Drug Use Surveillance of Takecab Tablets for "Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis"
Conditions: Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis
Sponsor: Takeda

 
 
Title: Drug Use Surveillance of Vonoprazan for "Gastric Ulcer, Duodenal Ulcer, and 
Reflux Esophagitis" 
 
NCT Number: NCT03214952 
Protocol Approve Date: 03-APR-2018 
 
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. 

 
 
 
 
 
Drug Use Surveillance Protocol 
Drug Use Surveillance for Takecab Tablets 
Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5001 
Version No. 
Version 7 
Preparation date 
April 3, 2018 
 

 
Table of Contents 
1.0 
Background ...................................................................................................................................................... 1 
2.0 
Objective .......................................................................................................................................................... 1 
3.0 
Planned sample size and justification .............................................................................................................. 1 
3.1 
Planned sample size .................................................................................................................................... 1 
3.2 
Justification ................................................................................................................................................ 1 
4.0 
Subject patients ................................................................................................................................................ 2 
5.0 
Dosage and administration ............................................................................................................................... 2 
6.0 
Planned number of medical institutions by department ................................................................................... 2 
7.0 
Methods ........................................................................................................................................................... 2 
7.1 
Duration of observation .............................................................................................................................. 2 
7.2 
Requests to, and agreements with, study sites ............................................................................................ 2 
7.3 
Patient registration ...................................................................................................................................... 3 
7.4 
Data entry in the surveillance form (electronic) and electronic signature .................................................. 3 
7.5 
Measures to be taken in case of serious adverse events ............................................................................. 4 
8.0 
Scheduled period.............................................................................................................................................. 4 
9.0 
Items for surveillance ....................................................................................................................................... 4 
9.1 
Patient enrollment ....................................................................................................................................... 4 
9.2 
Patient demographic information ............................................................................................................... 4 
9.3 
Treatment information ................................................................................................................................ 5 
9.4 
Items for examination and observation....................................................................................................... 5 
9.4.1 
Endoscopy ............................................................................................................................................. 5 
9.4.2 
Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early satiety, 
epigastralgia, epigastric burning, sensation of abdominal distention, nausea/vomiting, burping, 
anorexia)................................................................................................................................................ 5 
9.4.3 
Liver function test ................................................................................................................................. 6 
9.4.4 
Other items for observation ................................................................................................................... 6 
9.5 
Adverse events............................................................................................................................................ 6 
10.0 
Analysis items and methods........................................................................................................................... 10 
10.1 
Items concerning study population composition ...................................................................................... 10 
10.2 
Patient demographics................................................................................................................................ 10 
10.3 
Treatment details ...................................................................................................................................... 10 
10.4 
Matters concerning the safety ................................................................................................................... 10 
10.4.1 
Factors of onset of adverse events ....................................................................................................... 10 
10.4.2 
Factors that may affect the safety ........................................................................................................ 10 
10.5 
Matters concerning the safety ................................................................................................................... 11 
10.5.1 
Endoscopic cure rate ........................................................................................................................... 11 
10.5.2 
Subjective symptom amelioration rate ................................................................................................ 11 
10.5.3 
Factors that may affect the efficacy ..................................................................................................... 11 
11.0 
Surveillance information registry .................................................................................................................. 11 

 
12.0 
Organizational structure ................................................................................................................................. 11 
12.1 
Manager .................................................................................................................................................... 11 
13.0 
Contract research organization....................................................................................................................... 11 
14.0 
Other requirements ........................................................................................................................................ 12 
14.1 
Protocol revisions ..................................................................................................................................... 12 
14.2 
Measures to be taken in the event of problematic or doubtful issues ....................................................... 12 
 
Appendix Schedule of observations............................................................................................................................13 

 
1 
1.0 
Background 
The safety of Takecab Tablets 20 mg in the treatment of gastric ulcer, duodenal ulcer, and reflux 
esophagitis has been assessed in Japanese clinical studies in 244, 183, and 988 patients, 
respectively, showing no remarkable problems. In postmarketing routine practices, however, 
unlike in the clinical studies, the drug may be used in patients with various complications and 
patients receiving multiple concomitant drugs, which means that the possibility of onset of 
unexpected adverse drug reactions cannot be ruled out based on the results of the clinical studies. 
Hence, we planned a drug use surveillance (hereinafter referred to as this surveillance) study to 
assess the safety and efficacy of Takecab Tablets in the three acid-related diseases gastric ulcer, 
duodenal ulcer, and reflux esophagitis in actual routine practices. 
This surveillance will be conducted in compliance with the MHLW Ministerial Ordinance on 
GPSP and other related regulatory requirements. 
 
2.0 
Objective 
To assess the safety and efficacy of Takecab Tablets in patients with gastric ulcer, duodenal ulcer, 
and reflux esophagitis in actual use settings and routine practices. 
 
3.0 
Planned sample size and justification 
3.1 Planned sample size 
3,000 Patients 
The sample size will not be less than 500 patients for each of gastric ulcer and duodenal ulcer, 
and will not be less than 1,000 patients for reflux esophagitis. 
 
3.2 Justification 
Gastric ulcer, duodenal ulcer, and reflux esophagitis all share the same pathologic feature that 
gastrointestinal mucosal injury is caused by gastric acid. Duration of treatment in Japanese 
clinical studies of Takecab Tablets in various patient populations with each disease was roughly 
the same for gastric ulcer and reflux esophagitis (up to 8 weeks) and duodenal ulcer (up to 6 
weeks), and incidences and severity of adverse drug reactions and safety profiles for adverse 
drug reactions with high incidences were similar. 
Based on the above facts, a drug use-results surveillance study will be conducted with a planned 
sample size of 3,000 patients with the three acid-related diseases of gastric ulcer, duodenal ulcer, 
and reflux esophagitis. With regard to the minimum sample size allowing the safety of Takecab 
Tablets to be assessed in patients with each disease, we have decided to enroll at least 500 
patients with gastric ulcer and duodenal ulcer. Since the number of patients with reflux 
esophagitis has been increasing rapidly year by year in Japan, and the disease is considered to 
affect the largest number of patients for whom Takecab Tablets is indicated, we have decided to 
enroll at least 1,000 patients with reflux esophagitis. Hence, incidences and severity of adverse 
drug reactions and differences in major adverse drug reactions in actual use settings and routine 
practices seem to be assessable by disease (the sample size was not statistically calculated). 

 
2 
 
4.0 
Subject patients 
Patients with gastric ulcer, duodenal ulcer, and reflux esophagitis will be enrolled. However, the 
subjects should not meet any of the exclusion criteria shown below. Refer to the Precautions in 
the package insert. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the subjects of this 
surveillance. 
1) Patients with a past medical history of hypersensitivity to any of the ingredients of 
Takecab Tablets 
2) Patients on treatment with atazanavir sulfate or rilpivirine hydrochloride 
3) When the target disease for Takecab Tablets is gastric ulcer or duodenal ulcer, patients 
whose endoscopic stage classification by Sakita and Miwa at the start of treatment with 
Takecab Tablets is the scarring stage (S1, S2) 
4) When the target disease for Takecab Tablets is reflux esophagitis, patients whose rating 
by the Los Angeles Classification of Gastroesophageal Reflux Disease (modified by 
Hoshihara) at the start of treatment with Takecab Tablets is Grade N or Grade M 
 
5.0 
Dosage and administration 
The usual adult dosage is 20 mg of vonoprazan administered orally once daily. Usually, the 
duration of treatment should be up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal 
ulcer. For reflux esophagitis, the duration of treatment should usually be up to 4 weeks; if the 
effect is insufficient, however, the drug can be administered for up to 8 weeks. Refer to the 
Precautions in the package insert. 
 
6.0 
Planned number of medical institutions by department 
Gastroenterology and other departments: About 500 medical institutions 
 
7.0 
Methods 
7.1 Duration of observation 
Duration of observation will be 8 weeks for gastric ulcer and reflux esophagitis and 6 weeks for 
duodenal ulcer. 
However, if treatment with Takecab Tablets is completed with the goal of treatment attained, or 
treatment with Takecab Tablets is discontinued for any reason, the surveillance will be ended at 
that time. 
 
7.2 Requests to, and agreements with, study sites 
Requests to, and agreements with, study sites will be made using a web-based electronic data 
collection system (
). Prior to starting this surveillance, an officer of Takeda 
Pharmaceutical Company Limited (hereinafter referred to as Takeda officer) will provide the 
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3 
surveillance investigator with an explanation about the objective and contents of this 
surveillance, 
 operating procedures, electronic signature, user ID, and handling of 
passwords using the documents “Request for Your Cooperation in Drug Use-Results 
Surveillance,” “Implementation Guideline,” “Input Screen Image,” and “
 Operating 
Manual (Abridged Edition)” and conclude written agreements with the study site to ask it to 
conduct the surveillance within the specified surveillance period. 
 
7.3 Patient registration 
“Central registration” based on 
 will be used. For the patients with Takecab Tablets 
prescribed on or after the starting day of the period of agreements with the study site, the 
surveillance investigator will enter patient enrollment information (refer to Section 9.1) into 
 and will provide an electronic signature not later than 14 days after the day of 
prescribing Takecab Tablets (the prescribing day is defined as “Day 0” and the day after the 
prescribing day as “Day 1”). 
 
7.4 Data entry in the surveillance form (electronic) and electronic signature 
For all the patients enrolled, the surveillance investigator or a person designated by the 
surveillance investigator* will enter patient characteristics information, treatment information, 
and other information into 
 and the surveillance investigator will provide an 
electronic signature generally within 1 month after the end of the observation period for each 
patient. If Takecab Tablets are not confirmed to have actually been taken, this fact will be entered 
(no other items need to be entered). 
For the patients who have discontinued Takecab Tablets for any reason during the observation 
period, the surveillance investigator or a person designated by the surveillance investigator will 
enter patient characteristics information, treatment information, and other information into 
 and the surveillance investigator will provide an electronic signature generally 
within 1 month after completion of the observations required. For the patients who have 
discontinued Takecab Tablets because of development of any adverse event, however, the 
surveillance investigator will continue observations until the adverse event resolves or remits 
whenever possible after treatment discontinuation, the surveillance investigator or a person 
designated by the surveillance investigator will enter the observation results into 
 
and the surveillance investigator will provide an electronic signature. 
 
*The person designated by the surveillance investigator will be a person belonging to the 
medical institution (including those who have contract agreements with a medical institution 
such as a contract research organization (CRO)). The physicians who are the surveillance 
directors (one will be appointed for each study site or its department at the time of conclusion 
of contract agreements) will prepare records of the designees and designation dates and 
(whatever the form is) provide a signature or a signature and a seal, and submit the records to a 
Takeda officer before the person designated by the surveillance investigator enters data into 
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7.5 Measures to be taken in case of serious adverse events 
If any serious adverse event develops during the observation period, the surveillance 
investigator will immediately notify this fact to a Takeda officer. Upon request from a Takeda 
officer, the surveillance investigator will separately provide detailed information. 
 
