spontaneous abortion / stillbirth and fetal 
death 
•Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
•Confirmed or suspected transmission of 
infectious agent by a medicinal product 
•Hepatic necrosis 
•Confirmed or suspected endotoxin shock 
•Acute liver failure 
 

 
11 
 
 
 
 
Table 3 Criteria for assessing the relationship of each adverse event to Zacras Combination 
Tablets 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of the 
drug), or for which possible involvement of the drug can be argued, 
although factors other than the drug, such as underlying diseases, 
concurrent illnesses, concomitant drugs, and concomitant treatments, 
may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by 
other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal sequence 
from administration of a drug (including the course after withdrawal 
of the drug), underlying diseases, concurrent illnesses, concomitant 
drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients from whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics, including sex, age, duration of disease, 
predisposition to hypersensitivity, and concurrent illness, will be tabulated. 
 
10.3 Treatment Given 
Details on the use of Zacras Combination Tablets, details on the use of other antihypertensive, 
and details on the use of concomitant non-antihypertensive drug will be tabulated. 
 
10.4 Matters on Safety 
For the safety analysis set, data will be tabulated as described below. AEs will be coded 
according to the MedDRA/J and summarized using preferred term (PT) and system organ class 
(SOC). 
 

 
12 
 
 
 
 Occurrence of Adverse Events 
10.4.1
For AEs reported during the observation period, the incidence will be tabulated by type, time 
of onset, seriousness, and causal relationship to Zacras Combination Tablets. 
 
 Factors that May Affect the Safety 
10.4.2
For AEs reported during the observation period, the incidence will be tabulated by patient 
background factors (e.g., sex, age, presence or absence of concurrent renal impairment, 
presence or absence of concurrent hepatic impairment) and treatment given (e.g., details on 
the use of Zacras Combination Tablets, details on the use of concomitant drug). 
 
10.5 Matters on Efficacy 
For the efficacy analysis set, data will be tabulated as described below. 
 Office Blood Pressure 
10.5.1
For office blood pressure, measured value, change (measured value at each post-baseline 
time point of measurement - measured value at the start of treatment with Zacras 
Combination Tablets), and percentage change [(measured value at each time point of 
measurement - measured value at the start of treatment with Zacras Combination Tablets) ÷ 
measured value at the start of treatment with Zacras Combination Tablets × 100] at each 
time point of test will be tabulated. 
 
 Factors that May Affect the Efficacy 
10.5.2
Office blood pressure will be tabulated by patient background factors (e.g., sex, age) and 
treatment given (e.g., details on the use of Zacras Combination Tablets, details on the use of 
other antihypertensive). 
 
11.0 
Posting of Survey Information 
Takeda Pharmaceutical Company Limited will post survey information on Clinical Trials.gov 
and an open website (JAPIC-CTI*) before starting the survey.  
* Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization 
12.1 Administrative Manager 
Takeda Pharmaceutical 
Company Limited 
 
12.2 Central Registration Center 
PPD
PPD

 
13 
 
 
 
 
13.0 
Contract Research Organization 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the survey, attention will be paid to comprehend the status of progression of the survey, 
presence or absence of unexpected adverse drug reactions (ADRs)/serious ADRs (based on 
precautions), presence or absence of increased incidence of certain ADRs, and appropriateness 
of survey items, and this protocol will be reviewed and revised if necessary. If partial change to 
dosage and administration or indications is approved during the survey, the necessity of 
revising the protocol will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety or efficacy problem is detected, data will be carefully examined to discuss 
measures. 
 
PPD

 
14 
 
 
 
Appendix Observation schedule 
   Time point of survey 
 
 
Survey item 
Observation period 
At patient registration 
Start of treatment 
After 1 month of 
treatment 
After 2 months of 
treatment 
After 3 months of 
treatment 
After 4 months of 
treatment 
After 5 months of 
treatment 
After 6 months of 
treatment 
After 7 months of 
treatment 
After 8 months of 
treatment 
After 9 months of 
treatment 
After 10 months of 
treatment 
After 11 months of 
treatment 
After 12 months of 
treatment 
At discontinuation of 
treatment 
Patient registration 
Date of prescription of Zacras 
Combination Tablets 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient initials 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demographics and baseline characteristics 
Time of diagnosis of 
hypertension 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic category 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predisposition to hypersensitivity 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent illness 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence or absence of 
breast-feeding (only females) 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment given, etc. 
Details on the use of Zacras 
Combination Tablets 
 
○ 
○ 
Details on the use of other 
antihypertensive 
 
○ 
○ 
Details on the use of concomitant 
non-antihypertensive drug 
 
○ 
○ 
Tests/observations, etc. 
Office blood pressure 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pulse rate 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
White blood cell count 
 
○ 
○ 
Platelet count 
 
○ 
○ 
AST 
 
○ 
○ 
ALT 
 
○ 
○ 

 
15 
 
 
 
γ-GTP 
 
○ 
○ 
Serum creatinine 
 
○ 
○ 
BUN 
 
○ 
○ 
Serum potassium 
 
○ 
○ 
Presence or absence of 
pregnancy (only females) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○   : Performed 
○   : Performed throughout the period