8.0 
Scheduled period 
Surveillance period: March 2016 to October 31, 2018 
Accrual period: March 2016 to August 31, 2018Note) 
Note) Even for the patients with Takecab Tablets prescribed by August 31, 2018, patient 
enrollment (data entry in
) will not be accepted on and after September 1, 2018. 
If the number of enrolled patients reaches the planned sample size for this surveillance as a 
whole before August 31, 2018, registration will be terminated before the end of the patient 
accrual period. If the patient accrual period is shortened, the overall surveillance period will 
be changed in proportion to the shortage. 
In addition, enrollment may be subject to limitations for each target diseasebefore 
August 31, 2018 in view of the enrollment status for each target disease. 
 
9.0 
Items for surveillance 
The surveillance investigator or a person designated by the surveillance investigator will enter 
information on the items shown below into
: The schedule for this surveillance is 
shown in the Appendix. 
9.1 Patient enrollment 
1) Items for surveillance 
Date of prescribing Takecab Tablets, patient ID No., initialized patient name, sex, date of 
birth, target disease for Takecab Tablets, exclusion criteria ratings 
2) Surveillance times 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Items for surveillance 
Date of diagnosing the target disease, Inpatient/outpatient classification (from the start of 
treatment with Takecab Tablets), predisposition to hypersensitivity (presence/absence and 
details), complications (presence/absence and details), past medical history of gastric 
ulcer/duodenal ulcer/reflux esophagitis (presence/absence and details), height, body weight, 
presence/absence of Helicobacter pylori infection (from the start of treatment with Takecab 
Tablets), presence/absence of esophageal hiatal hernia, smoking history, drinking history, 
treatments prior to the start of Takecab Tablets [presence/absence, names of drugs, doses 
(excluding H2 blockers), and duration of treatment] 
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5 
2) Surveillance times 
At the start of treatment with Takecab Tablets 
 
9.3 Treatment information 
1) Items for surveillance 
Use of Takecab Tablets (daily dose, duration of treatment, and reason for treatment 
discontinuation), use of concomitant drugs (presence/absence, names of drugs, and purpose 
of administration) 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance will 
be at the time of treatment discontinuation. 
 
9.4 Items for examination and observation 
9.4.1 Endoscopy 
1) Items for examination 
Endoscopy (check date and findings*1) 
*1: Gastric ulcer and duodenal ulcer will be assessed using the endoscopic stage classification by 
Sakita and Miwa, and reflux esophagitis will be assessed using the classification of mucosal 
injuries according to the Los Angeles Classification of Gastroesophageal Reflux Disease 
(modified by Hoshihara). 
2) Surveillance times 
Examination time points at the start of treatment with Takecab Tablets*2 and the end of the 
surveillance*3 
*2: The time point will be essentially between 7 days before the start of treatment and the day of the 
start of treatment. 
*3: The time point will be essentially until 14 days after Week 8 for gastric ulcer and reflux esophagitis 
and after Week 6 for duodenal ulcer. If Takecab Tablets are discontinued before these times, the 
time point will be essentially until 14 days after treatment discontinuation. 
 
9.4.2 Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early 
satiety, epigastralgia, epigastric burning, sensation of abdominal distention, 
nausea/vomiting, burping, anorexia) 
1) Items for observation 
Subjective symptoms (presence/absence and severity*1) 
*1: Mild: Occasionally or slightly symptomatic. 
Moderate: Considerably symptomatic. 
Severe: Unendurably symptomatic. 
2) Surveillance times 

 
6 
Interview time points at the start of treatment with Takecab Tablets, at Week 2, at Week 4, 
and at the end of the surveillance*2. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the 
surveillance will be at the time of treatment discontinuation. 
 
9.4.3 Liver function test 
1) Parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Surveillance times 
Examination time points from the start of treatment with Takecab Tablets*1 to the end of 
the surveillance*2 
*1: Within 1 month before the start of treatment. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.4 Other items for observation 
1) Items for observation 
Presence/absence of pregnancy during the observation period (for women only) 
If the subject is found to be pregnant during the observation period, this fact should 
immediately be notified to a Takeda officer. Upon request by the Takeda officer, the 
surveillance investigator will provide detailed information (including information up to 
delivery, including details of premature birth and other outcomes) separately using a 
pregnant-woman sheet. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.5 Adverse events 
1) Items for surveillance 
Presence/absence of adverse events (see Table 1), names of adverse events, onset days, 
seriousness and rationale for the seriousness rating (see Table 2), cause of discontinuation 
of Takecab Tablets, outcome determination day, outcome, causality with Takecab Tablets* 
(see Table 3). 
If the outcome is “unresolved” or “unknown” and if the causality is indeterminable, a 

 
7 
follow-up surveillance will be performed whenever possible. 
In the event of manifested hepatic dysfunction or gastrointestinal infections with 
Clostridium difficile, detailed information (clinical courses, results of tests performed for 
diagnostic purposes, etc.) will be collected as much as possible. 
*If the rating of causality with Takecab Tablets is “unrelated”, information on the justification for the 
rating will be collected. If the rating is “indeterminable”, the reason will be recorded. 
Note) Matters to be taken into account with regard to adverse events 
Abnormal exacerbations of the target disease, including those exceeding the foreseeable 
spontaneous course of the condition, will be handled as adverse events. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
8 
Table 1 Definition of an adverse event 
An adverse event (AE) refers to any unwanted medical event appearing in a patient receiving a drug. An 
AE does not always represent an event for which causality with administration of the drug is evident. 
Hence, an adverse event refers to any unwanted or unintended sign (including abnormal laboratory 
values), symptom, or disease that has occurred in a subject receiving the test drug, irrespective of the 
presence/absence of causality with the drug. 
The following cases will also be handled as adverse events: 
•Symptoms etc. that have developed in infants breastfed by mothers on treatment with the drug 
•Unwanted symptoms etc. that have developed in children receiving the drug 
•Symptoms etc. that have developed with occupational exposure to the drug 
•Symptoms etc. that have developed with administration of a false drug imitating an ethical drug 
marketed by our company 
•Unwanted symptoms that have developed in persons using the drug and have become known by a 
lawsuit or any other legal act 
 
 

 
9 
Table 2 Seriousness rating criteria 
If any of the following criteria applies, the event will be rated as “serious.” 
1. Results in death (death) 
2. Life-threatening (possible death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (hospital admission 
or prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disorders) 
5. Causes congenital anomalies 
6. Medically important states secondary to Items 1 to 5 AEs included in the “Takeda Medically 
Significant AE List” will be included in this section 
 
Takeda Medically Significant AE List 
• Acute respiratory insufficiency/acute 
respiratory distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsades de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizures (including 
convulsions and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperpyrexia 
• Aplastic anemia 
• Spontaneous abortions/stillbirths and fetal deaths 
• Toxic epidermal 
necrolysis/oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of drug-
mediated infection 
• Acute hepatic failure 
• Endotoxin shock or, suspected 
• Hepatic necrosis 
 
 
 

 
10 
Table 3 Acceptance criteria for causality between adverse events and Takecab Tablets 
Rating 
Acceptance criteria 
Related 
A temporal correlation (including post-discontinuation courses) is found. 
Alternatively, although other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures, may also 
be involved, the event is attributable to the study drug. 
Unrelated 
No temporal correlation with the drug is found. Alternatively, the event is 
reasonably attributable to other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures. 
Indeterminable 
Information essential for assessments, such as temporal correlations 
(including post-discontinuation courses), primary disease, complications, 
concomitant drugs, and concomitant procedures, are lacking. 
 
10.0 
Analysis items and methods 
10.1 Items concerning study population composition 
Number of patients enrolled, number of patients from whom the surveillance form (electronic) 
has been collected, numbers of patients included in the safety and efficacy analysis sets, number 
of patients excluded from analysis and reasons for removal, and other items will be tabulated. 
 
10.2 Patient demographics 
Data on patient demographics, including sex, age, predisposition to hypersensitivity, and 
complications, will be tabulated. 
 
10.3 Treatment details 
Data on the use of Takecab Tablets and the use of concomitant drugs will be tabulated. 
 
10.4 Matters concerning the safety 
Data for the safety analysis set will be tabulated as follows: AEs will be reworded using the 
MedDRA/J and summarized with Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Factors of onset of adverse events 
With regard to the adverse events occurring during the observation period, frequency data 
will be tabulated by type, onset time, seriousness, causality with Takecab Tablets, and other 
aspects. 
 
10.4.2 Factors that may affect the safety 
With regard to the adverse drug reactions occurring during the observation period, 
frequency data will be tabulated by target disease, patient demographic factors (sex, age, 
presence/absence of complicating renal dysfunction, presence/absence of complicating 
hepatic dysfunction, etc.), and treatment (use of Takecab Tablets and use of concomitant 
drugs). 

 
11 
 
10.5 Matters concerning the safety 
Data for the efficacy analysis set will be tabulated as follows: 
10.5.1 Endoscopic cure rate 
Data on endoscopic cure rates in patients with endoscopic findings available at the start of 
treatment with Takecab Tablets and the end of the surveillance* will be tabulated by target 
disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation 
 
10.5.2 Subjective symptom amelioration rate 
Data on subjective symptom amelioration rates in patients with severity findings available 
from the start of treatment with Takecab Tablets to the end of the surveillance will be 
tabulated by target disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation. 
 
10.5.3 Factors that may affect the efficacy 
Data on endoscopic cure rates and subjective symptom amelioration rates will be tabulated 
by target disease, patient demographic factors (sex, age, presence/absence of complicating 
renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), and 
treatment (use of Takecab Tablets, use of concomitant drugs). 
 
11.0 
Surveillance information registry 
Takeda Pharmaceutical Company Limited will register information on this surveillance study 
prior to its start date with an open-access website. 
•Japan Pharmaceutical Information Center Clinical Trials Information 
 
12.0 
Organizational structure 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract research organization 
PPD
PPD

12 
 
14.0 
Other requirements 
14.1 Protocol revisions 
Study progression, onset of adverse drug reactions and serious adverse drug reactions that are 
unexpected from the Precautions, presence/absence of increased incidences of particular 
adverse drug reactions, validity of survey items, etc. will be monitored during the survey period 
and, if necessary, this protocol will be reconsidered and revised. If partial changes in the dosage 
and administration or indications are approved during the surveillance period, the necessity for 
revising this protocol will be determined as required, and the protocol will be revised if 
necessary. 
 
14.2 Measures to be taken in the event of problematic or doubtful issues 
If any problematic finding is found regarding safety and efficacy, the data will be checked 
extensively, and appropriate countermeasures will be considered. 
PPD

 
13 
Appendix: Schedule of observations 
Surveillance information entry times 
 
 
Items for surveillance 
Duration of observation 
At the time 
of patient 
enrollment 
At the 
start of 
treatment 
with 
Takecab 
Tablets 
 
 
Week 
2 
 
 
 
Week 
4  
 
 
Week 
6 
Note 1) 
 
 
Week 
8 
Note 2) 
At the time of 
treatment 
discontinuation 
Patient 
enrollment 
Date of prescribing Takecab 
Tablets 
○ 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
Initialized name of patient 
○ 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
Target disease for Takecab Tablets 
○ 
 
 
 
 
 
 
Exclusion criteria rating 
○ 
 
 
 
 
 
 
Patient 
demographic 
information 
Date of diagnosing the target 
disease 
 
○ 
 
 
 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
 
 
Complications 
 
○ 
 
 
 
 
 
Past medical history of gastric 
ulcer/duodenal ulcer/reflux 
esophagitis 
 
○ 
 
 
 
 
 
Height, weight 
 
○ 
 
 
 
 
 
Presence/absence of Helicobacter 
pylori infection 
 
○ 
 
 
 
 
 
Presence/absence of esophageal 
hiatal hernia 
 
○ 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
Treatment prior to starting 
Takecab Tablets 
 
○ 
 
 
 
 
 
Treatment 
information 
Use of Takecab Tablets 
 
○ 
○ 
Use of concomitant drugs 
 
○ 
○ 
Items for 
examination 
and 
observation 
 
 
Endoscopy 
 
○ 
Note 3) 
 
 
○ 
Note 4) 
○ 
Note 4) 
○ 
Note 4) 
Severity of subjective symptoms 
 
○ 
○ 
○ 
○ 
○ 
○ 
Liver function test 
 
○Note 5) 
○ 
Presence/absence of pregnancy 
(for women only) 
 
○ 
○ 
Adverse events 
 
○ 
○ 

 
14 
○ : Performed. 
○     : Performed throughout the surveillance period. 
Note 1) Gastric ulcer and reflux esophagitis are excluded. 
Note 2) Duodenal ulcer is excluded. 
Note 3) The time point will be essentially from 7 days before the start of treatment to the treatment 
start day. 
Note 4) The time point will be essentially until 14 days after the end of the surveillance (Week 8 
for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, or at treatment 
discontinuation). 
Note 5) Within 1 month before the start of treatment to the end of the surveillance. 

 
 
 
 
 
Drug Use Surveillance Protocol 
Drug Use Surveillance for Takecab Tablets 
Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5001 
Version No. 
Version 6 
Preparation date 
November 13, 2017 
 

 
Table of Contents 
1.0 
Background ...................................................................................................................................................... 1 
2.0 
Objective .......................................................................................................................................................... 1 
3.0 
Planned sample size and justification .............................................................................................................. 1 
3.1 
Planned sample size .................................................................................................................................... 1 
3.2 
Justification ................................................................................................................................................ 1 
4.0 
Subject patients ................................................................................................................................................ 2 
5.0 
Dosage and administration ............................................................................................................................... 2 
6.0 
Planned number of medical institutions by department ................................................................................... 2 
7.0 
Methods ........................................................................................................................................................... 2 
7.1 
Duration of observation .............................................................................................................................. 2 
7.2 
Requests to, and agreements with, study sites ............................................................................................ 2 
7.3 
Patient registration ...................................................................................................................................... 3 
7.4 
Data entry in the surveillance form (electronic) and electronic signature .................................................. 3 
7.5 
Measures to be taken in case of serious adverse events ............................................................................. 4 
8.0 
Scheduled period.............................................................................................................................................. 4 
9.0 
Items for surveillance ....................................................................................................................................... 4 
9.1 
Patient enrollment ....................................................................................................................................... 4 
9.2 
Patient demographic information ............................................................................................................... 4 
9.3 
Treatment information ................................................................................................................................ 5 
9.4 
Items for examination and observation....................................................................................................... 5 
9.4.1 
Endoscopy ............................................................................................................................................. 5 
9.4.2 
Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early satiety, 
epigastralgia, epigastric burning, sensation of abdominal distention, nausea/vomiting, burping, 
anorexia)................................................................................................................................................ 5 
9.4.3 
Liver function test ................................................................................................................................. 6 
9.4.4 
Other items for observation ................................................................................................................... 6 
9.5 
Adverse events............................................................................................................................................ 6 
10.0 
Analysis items and methods........................................................................................................................... 10 
10.1 
Items concerning study population composition ...................................................................................... 10 
10.2 
Patient demographics................................................................................................................................ 10 
10.3 
Treatment details ...................................................................................................................................... 10 
10.4 
Matters concerning the safety ................................................................................................................... 10 
10.4.1 
Factors of onset of adverse events ....................................................................................................... 10 
10.4.2 
Factors that may affect the safety ........................................................................................................ 10 
10.5 
Matters concerning the safety ................................................................................................................... 11 
10.5.1 
Endoscopic cure rate ........................................................................................................................... 11 
10.5.2 
Subjective symptom amelioration rate ................................................................................................ 11 
10.5.3 
Factors that may affect the efficacy ..................................................................................................... 11 
11.0 
Surveillance information registry .................................................................................................................. 11 

 
12.0 
Organizational structure ................................................................................................................................. 11 
12.1 
Manager .................................................................................................................................................... 11 
13.0 
Contract research organization....................................................................................................................... 11 
14.0 
Other requirements ........................................................................................................................................ 12 
14.1 
Protocol revisions ..................................................................................................................................... 12 
14.2 
Measures to be taken in the event of problematic or doubtful issues ....................................................... 12 
 
Appendix Schedule of observations............................................................................................................................13 

 
1 
1.0 
Background 
The safety of Takecab Tablets 20 mg in the treatment of gastric ulcer, duodenal ulcer, and reflux 
esophagitis has been assessed in Japanese clinical studies in 244, 183, and 988 patients, 
respectively, showing no remarkable problems. In postmarketing routine practices, however, 
unlike in the clinical studies, the drug may be used in patients with various complications and 
patients receiving multiple concomitant drugs, which means that the possibility of onset of 
unexpected adverse drug reactions cannot be ruled out based on the results of the clinical studies. 
Hence, we planned a drug use surveillance (hereinafter referred to as this surveillance) study to 
assess the safety and efficacy of Takecab Tablets in the three acid-related diseases gastric ulcer, 
duodenal ulcer, and reflux esophagitis in actual routine practices. 
This surveillance will be conducted in compliance with the MHLW Ministerial Ordinance on 
GPSP and other related regulatory requirements. 
 
2.0 
Objective 
To assess the safety and efficacy of Takecab Tablets in patients with gastric ulcer, duodenal ulcer, 
and reflux esophagitis in actual use settings and routine practices. 
 
3.0 
Planned sample size and justification 
3.1 Planned sample size 
3,000 Patients 
The sample size will not be less than 500 patients for each of gastric ulcer and duodenal ulcer, 
and will not be less than 1,000 patients for reflux esophagitis. 
 
3.2 Justification 
Gastric ulcer, duodenal ulcer, and reflux esophagitis all share the same pathologic feature that 
gastrointestinal mucosal injury is caused by gastric acid. Duration of treatment in Japanese 
clinical studies of Takecab Tablets in various patient populations with each disease was roughly 
the same for gastric ulcer and reflux esophagitis (up to 8 weeks) and duodenal ulcer (up to 6 
weeks), and incidences and severity of adverse drug reactions and safety profiles for adverse 
drug reactions with high incidences were similar. 
Based on the above facts, a drug use-results surveillance study will be conducted with a planned 
sample size of 3,000 patients with the three acid-related diseases of gastric ulcer, duodenal ulcer, 
and reflux esophagitis. With regard to the minimum sample size allowing the safety of Takecab 
Tablets to be assessed in patients with each disease, we have decided to enroll at least 500 
patients with gastric ulcer and duodenal ulcer. Since the number of patients with reflux 
esophagitis has been increasing rapidly year by year in Japan, and the disease is considered to 
affect the largest number of patients for whom Takecab Tablets is indicated, we have decided to 
enroll at least 1,000 patients with reflux esophagitis. Hence, incidences and severity of adverse 
drug reactions and differences in major adverse drug reactions in actual use settings and routine 
practices seem to be assessable by disease (the sample size was not statistically calculated). 

 
2 
 
4.0 
Subject patients 
Patients with gastric ulcer, duodenal ulcer, and reflux esophagitis will be enrolled. However, the 
subjects should not meet any of the exclusion criteria shown below. Refer to the Precautions in 
the package insert. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the subjects of this 
surveillance. 
1) Patients with a past medical history of hypersensitivity to any of the ingredients of 
Takecab Tablets 
2) Patients on treatment with atazanavir sulfate or rilpivirine hydrochloride 
3) When the target disease for Takecab Tablets is gastric ulcer or duodenal ulcer, patients 
whose endoscopic stage classification by Sakita and Miwa at the start of treatment with 
Takecab Tablets is the scarring stage (S1, S2) 
4) When the target disease for Takecab Tablets is reflux esophagitis, patients whose rating 
by the Los Angeles Classification of Gastroesophageal Reflux Disease (modified by 
Hoshihara) at the start of treatment with Takecab Tablets is Grade N or Grade M 
 
5.0 
Dosage and administration 
The usual adult dosage is 20 mg of vonoprazan administered orally once daily. Usually, the 
duration of treatment should be up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal 
ulcer. For reflux esophagitis, the duration of treatment should usually be up to 4 weeks; if the 
effect is insufficient, however, the drug can be administered for up to 8 weeks. Refer to the 
Precautions in the package insert. 
 
6.0 
Planned number of medical institutions by department 
Gastroenterology and other departments: About 500 medical institutions 
 
7.0 
Methods 
7.1 Duration of observation 
Duration of observation will be 8 weeks for gastric ulcer and reflux esophagitis and 6 weeks for 
duodenal ulcer. 
However, if treatment with Takecab Tablets is completed with the goal of treatment attained, or 
treatment with Takecab Tablets is discontinued for any reason, the surveillance will be ended at 
that time. 
 
7.2 Requests to, and agreements with, study sites 
Requests to, and agreements with, study sites will be made using a web-based electronic data 
collection system (
). Prior to starting this surveillance, an officer of Takeda 
Pharmaceutical Company Limited (hereinafter referred to as Takeda officer) will provide the 
CCI

 
3 
surveillance investigator with an explanation about the objective and contents of this 
surveillance, 
 operating procedures, electronic signature, user ID, and handling of 
passwords using the documents “Request for Your Cooperation in Drug Use-Results 
Surveillance,” “Implementation Guideline,” “Input Screen Image,” and “
 Operating 
Manual (Abridged Edition)” and conclude written agreements with the study site to ask it to 
conduct the surveillance within the specified surveillance period. 
 
7.3 Patient registration 
“Central registration” based on 
 will be used. For the patients with Takecab Tablets 
prescribed on or after the starting day of the period of agreements with the study site, the 
surveillance investigator will enter patient enrollment information (refer to Section 9.1) into 
 and will provide an electronic signature not later than 14 days after the day of 
prescribing Takecab Tablets (the prescribing day is defined as “Day 0” and the day after the 
prescribing day as “Day 1”). 
 
7.4 Data entry in the surveillance form (electronic) and electronic signature 
For all the patients enrolled, the surveillance investigator or a person designated by the 
surveillance investigator* will enter patient characteristics information, treatment information, 
and other information into 
 and the surveillance investigator will provide an 
electronic signature generally within 1 month after the end of the observation period for each 
patient. If Takecab Tablets are not confirmed to have actually been taken, this fact will be entered 
(no other items need to be entered). 
For the patients who have discontinued Takecab Tablets for any reason during the observation 
period, the surveillance investigator or a person designated by the surveillance investigator will 
enter patient characteristics information, treatment information, and other information into 
 and the surveillance investigator will provide an electronic signature generally 
within 1 month after completion of the observations required. For the patients who have 
discontinued Takecab Tablets because of development of any adverse event, however, the 
surveillance investigator will continue observations until the adverse event resolves or remits 
whenever possible after treatment discontinuation, the surveillance investigator or a person 
designated by the surveillance investigator will enter the observation results into 
 
and the surveillance investigator will provide an electronic signature. 
 
*The person designated by the surveillance investigator will be a person belonging to the 
medical institution (including those who have contract agreements with a medical institution 
such as a contract research organization (CRO)). The physicians who are the surveillance 
directors (one will be appointed for each study site or its department at the time of conclusion 
of contract agreements) will prepare records of the designees and designation dates and 
(whatever the form is) provide a signature or a signature and a seal, and submit the records to a 
Takeda officer before the person designated by the surveillance investigator enters data into 
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4 
 
 
7.5 Measures to be taken in case of serious adverse events 
If any serious adverse event develops during the observation period, the surveillance 
investigator will immediately notify this fact to a Takeda officer. Upon request from a Takeda 
officer, the surveillance investigator will separately provide detailed information. 
 
8.0 
Scheduled period 
Surveillance period: March 2016 to October 31, 2018 
Accrual period: March 2016 to August 31, 2018Note) 
Note) Even for the patients with Takecab Tablets prescribed by August 31, 2018, patient 
enrollment (data entry in
) will not be accepted on and after September 1, 2018. 
If the number of enrolled patients reaches the planned sample size for this surveillance as a 
whole before August 31, 2018, registration will be terminated before the end of the patient 
accrual period. If the patient accrual period is shortened, the overall surveillance period will 
be changed in proportion to the shortage. 
In addition, enrollment may be subject to limitations for each target diseasebefore 
August 31, 2018 in view of the enrollment status for each target disease. 
 
9.0 
Items for surveillance 
The surveillance investigator or a person designated by the surveillance investigator will enter 
information on the items shown below into
: The schedule for this surveillance is 
shown in the Appendix. 
9.1 Patient enrollment 
1) Items for surveillance 
Date of prescribing Takecab Tablets, patient ID No., initialized patient name, sex, date of 
birth, target disease for Takecab Tablets, exclusion criteria ratings 
2) Surveillance times 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Items for surveillance 
Date of diagnosing the target disease, Inpatient/outpatient classification (from the start of 
treatment with Takecab Tablets), predisposition to hypersensitivity (presence/absence and 
details), complications (presence/absence and details), past medical history of gastric 
ulcer/duodenal ulcer/reflux esophagitis (presence/absence and details), height, body weight, 
presence/absence of Helicobacter pylori infection (from the start of treatment with Takecab 
Tablets), presence/absence of esophageal hiatal hernia, smoking history, drinking history, 
treatments prior to the start of Takecab Tablets [presence/absence, names of drugs, doses 
(excluding H2 blockers), and duration of treatment] 
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5 
2) Surveillance times 
At the start of treatment with Takecab Tablets 
 
9.3 Treatment information 
1) Items for surveillance 
Use of Takecab Tablets (daily dose, duration of treatment, and reason for treatment 
discontinuation), use of concomitant drugs (presence/absence, names of drugs, and purpose 
of administration) 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance will 
be at the time of treatment discontinuation. 
 
9.4 Items for examination and observation 
9.4.1 Endoscopy 
1) Items for examination 
Endoscopy (check date and findings*1) 
*1: Gastric ulcer and duodenal ulcer will be assessed using the endoscopic stage classification by 
Sakita and Miwa, and reflux esophagitis will be assessed using the classification of mucosal 
injuries according to the Los Angeles Classification of Gastroesophageal Reflux Disease 
(modified by Hoshihara). 
2) Surveillance times 
Examination time points at the start of treatment with Takecab Tablets*2 and the end of the 
surveillance*3 
*2: The time point will be essentially between 7 days before the start of treatment and the day of the 
start of treatment. 
*3: The time point will be essentially until 14 days after Week 8 for gastric ulcer and reflux esophagitis 
and after Week 6 for duodenal ulcer. If Takecab Tablets are discontinued before these times, the 
time point will be essentially until 14 days after treatment discontinuation. 
 
9.4.2 Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early 
satiety, epigastralgia, epigastric burning, sensation of abdominal distention, 
nausea/vomiting, burping, anorexia) 
1) Items for observation 
Subjective symptoms (presence/absence and severity*1) 
*1: Mild: Occasionally or slightly symptomatic. 
Moderate: Considerably symptomatic. 
Severe: Unendurably symptomatic. 
2) Surveillance times 

 
6 
Interview time points at the start of treatment with Takecab Tablets, at Week 2, at Week 4, 
and at the end of the surveillance*2. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the 
surveillance will be at the time of treatment discontinuation. 
 
9.4.3 Liver function test 
1) Parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Surveillance times 
Examination time points from the start of treatment with Takecab Tablets*1 to the end of 
the surveillance*2 
*1: Within 1 month before the start of treatment. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.4 Other items for observation 
1) Items for observation 
Presence/absence of pregnancy during the observation period (for women only) 
If the subject is found to be pregnant during the observation period, this fact should 
immediately be notified to a Takeda officer. Upon request by the Takeda officer, the 
surveillance investigator will provide detailed information (including information up to 
delivery, including details of premature birth and other outcomes) separately using a 
pregnant-woman sheet. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.5 Adverse events 
1) Items for surveillance 
Presence/absence of adverse events (see Table 1), names of adverse events, onset days, 
seriousness and rationale for the seriousness rating (see Table 2), cause of discontinuation 
of Takecab Tablets, outcome determination day, outcome, causality with Takecab Tablets* 
(see Table 3). 
If the outcome is “unresolved” or “unknown” and if the causality is indeterminable, a 

 
7 
follow-up surveillance will be performed whenever possible. 
In the event of manifested hepatic dysfunction or gastrointestinal infections with 
Clostridium difficile, detailed information (clinical courses, results of tests performed for 
diagnostic purposes, etc.) will be collected as much as possible. 
*If the rating of causality with Takecab Tablets is “unrelated”, information on the justification for the 
rating will be collected. If the rating is “indeterminable”, the reason will be recorded. 
Note) Matters to be taken into account with regard to adverse events 
Abnormal exacerbations of the target disease, including those exceeding the foreseeable 
spontaneous course of the condition, will be handled as adverse events. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
8 
Table 1 Definition of an adverse event 
An adverse event (AE) refers to any unwanted medical event appearing in a patient receiving a drug. An 
AE does not always represent an event for which causality with administration of the drug is evident. 
Hence, an adverse event refers to any unwanted or unintended sign (including abnormal laboratory 
values), symptom, or disease that has occurred in a subject receiving the test drug, irrespective of the 
presence/absence of causality with the drug. 
The following cases will also be handled as adverse events: 
•Symptoms etc. that have developed in infants breastfed by mothers on treatment with the drug 
•Unwanted symptoms etc. that have developed in children receiving the drug 
•Symptoms etc. that have developed with occupational exposure to the drug 
•Symptoms etc. that have developed with administration of a false drug imitating an ethical drug 
marketed by our company 
•Unwanted symptoms that have developed in persons using the drug and have become known by a 
lawsuit or any other legal act 
 
 

 
9 
Table 2 Seriousness rating criteria 
If any of the following criteria applies, the event will be rated as “serious.” 
1. Results in death (death) 
2. Life-threatening (possible death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (hospital admission 
or prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disorders) 
5. Causes congenital anomalies 
6. Medically important states secondary to Items 1 to 5 AEs included in the “Takeda Medically 
Significant AE List” will be included in this section 
 
Takeda Medically Significant AE List 
• Acute respiratory insufficiency/acute 
respiratory distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsades de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizures (including 
convulsions and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperpyrexia 
• Aplastic anemia 
• Spontaneous abortions/stillbirths and fetal deaths 
• Toxic epidermal 
necrolysis/oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of drug-
mediated infection 
• Acute hepatic failure 
• Endotoxin shock or, suspected 
• Hepatic necrosis 
 
 
 

 
10 
Table 3 Acceptance criteria for causality between adverse events and Takecab Tablets 
Rating 
Acceptance criteria 
Related 
A temporal correlation (including post-discontinuation courses) is found. 
Alternatively, although other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures, may also 
be involved, the event is attributable to the study drug. 
Unrelated 
No temporal correlation with the drug is found. Alternatively, the event is 
reasonably attributable to other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures. 
Indeterminable 
Information essential for assessments, such as temporal correlations 
(including post-discontinuation courses), primary disease, complications, 
concomitant drugs, and concomitant procedures, are lacking. 
 
10.0 
Analysis items and methods 
10.1 Items concerning study population composition 
Number of patients enrolled, number of patients from whom the surveillance form (electronic) 
has been collected, numbers of patients included in the safety and efficacy analysis sets, number 
of patients excluded from analysis and reasons for removal, and other items will be tabulated. 
 
10.2 Patient demographics 
Data on patient demographics, including sex, age, predisposition to hypersensitivity, and 
complications, will be tabulated. 
 
10.3 Treatment details 
Data on the use of Takecab Tablets and the use of concomitant drugs will be tabulated. 
 
10.4 Matters concerning the safety 
Data for the safety analysis set will be tabulated as follows: AEs will be reworded using the 
MedDRA/J and summarized with Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Factors of onset of adverse events 
With regard to the adverse events occurring during the observation period, frequency data 
will be tabulated by type, onset time, seriousness, causality with Takecab Tablets, and other 
aspects. 
 
10.4.2 Factors that may affect the safety 
With regard to the adverse drug reactions occurring during the observation period, 
frequency data will be tabulated by target disease, patient demographic factors (sex, age, 
presence/absence of complicating renal dysfunction, presence/absence of complicating 
hepatic dysfunction, etc.), and treatment (use of Takecab Tablets and use of concomitant 
drugs). 

 
11 
 
10.5 Matters concerning the safety 
Data for the efficacy analysis set will be tabulated as follows: 
10.5.1 Endoscopic cure rate 
Data on endoscopic cure rates in patients with endoscopic findings available at the start of 
treatment with Takecab Tablets and the end of the surveillance* will be tabulated by target 
disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation 
 
10.5.2 Subjective symptom amelioration rate 
Data on subjective symptom amelioration rates in patients with severity findings available 
from the start of treatment with Takecab Tablets to the end of the surveillance will be 
tabulated by target disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation. 
 
10.5.3 Factors that may affect the efficacy 
Data on endoscopic cure rates and subjective symptom amelioration rates will be tabulated 
by target disease, patient demographic factors (sex, age, presence/absence of complicating 
renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), and 
treatment (use of Takecab Tablets, use of concomitant drugs). 
 
11.0 
Surveillance information registry 
Takeda Pharmaceutical Company Limited will register information on this surveillance study 
prior to its start date with an open-access website. 
•Japan Pharmaceutical Information Center Clinical Trials Information 
 
12.0 
Organizational structure 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract research organization 
PPD
PPD

12 
 
14.0 
Other requirements 
14.1 Protocol revisions 
Study progression, onset of adverse drug reactions and serious adverse drug reactions that are 
unexpected from the Precautions, presence/absence of increased incidences of particular 
adverse drug reactions, validity of survey items, etc. will be monitored during the survey period 
and, if necessary, this protocol will be reconsidered and revised. If partial changes in the dosage 
and administration or indications are approved during the surveillance period, the necessity for 
revising this protocol will be determined as required, and the protocol will be revised if 
necessary. 
 
14.2 Measures to be taken in the event of problematic or doubtful issues 
If any problematic finding is found regarding safety and efficacy, the data will be checked 
extensively, and appropriate countermeasures will be considered. 
PPD

 
13 
Appendix: Schedule of observations 
Surveillance information entry times 
 
 
Items for surveillance 
Duration of observation 
At the time 
of patient 
enrollment 
At the 
start of 
treatment 
with 
Takecab 
Tablets 
 
 
Week 
2 
 
 
 
Week 
4  
 
 
Week 
6 
Note 1) 
 
 
Week 
8 
Note 2) 
At the time of 
treatment 
discontinuation 
Patient 
enrollment 
Date of prescribing Takecab 
Tablets 
○ 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
Initialized name of patient 
○ 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
Target disease for Takecab Tablets 
○ 
 
 
 
 
 
 
Exclusion criteria rating 
○ 
 
 
 
 
 
 
Patient 
demographic 
information 
Date of diagnosing the target 
disease 
 
○ 
 
 
 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
 
 
Complications 
 
○ 
 
 
 
 
 
Past medical history of gastric 
ulcer/duodenal ulcer/reflux 
esophagitis 
 
○ 
 
 
 
 
 
Height, weight 
 
○ 
 
 
 
 
 
Presence/absence of Helicobacter 
pylori infection 
 
○ 
 
 
 
 
 
Presence/absence of esophageal 
hiatal hernia 
 
○ 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
Treatment prior to starting 
Takecab Tablets 
 
○ 
 
 
 
 
 
Treatment 
information 
Use of Takecab Tablets 
 
○ 
○ 
Use of concomitant drugs 
 
○ 
○ 
Items for 
examination 
and 
observation 
 
 
Endoscopy 
 
○ 
Note 3) 
 
 
○ 
Note 4) 
○ 
Note 4) 
○ 
Note 4) 
Severity of subjective symptoms 
 
○ 
○ 
○ 
○ 
○ 
○ 
Liver function test 
 
○Note 5) 
○ 
Presence/absence of pregnancy 
(for women only) 
 
○ 
○ 
Adverse events 
 
○ 
○ 

 
14 
○ : Performed. 
○     : Performed throughout the surveillance period. 
Note 1) Gastric ulcer and reflux esophagitis are excluded. 
Note 2) Duodenal ulcer is excluded. 
Note 3) The time point will be essentially from 7 days before the start of treatment to the treatment 
start day. 
Note 4) The time point will be essentially until 14 days after the end of the surveillance (Week 8 
for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, or at treatment 
discontinuation). 
Note 5) Within 1 month before the start of treatment to the end of the surveillance. 

 
 
 
 
 
Drug Use Surveillance Protocol 
Drug Use Surveillance for Takecab Tablets 
Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5001 
Version No. 
Version 5 
Preparation date 
June 2, 2017 
 

 
Table of Contents 
1.0 
Background ...................................................................................................................................................... 1 
2.0 
Objective .......................................................................................................................................................... 1 
3.0 
Planned sample size and justification .............................................................................................................. 1 
3.1 
Planned sample size .................................................................................................................................... 1 
3.2 
Justification ................................................................................................................................................ 1 
4.0 
Subject patients ................................................................................................................................................ 2 
5.0 
Dosage and administration ............................................................................................................................... 2 
6.0 
Planned number of medical institutions by department ................................................................................... 2 
7.0 
Methods ........................................................................................................................................................... 2 
7.1 
Duration of observation .............................................................................................................................. 2 
7.2 
Requests to, and agreements with, study sites ............................................................................................ 2 
7.3 
Patient registration ...................................................................................................................................... 3 
7.4 
Data entry in the surveillance form (electronic) and electronic signature .................................................. 3 
7.5 
Measures to be taken in case of serious adverse events ............................................................................. 4 
8.0 
Scheduled period.............................................................................................................................................. 4 
9.0 
Items for surveillance ....................................................................................................................................... 4 
9.1 
Patient enrollment ....................................................................................................................................... 4 
9.2 
Patient demographic information ............................................................................................................... 4 
9.3 
Treatment information ................................................................................................................................ 5 
9.4 
Items for examination and observation....................................................................................................... 5 
9.4.1 
Endoscopy ............................................................................................................................................. 5 
9.4.2 
Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early satiety, 
epigastralgia, epigastric burning, sensation of abdominal distention, nausea/vomiting, burping, 
anorexia)................................................................................................................................................ 5 
9.4.3 
Liver function test ................................................................................................................................. 6 
9.4.4 
Other items for observation ................................................................................................................... 6 
9.5 
Adverse events............................................................................................................................................ 6 
10.0 
Analysis items and methods........................................................................................................................... 10 
10.1 
Items concerning study population composition ...................................................................................... 10 
10.2 
Patient demographics................................................................................................................................ 10 
10.3 
Treatment details ...................................................................................................................................... 10 
10.4 
Matters concerning the safety ................................................................................................................... 10 
10.4.1 
Factors of onset of adverse events ....................................................................................................... 10 
10.4.2 
Factors that may affect the safety ........................................................................................................ 10 
10.5 
Matters concerning the safety ................................................................................................................... 11 
10.5.1 
Endoscopic cure rate ........................................................................................................................... 11 
10.5.2 
Subjective symptom amelioration rate ................................................................................................ 11 
10.5.3 
Factors that may affect the efficacy ..................................................................................................... 11 
11.0 
Surveillance information registry .................................................................................................................. 11 

 
12.0 
Organizational structure ................................................................................................................................. 11 
12.1 
Manager .................................................................................................................................................... 11 
13.0 
Contract research organization....................................................................................................................... 11 
14.0 
Other requirements ........................................................................................................................................ 12 
14.1 
Protocol revisions ..................................................................................................................................... 12 
14.2 
Measures to be taken in the event of problematic or doubtful issues ....................................................... 12 
 
Appendix Schedule of observations............................................................................................................................13 

 
1 
1.0 
Background 
The safety of Takecab Tablets 20 mg in the treatment of gastric ulcer, duodenal ulcer, and reflux 
esophagitis has been assessed in Japanese clinical studies in 244, 183, and 988 patients, 
respectively, showing no remarkable problems. In postmarketing routine practices, however, 
unlike in the clinical studies, the drug may be used in patients with various complications and 
patients receiving multiple concomitant drugs, which means that the possibility of onset of 
unexpected adverse drug reactions cannot be ruled out based on the results of the clinical studies. 
Hence, we planned a drug use surveillance (hereinafter referred to as this surveillance) study to 
assess the safety and efficacy of Takecab Tablets in the three acid-related diseases gastric ulcer, 
duodenal ulcer, and reflux esophagitis in actual routine practices. 
This surveillance will be conducted in compliance with the MHLW Ministerial Ordinance on 
GPSP and other related regulatory requirements. 
 
2.0 
Objective 
To assess the safety and efficacy of Takecab Tablets in patients with gastric ulcer, duodenal ulcer, 
and reflux esophagitis in actual use settings and routine practices. 
 
3.0 
Planned sample size and justification 
3.1 Planned sample size 
3,000 Patients 
The sample size will not be less than 500 patients for each of gastric ulcer and duodenal ulcer, 
and will not be less than 1,000 patients for reflux esophagitis. 
 
3.2 Justification 
Gastric ulcer, duodenal ulcer, and reflux esophagitis all share the same pathologic feature that 
gastrointestinal mucosal injury is caused by gastric acid. Duration of treatment in Japanese 
clinical studies of Takecab Tablets in various patient populations with each disease was roughly 
the same for gastric ulcer and reflux esophagitis (up to 8 weeks) and duodenal ulcer (up to 6 
weeks), and incidences and severity of adverse drug reactions and safety profiles for adverse 
drug reactions with high incidences were similar. 
Based on the above facts, a drug use-results surveillance study will be conducted with a planned 
sample size of 3,000 patients with the three acid-related diseases of gastric ulcer, duodenal ulcer, 
and reflux esophagitis. With regard to the minimum sample size allowing the safety of Takecab 
Tablets to be assessed in patients with each disease, we have decided to enroll at least 500 
patients with gastric ulcer and duodenal ulcer. Since the number of patients with reflux 
esophagitis has been increasing rapidly year by year in Japan, and the disease is considered to 
affect the largest number of patients for whom Takecab Tablets is indicated, we have decided to 
enroll at least 1,000 patients with reflux esophagitis. Hence, incidences and severity of adverse 
drug reactions and differences in major adverse drug reactions in actual use settings and routine 
practices seem to be assessable by disease (the sample size was not statistically calculated). 

 
2 
 
4.0 
Subject patients 
Patients with gastric ulcer, duodenal ulcer, and reflux esophagitis will be enrolled. However, the 
subjects should not meet any of the exclusion criteria shown below. Refer to the Precautions in 
the package insert. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the subjects of this 
surveillance. 
1) Patients with a past medical history of hypersensitivity to any of the ingredients of 
Takecab Tablets 
2) Patients on treatment with atazanavir sulfate or rilpivirine hydrochloride 
3) When the target disease for Takecab Tablets is gastric ulcer or duodenal ulcer, patients 
whose endoscopic stage classification by Sakita and Miwa at the start of treatment with 
Takecab Tablets is the scarring stage (S1, S2) 
4) When the target disease for Takecab Tablets is reflux esophagitis, patients whose rating 
by the Los Angeles Classification of Gastroesophageal Reflux Disease (modified by 
Hoshihara) at the start of treatment with Takecab Tablets is Grade N or Grade M 
 
5.0 
Dosage and administration 
The usual adult dosage is 20 mg of vonoprazan administered orally once daily. Usually, the 
duration of treatment should be up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal 
ulcer. For reflux esophagitis, the duration of treatment should usually be up to 4 weeks; if the 
effect is insufficient, however, the drug can be administered for up to 8 weeks. Refer to the 
Precautions in the package insert. 
 
6.0 
Planned number of medical institutions by department 
Gastroenterology and other departments: About 500 medical institutions 
 
7.0 
Methods 
7.1 Duration of observation 
Duration of observation will be 8 weeks for gastric ulcer and reflux esophagitis and 6 weeks for 
duodenal ulcer. 
However, if treatment with Takecab Tablets is completed with the goal of treatment attained, or 
treatment with Takecab Tablets is discontinued for any reason, the surveillance will be ended at 
that time. 
 
7.2 Requests to, and agreements with, study sites 
Requests to, and agreements with, study sites will be made using a web-based electronic data 
collection system (
). Prior to starting this surveillance, an officer of Takeda 
Pharmaceutical Company Limited (hereinafter referred to as Takeda officer) will provide the 
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3 
surveillance investigator with an explanation about the objective and contents of this 
surveillance, 
 operating procedures, electronic signature, user ID, and handling of 
passwords using the documents “Request for Your Cooperation in Drug Use-Results 
Surveillance,” “Implementation Guideline,” “Input Screen Image,” and “
 Operating 
Manual (Abridged Edition)” and conclude written agreements with the study site to ask it to 
conduct the surveillance within the specified surveillance period. 
 
7.3 Patient registration 
“Central registration” based on 
 will be used. For the patients with Takecab Tablets 
prescribed on or after the starting day of the period of agreements with the study site, the 
surveillance investigator will enter patient enrollment information (refer to Section 9.1) into 
 and will provide an electronic signature not later than 14 days after the day of 
prescribing Takecab Tablets (the prescribing day is defined as “Day 0” and the day after the 
prescribing day as “Day 1”). 
 
7.4 Data entry in the surveillance form (electronic) and electronic signature 
For all the patients enrolled, the surveillance investigator or a person designated by the 
surveillance investigator* will enter patient characteristics information, treatment information, 
and other information into 
 and the surveillance investigator will provide an 
electronic signature generally within 1 month after the end of the observation period for each 
patient. If Takecab Tablets are not confirmed to have actually been taken, this fact will be entered 
(no other items need to be entered). 
For the patients who have discontinued Takecab Tablets for any reason during the observation 
period, the surveillance investigator or a person designated by the surveillance investigator will 
enter patient characteristics information, treatment information, and other information into 
 and the surveillance investigator will provide an electronic signature generally 
within 1 month after completion of the observations required. For the patients who have 
discontinued Takecab Tablets because of development of any adverse event, however, the 
surveillance investigator will continue observations until the adverse event resolves or remits 
whenever possible after treatment discontinuation, the surveillance investigator or a person 
designated by the surveillance investigator will enter the observation results into 
 
and the surveillance investigator will provide an electronic signature. 
 
*The person designated by the surveillance investigator will be a person belonging to the 
medical institution (including those who have contract agreements with a medical institution 
such as a contract research organization (CRO)). The physicians who are the surveillance 
directors (one will be appointed for each study site or its department at the time of conclusion 
of contract agreements) will prepare records of the designees and designation dates and 
(whatever the form is) provide a signature or a signature and a seal, and submit the records to a 
Takeda officer before the person designated by the surveillance investigator enters data into 
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4 
 
 
7.5 Measures to be taken in case of serious adverse events 
If any serious adverse event develops during the observation period, the surveillance 
investigator will immediately notify this fact to a Takeda officer. Upon request from a Takeda 
officer, the surveillance investigator will separately provide detailed information. 
 
8.0 
Scheduled period 
Surveillance period: March 2016 to April 30, 2018 
Accrual period: March 2016 to February 28, 2018Note) 
Note) Even for the patients with Takecab Tablets prescribed by February 28, 2018, patient 
enrollment (data entry in
) will not be accepted on and after March 1, 2018. 
If the number of enrolled patients reaches the planned sample size for this surveillance as a 
whole before February 28, 2018, registration will be terminated before the end of the patient 
accrual period. If the patient accrual period is shortened, the overall surveillance period will 
be changed in proportion to the shortage. 
In addition, enrollment may be subject to limitations for each target diseasebefore 
February 28, 2018 in view of the enrollment status for each target disease. 
 
9.0 
Items for surveillance 
The surveillance investigator or a person designated by the surveillance investigator will enter 
information on the items shown below into
: The schedule for this surveillance is 
shown in the Appendix. 
9.1 Patient enrollment 
1) Items for surveillance 
Date of prescribing Takecab Tablets, patient ID No., initialized patient name, sex, date of 
birth, target disease for Takecab Tablets, exclusion criteria ratings 
2) Surveillance times 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Items for surveillance 
Date of diagnosing the target disease, Inpatient/outpatient classification (from the start of 
treatment with Takecab Tablets), predisposition to hypersensitivity (presence/absence and 
details), complications (presence/absence and details), past medical history of gastric 
ulcer/duodenal ulcer/reflux esophagitis (presence/absence and details), height, body weight, 
presence/absence of Helicobacter pylori infection (from the start of treatment with Takecab 
Tablets), presence/absence of esophageal hiatal hernia, smoking history, drinking history, 
treatments prior to the start of Takecab Tablets [presence/absence, names of drugs, doses 
(excluding H2 blockers), and duration of treatment] 
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5 
2) Surveillance times 
At the start of treatment with Takecab Tablets 
 
9.3 Treatment information 
1) Items for surveillance 
Use of Takecab Tablets (daily dose, duration of treatment, and reason for treatment 
discontinuation), use of concomitant drugs (presence/absence, names of drugs, and purpose 
of administration) 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance will 
be at the time of treatment discontinuation. 
 
9.4 Items for examination and observation 
9.4.1 Endoscopy 
1) Items for examination 
Endoscopy (check date and findings*1) 
*1: Gastric ulcer and duodenal ulcer will be assessed using the endoscopic stage classification by 
Sakita and Miwa, and reflux esophagitis will be assessed using the classification of mucosal 
injuries according to the Los Angeles Classification of Gastroesophageal Reflux Disease 
(modified by Hoshihara). 
2) Surveillance times 
Examination time points at the start of treatment with Takecab Tablets*2 and the end of the 
surveillance*3 
*2: The time point will be essentially between 7 days before the start of treatment and the day of the 
start of treatment. 
*3: The time point will be essentially until 14 days after Week 8 for gastric ulcer and reflux esophagitis 
and after Week 6 for duodenal ulcer. If Takecab Tablets are discontinued before these times, the 
time point will be essentially until 14 days after treatment discontinuation. 
 
9.4.2 Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early 
satiety, epigastralgia, epigastric burning, sensation of abdominal distention, 
nausea/vomiting, burping, anorexia) 
1) Items for observation 
Subjective symptoms (presence/absence and severity*1) 
*1: Mild: Occasionally or slightly symptomatic. 
Moderate: Considerably symptomatic. 
Severe: Unendurably symptomatic. 
2) Surveillance times 

 
6 
Interview time points at the start of treatment with Takecab Tablets, at Week 2, at Week 4, 
and at the end of the surveillance*2. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the 
surveillance will be at the time of treatment discontinuation. 
 
9.4.3 Liver function test 
1) Parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Surveillance times 
Examination time points from the start of treatment with Takecab Tablets*1 to the end of 
the surveillance*2 
*1: Within 1 month before the start of treatment. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.4 Other items for observation 
1) Items for observation 
Presence/absence of pregnancy during the observation period (for women only) 
If the subject is found to be pregnant during the observation period, this fact should 
immediately be notified to a Takeda officer. Upon request by the Takeda officer, the 
surveillance investigator will provide detailed information (including information up to 
delivery, including details of premature birth and other outcomes) separately using a 
pregnant-woman sheet. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.5 Adverse events 
1) Items for surveillance 
Presence/absence of adverse events (see Table 1), names of adverse events, onset days, 
seriousness and rationale for the seriousness rating (see Table 2), cause of discontinuation 
of Takecab Tablets, outcome determination day, outcome, causality with Takecab Tablets* 
(see Table 3). 
If the outcome is “unresolved” or “unknown” and if the causality is indeterminable, a 

 
7 
follow-up surveillance will be performed whenever possible. 
In the event of manifested hepatic dysfunction or gastrointestinal infections with 
Clostridium difficile, detailed information (clinical courses, results of tests performed for 
diagnostic purposes, etc.) will be collected as much as possible. 
*If the rating of causality with Takecab Tablets is “unrelated”, information on the justification for the 
rating will be collected. If the rating is “indeterminable”, the reason will be recorded. 
Note) Matters to be taken into account with regard to adverse events 
Abnormal exacerbations of the target disease, including those exceeding the foreseeable 
spontaneous course of the condition, will be handled as adverse events. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
8 
Table 1 Definition of an adverse event 
An adverse event (AE) refers to any unwanted medical event appearing in a patient receiving a drug. An 
AE does not always represent an event for which causality with administration of the drug is evident. 
Hence, an adverse event refers to any unwanted or unintended sign (including abnormal laboratory 
values), symptom, or disease that has occurred in a subject receiving the test drug, irrespective of the 
presence/absence of causality with the drug. 
The following cases will also be handled as adverse events: 
•Symptoms etc. that have developed in infants breastfed by mothers on treatment with the drug 
•Unwanted symptoms etc. that have developed in children receiving the drug 
•Symptoms etc. that have developed with occupational exposure to the drug 
•Symptoms etc. that have developed with administration of a false drug imitating an ethical drug 
marketed by our company 
•Unwanted symptoms that have developed in persons using the drug and have become known by a 
lawsuit or any other legal act 
 
 

 
9 
Table 2 Seriousness rating criteria 
If any of the following criteria applies, the event will be rated as “serious.” 
1. Results in death (death) 
2. Life-threatening (possible death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (hospital admission 
or prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disorders) 
5. Causes congenital anomalies 
6. Medically important states secondary to Items 1 to 5 AEs included in the “Takeda Medically 
Significant AE List” will be included in this section 
 
Takeda Medically Significant AE List 
• Acute respiratory insufficiency/acute 
respiratory distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsades de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizures (including 
convulsions and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperpyrexia 
• Aplastic anemia 
• Spontaneous abortions/stillbirths and fetal deaths 
• Toxic epidermal 
necrolysis/oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of drug-
mediated infection 
• Acute hepatic failure 
• Endotoxin shock or, suspected 
• Hepatic necrosis 
 
 
 

 
10 
Table 3 Acceptance criteria for causality between adverse events and Takecab Tablets 
Rating 
Acceptance criteria 
Related 
A temporal correlation (including post-discontinuation courses) is found. 
Alternatively, although other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures, may also 
be involved, the event is attributable to the study drug. 
Unrelated 
No temporal correlation with the drug is found. Alternatively, the event is 
reasonably attributable to other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures. 
Indeterminable 
Information essential for assessments, such as temporal correlations 
(including post-discontinuation courses), primary disease, complications, 
concomitant drugs, and concomitant procedures, are lacking. 
 
10.0 
Analysis items and methods 
10.1 Items concerning study population composition 
Number of patients enrolled, number of patients from whom the surveillance form (electronic) 
has been collected, numbers of patients included in the safety and efficacy analysis sets, number 
of patients excluded from analysis and reasons for removal, and other items will be tabulated. 
 
10.2 Patient demographics 
Data on patient demographics, including sex, age, predisposition to hypersensitivity, and 
complications, will be tabulated. 
 
10.3 Treatment details 
Data on the use of Takecab Tablets and the use of concomitant drugs will be tabulated. 
 
10.4 Matters concerning the safety 
Data for the safety analysis set will be tabulated as follows: AEs will be reworded using the 
MedDRA/J and summarized with Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Factors of onset of adverse events 
With regard to the adverse events occurring during the observation period, frequency data 
will be tabulated by type, onset time, seriousness, causality with Takecab Tablets, and other 
aspects. 
 
10.4.2 Factors that may affect the safety 
With regard to the adverse drug reactions occurring during the observation period, 
frequency data will be tabulated by target disease, patient demographic factors (sex, age, 
presence/absence of complicating renal dysfunction, presence/absence of complicating 
hepatic dysfunction, etc.), and treatment (use of Takecab Tablets and use of concomitant 
drugs). 

 
11 
 
10.5 Matters concerning the safety 
Data for the efficacy analysis set will be tabulated as follows: 
10.5.1 Endoscopic cure rate 
Data on endoscopic cure rates in patients with endoscopic findings available at the start of 
treatment with Takecab Tablets and the end of the surveillance* will be tabulated by target 
disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation 
 
10.5.2 Subjective symptom amelioration rate 
Data on subjective symptom amelioration rates in patients with severity findings available 
from the start of treatment with Takecab Tablets to the end of the surveillance will be 
tabulated by target disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation. 
 
10.5.3 Factors that may affect the efficacy 
Data on endoscopic cure rates and subjective symptom amelioration rates will be tabulated 
by target disease, patient demographic factors (sex, age, presence/absence of complicating 
renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), and 
treatment (use of Takecab Tablets, use of concomitant drugs). 
 
11.0 
Surveillance information registry 
Takeda Pharmaceutical Company Limited will register information on this surveillance study 
prior to its start date with an open-access website. 
•Japan Pharmaceutical Information Center Clinical Trials Information 
 
12.0 
Organizational structure 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract research organization 
PPD
PPD

12 
 
 
14.0 
Other requirements 
14.1 Protocol revisions 
Study progression, onset of adverse drug reactions and serious adverse drug reactions that are 
unexpected from the Precautions, presence/absence of increased incidences of particular 
adverse drug reactions, validity of survey items, etc. will be monitored during the survey period 
and, if necessary, this protocol will be reconsidered and revised. If partial changes in the dosage 
and administration or indications are approved during the surveillance period, the necessity for 
revising this protocol will be determined as required, and the protocol will be revised if 
necessary. 
 
14.2 Measures to be taken in the event of problematic or doubtful issues 
If any problematic finding is found regarding safety and efficacy, the data will be checked 
extensively, and appropriate countermeasures will be considered. 
PPD

 
13 
Appendix: Schedule of observations 
Surveillance information entry times 
 
 
Items for surveillance 
Duration of observation 
At the time 
of patient 
enrollment 
At the 
start of 
treatment 
with 
Takecab 
Tablets 
 
 
Week 
2 
 
 
 
Week 
4  
 
 
Week 
6 
Note 1) 
 
 
Week 
8 
Note 2) 
At the time of 
treatment 
discontinuation 
Patient 
enrollment 
Date of prescribing Takecab 
Tablets 
○ 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
Initialized name of patient 
○ 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
Target disease for Takecab Tablets 
○ 
 
 
 
 
 
 
Exclusion criteria rating 
○ 
 
 
 
 
 
 
Patient 
demographic 
information 
Date of diagnosing the target 
disease 
 
○ 
 
 
 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
 
 
Complications 
 
○ 
 
 
 
 
 
Past medical history of gastric 
ulcer/duodenal ulcer/reflux 
esophagitis 
 
○ 
 
 
 
 
 
Height, weight 
 
○ 
 
 
 
 
 
Presence/absence of Helicobacter 
pylori infection 
 
○ 
 
 
 
 
 
Presence/absence of esophageal 
hiatal hernia 
 
○ 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
Treatment prior to starting 
Takecab Tablets 
 
○ 
 
 
 
 
 
Treatment 
information 
Use of Takecab Tablets 
 
○ 
○ 
Use of concomitant drugs 
 
○ 
○ 
Items for 
examination 
and 
observation 
 
 
Endoscopy 
 
○ 
Note 3) 
 
 
○ 
Note 4) 
○ 
Note 4) 
○ 
Note 4) 
Severity of subjective symptoms 
 
○ 
○ 
○ 
○ 
○ 
○ 
Liver function test 
 
○Note 5) 
○ 
Presence/absence of pregnancy 
(for women only) 
 
○ 
○ 
Adverse events 
 
○ 
○ 

 
14 
○ : Performed. 
○     : Performed throughout the surveillance period. 
Note 1) Gastric ulcer and reflux esophagitis are excluded. 
Note 2) Duodenal ulcer is excluded. 
Note 3) The time point will be essentially from 7 days before the start of treatment to the treatment 
start day. 
Note 4) The time point will be essentially until 14 days after the end of the surveillance (Week 8 
for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, or at treatment 
discontinuation). 
Note 5) Within 1 month before the start of treatment to the end of the surveillance. 

 
 
 
 
 
Drug Use Surveillance Protocol 
Drug Use Surveillance for Takecab Tablets 
Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5001 
Version No. 
Version 4 
Preparation date 
August 5, 2016 
 

 
Table of Contents 
1.0 
Background ...................................................................................................................................................... 1 
2.0 
Objective .......................................................................................................................................................... 1 
3.0 
Planned sample size and justification .............................................................................................................. 1 
3.1 
Planned sample size .................................................................................................................................... 1 
3.2 
Justification ................................................................................................................................................ 1 
4.0 
Subject patients ................................................................................................................................................ 2 
5.0 
Dosage and administration ............................................................................................................................... 2 
6.0 
Planned number of medical institutions by department ................................................................................... 2 
7.0 
Methods ........................................................................................................................................................... 2 
7.1 
Duration of observation .............................................................................................................................. 2 
7.2 
Requests to, and agreements with, study sites ............................................................................................ 2 
7.3 
Patient registration ...................................................................................................................................... 3 
7.4 
Data entry in the surveillance form (electronic) and electronic signature .................................................. 3 
7.5 
Measures to be taken in case of serious adverse events ............................................................................. 4 
8.0 
Scheduled period.............................................................................................................................................. 4 
9.0 
Items for surveillance ....................................................................................................................................... 4 
9.1 
Patient enrollment ....................................................................................................................................... 4 
9.2 
Patient demographic information ............................................................................................................... 4 
9.3 
Treatment information ................................................................................................................................ 5 
9.4 
Items for examination and observation....................................................................................................... 5 
9.4.1 
Endoscopy ............................................................................................................................................. 5 
9.4.2 
Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early satiety, 
epigastralgia, epigastric burning, sensation of abdominal distention, nausea/vomiting, burping, 
anorexia)................................................................................................................................................ 5 
9.4.3 
Liver function test ................................................................................................................................. 6 
9.4.4 
Other items for observation ................................................................................................................... 6 
9.5 
Adverse events............................................................................................................................................ 6 
10.0 
Analysis items and methods........................................................................................................................... 10 
10.1 
Items concerning study population composition ...................................................................................... 10 
10.2 
Patient demographics................................................................................................................................ 10 
10.3 
Treatment details ...................................................................................................................................... 10 
10.4 
Matters concerning the safety ................................................................................................................... 10 
10.4.1 
Factors of onset of adverse events ....................................................................................................... 10 
10.4.2 
Factors that may affect the safety ........................................................................................................ 10 
10.5 
Matters concerning the safety ................................................................................................................... 11 
10.5.1 
Endoscopic cure rate ........................................................................................................................... 11 
10.5.2 
Subjective symptom amelioration rate ................................................................................................ 11 
10.5.3 
Factors that may affect the efficacy ..................................................................................................... 11 
11.0 
Surveillance information registry .................................................................................................................. 11 

 
12.0 
Organizational structure ................................................................................................................................. 11 
12.1 
Manager .................................................................................................................................................... 11 
13.0 
Contract research organization....................................................................................................................... 11 
14.0 
Other requirements ........................................................................................................................................ 12 
14.1 
Protocol revisions ..................................................................................................................................... 12 
14.2 
Measures to be taken in the event of problematic or doubtful issues ....................................................... 12 
 
Appendix Schedule of observations............................................................................................................................13 

 
1 
1.0 
Background 
The safety of Takecab Tablets 20 mg in the treatment of gastric ulcer, duodenal ulcer, and reflux 
esophagitis has been assessed in Japanese clinical studies in 244, 183, and 988 patients, 
respectively, showing no remarkable problems. In postmarketing routine practices, however, 
unlike in the clinical studies, the drug may be used in patients with various complications and 
patients receiving multiple concomitant drugs, which means that the possibility of onset of 
unexpected adverse drug reactions cannot be ruled out based on the results of the clinical studies. 
Hence, we planned a drug use surveillance (hereinafter referred to as this surveillance) study to 
assess the safety and efficacy of Takecab Tablets in the three acid-related diseases gastric ulcer, 
duodenal ulcer, and reflux esophagitis in actual routine practices. 
This surveillance will be conducted in compliance with the MHLW Ministerial Ordinance on 
GPSP and other related regulatory requirements. 
 
2.0 
Objective 
To assess the safety and efficacy of Takecab Tablets in patients with gastric ulcer, duodenal ulcer, 
and reflux esophagitis in actual use settings and routine practices. 
 
3.0 
Planned sample size and justification 
3.1 Planned sample size 
3,000 Patients 
The sample size will not be less than 500 patients for each of gastric ulcer and duodenal ulcer, 
and will not be less than 1,000 patients for reflux esophagitis. 
 
3.2 Justification 
Gastric ulcer, duodenal ulcer, and reflux esophagitis all share the same pathologic feature that 
gastrointestinal mucosal injury is caused by gastric acid. Duration of treatment in Japanese 
clinical studies of Takecab Tablets in various patient populations with each disease was roughly 
the same for gastric ulcer and reflux esophagitis (up to 8 weeks) and duodenal ulcer (up to 6 
weeks), and incidences and severity of adverse drug reactions and safety profiles for adverse 
drug reactions with high incidences were similar. 
Based on the above facts, a drug use-results surveillance study will be conducted with a planned 
sample size of 3,000 patients with the three acid-related diseases of gastric ulcer, duodenal ulcer, 
and reflux esophagitis. With regard to the minimum sample size allowing the safety of Takecab 
Tablets to be assessed in patients with each disease, we have decided to enroll at least 500 
patients with gastric ulcer and duodenal ulcer. Since the number of patients with reflux 
esophagitis has been increasing rapidly year by year in Japan, and the disease is considered to 
affect the largest number of patients for whom Takecab Tablets is indicated, we have decided to 
enroll at least 1,000 patients with reflux esophagitis. Hence, incidences and severity of adverse 
drug reactions and differences in major adverse drug reactions in actual use settings and routine 
practices seem to be assessable by disease (the sample size was not statistically calculated). 

 
2 
 
4.0 
Subject patients 
Patients with gastric ulcer, duodenal ulcer, and reflux esophagitis will be enrolled. However, the 
subjects should not meet any of the exclusion criteria shown below. Refer to the Precautions in 
the package insert. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the subjects of this 
surveillance. 
1) Patients with a past medical history of hypersensitivity to any of the ingredients of 
Takecab Tablets 
2) Patients on treatment with atazanavir sulfate or rilpivirine hydrochloride 
3) When the target disease for Takecab Tablets is gastric ulcer or duodenal ulcer, patients 
whose endoscopic stage classification by Sakita and Miwa at the start of treatment with 
Takecab Tablets is the scarring stage (S1, S2) 
4) When the target disease for Takecab Tablets is reflux esophagitis, patients whose rating 
by the Los Angeles Classification of Gastroesophageal Reflux Disease (modified by 
Hoshihara) at the start of treatment with Takecab Tablets is Grade N or Grade M 
 
5.0 
Dosage and administration 
The usual adult dosage is 20 mg of vonoprazan administered orally once daily. Usually, the 
duration of treatment should be up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal 
ulcer. For reflux esophagitis, the duration of treatment should usually be up to 4 weeks; if the 
effect is insufficient, however, the drug can be administered for up to 8 weeks. Refer to the 
Precautions in the package insert. 
 
6.0 
Planned number of medical institutions by department 
Gastroenterology and other departments: About 500 medical institutions 
 
7.0 
Methods 
7.1 Duration of observation 
Duration of observation will be 8 weeks for gastric ulcer and reflux esophagitis and 6 weeks for 
duodenal ulcer. 
However, if treatment with Takecab Tablets is completed with the goal of treatment attained, or 
treatment with Takecab Tablets is discontinued for any reason, the surveillance will be ended at 
that time. 
 
7.2 Requests to, and agreements with, study sites 
Requests to, and agreements with, study sites will be made using a web-based electronic data 
collection system (
). Prior to starting this surveillance, an officer of Takeda 
Pharmaceutical Company Limited (hereinafter referred to as Takeda officer) will provide the 
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3 
surveillance investigator with an explanation about the objective and contents of this 
surveillance, 
 operating procedures, electronic signature, user ID, and handling of 
passwords using the documents “Request for Your Cooperation in Drug Use-Results 
Surveillance,” “Implementation Guideline,” “Input Screen Image,” and “
 Operating 
Manual (Abridged Edition)” and conclude written agreements with the study site to ask it to 
conduct the surveillance within the specified surveillance period. 
 
7.3 Patient registration 
“Central registration” based on 
 will be used. For the patients with Takecab Tablets 
prescribed on or after the starting day of the period of agreements with the study site, the 
surveillance investigator will enter patient enrollment information (refer to Section 9.1) into 
 and will provide an electronic signature not later than 14 days after the day of 
prescribing Takecab Tablets (the prescribing day is defined as “Day 0” and the day after the 
prescribing day as “Day 1”). 
 
7.4 Data entry in the surveillance form (electronic) and electronic signature 
For all the patients enrolled, the surveillance investigator or a person designated by the 
surveillance investigator* will enter patient characteristics information, treatment information, 
and other information into 
 and the surveillance investigator will provide an 
electronic signature generally within 1 month after the end of the observation period for each 
patient. If Takecab Tablets are not confirmed to have actually been taken, this fact will be entered 
(no other items need to be entered). 
For the patients who have discontinued Takecab Tablets for any reason during the observation 
period, the surveillance investigator or a person designated by the surveillance investigator will 
enter patient characteristics information, treatment information, and other information into 
 and the surveillance investigator will provide an electronic signature generally 
within 1 month after completion of the observations required. For the patients who have 
discontinued Takecab Tablets because of development of any adverse event, however, the 
surveillance investigator will continue observations until the adverse event resolves or remits 
whenever possible after treatment discontinuation, the surveillance investigator or a person 
designated by the surveillance investigator will enter the observation results into 
 
and the surveillance investigator will provide an electronic signature. 
 
*The person designated by the surveillance investigator will be a person belonging to the 
medical institution [including those who have contract agreements with a medical institution 
such as a contract research organization (CRO)]. The physicians who are the surveillance 
directors (one will be appointed for each study site or its department at the time of conclusion 
of contract agreements) will prepare records of the designees and designation dates and 
(whatever the form is) provide a signature or a signature and a seal, and submit the records to a 
Takeda officer before the person designated by the surveillance investigator enters data into 
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4 
 
 
7.5 Measures to be taken in case of serious adverse events 
If any serious adverse event develops during the observation period, the surveillance 
investigator will immediately notify this fact to a Takeda officer. Upon request from a Takeda 
officer, the surveillance investigator will separately provide detailed information. 
 
8.0 
Scheduled period 
Surveillance period: March 2016 to April 30, 2018 
Accrual period: March 2016 to February 28, 2018Note) 
Note) Even for the patients with Takecab Tablets prescribed by February 28, 2018, patient 
enrollment (data entry in 
) will not be accepted on and after March 1, 2018. 
If the number of enrolled patients reaches the planned sample size for this surveillance as a 
whole before February 28, 2018, registration will be terminated before the end of the patient 
accrual period. If the patient accrual period is shortened, the overall surveillance period will 
be changed in proportion to the shortage. 
In addition, enrollment may be subject to limitations for each target diseasebefore 
February 28, 2018 in view of the enrollment status for each target disease. 
 
9.0 
Items for surveillance 
The surveillance investigator or a person designated by the surveillance investigator will enter 
information on the items shown below into
: The schedule for this surveillance is 
shown in the Appendix. 
 
9.1 Patient enrollment 
1) Items for surveillance 
Date of prescribing Takecab Tablets, patient ID No., initialized patient name, sex, date of 
birth, target disease for Takecab Tablets, exclusion criteria ratings 
2) Surveillance times 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Items for surveillance 
Date of diagnosing the target disease, Inpatient/outpatient classification (from the start of 
treatment with Takecab Tablets), predisposition to hypersensitivity (presence/absence and 
details), complications (presence/absence and details), past medical history of gastric 
ulcer/duodenal ulcer/reflux esophagitis (presence/absence and details), height, body weight, 
presence/absence of Helicobacter pylori infection (from the start of treatment with Takecab 
Tablets), presence/absence of esophageal hiatal hernia, smoking history, drinking history, 
treatments prior to the start of Takecab Tablets [presence/absence, names of drugs, doses 
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5 
(excluding H2 blockers), and duration of treatment] 
2) Surveillance times 
At the start of treatment with Takecab Tablets 
 
9.3 Treatment information 
1) Items for surveillance 
Use of Takecab Tablets (daily dose, duration of treatment, and reason for treatment 
discontinuation), use of concomitant drugs (presence/absence, names of drugs, and purpose 
of administration) 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance will 
be at the time of treatment discontinuation. 
 
9.4 Items for examination and observation 
9.4.1 Endoscopy 
1) Items for examination 
Endoscopy (check date and findings*1) 
*1: Gastric ulcer and duodenal ulcer will be assessed using the endoscopic stage classification by 
Sakita and Miwa, and reflux esophagitis will be assessed using the classification of mucosal 
injuries according to the Los Angeles Classification of Gastroesophageal Reflux Disease 
(modified by Hoshihara). 
2) Surveillance times 
Examination time points at the start of treatment with Takecab Tablets*2 and the end of the 
surveillance*3 
*2: The time point will be essentially between 7 days before the start of treatment and the day of the 
start of treatment. 
*3: The time point will be essentially until 14 days after Week 8 for gastric ulcer and reflux esophagitis 
and after Week 6 for duodenal ulcer. If Takecab Tablets are discontinued before these times, the 
time point will be essentially until 14 days after treatment discontinuation. 
 
9.4.2 Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early 
satiety, epigastralgia, epigastric burning, sensation of abdominal distention, 
nausea/vomiting, burping, anorexia) 
1) Items for observation 
Subjective symptoms (presence/absence and severity*1) 
*1: Mild: Occasionally or slightly symptomatic. 
Moderate: Considerably symptomatic. 
Severe: Unendurably symptomatic. 

 
6 
2) Surveillance times 
Interview time points at the start of treatment with Takecab Tablets, at Week 2, at Week 4, 
and at the end of the surveillance*2. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the 
surveillance will be at the time of treatment discontinuation. 
 
9.4.3 Liver function test 
1) Parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Surveillance times 
Examination time points from the start of treatment with Takecab Tablets*1 to the end of 
the surveillance*2 
*1: Within 1 month before the start of treatment. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.4 Other items for observation 
1) Items for observation 
Presence/absence of pregnancy during the observation period (for women only) 
If the subject is found to be pregnant during the observation period, this fact should 
immediately be notified to a Takeda officer. Upon request by the Takeda officer, the 
surveillance investigator will provide detailed information (including information up to 
delivery, including details of premature birth and other outcomes) separately using a 
pregnant-woman sheet. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.5 Adverse events 
1) Items for surveillance 
Presence/absence of adverse events (see Table 1), names of adverse events, onset days, 
seriousness and rationale for the seriousness rating (see Table 2), cause of discontinuation 
of Takecab Tablets, outcome determination day, outcome, causality with Takecab Tablets* 
(see Table 3). 

 
7 
If the outcome is “unresolved” or “unknown” and if the causality is indeterminable, a 
follow-up surveillance will be performed whenever possible. 
In the event of manifested hepatic dysfunction or gastrointestinal infections with 
Clostridium difficile, detailed information (clinical courses, results of tests performed for 
diagnostic purposes, etc.) will be collected as much as possible. 
*If the rating of causality with Takecab Tablets is “unrelated”, information on the justification for the 
rating will be collected. If the rating is “indeterminable”, the reason will be recorded. 
Note) Matters to be taken into account with regard to adverse events 
Abnormal exacerbations of the target disease, including those exceeding the foreseeable 
spontaneous course of the condition, will be handled as adverse events. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
8 
Table 1 Definition of an adverse event 
An adverse event (AE) refers to any unwanted medical event appearing in a patient receiving a drug. 
An AE does not always represent an event for which causality with administration of the drug is 
evident. 
Hence, an adverse event refers to any unwanted or unintended sign (including abnormal laboratory 
values), symptom, or disease that has occurred in a subject receiving the test drug, irrespective of 
the presence/absence of causality with the drug. 
The following cases will also be handled as adverse events: 
•Symptoms etc. that have developed in infants breastfed by mothers on treatment with the drug 
•Unwanted symptoms etc. that have developed in children receiving the drug 
•Symptoms etc. that have developed with occupational exposure to the drug 
•Symptoms etc. that have developed with administration of a false drug imitating an ethical drug 
marketed by our company 
•Unwanted symptoms that have developed in persons using the drug and have become known by a 
lawsuit or any other legal act 
 
 

 
9 
Table 2 Seriousness rating criteria 
If any of the following criteria applies, the event will be rated as “serious.” 
1. Results in death (death) 
2. Life-threatening (possible death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (hospital admission 
or prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disorders) 
5. Causes congenital anomalies 
6. Medically important states secondary to Items 1 to 5 AEs included in the “Takeda Medically 
Significant AE List” will be included in this section 
 
Takeda Medically Significant AE List 
• Acute respiratory insufficiency/acute 
respiratory distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsades de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizures (including 
convulsions and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperpyrexia 
• Aplastic anemia 
• Spontaneous abortions/stillbirths and fetal deaths 
• Toxic epidermal 
necrolysis/oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of drug-
mediated infection 
• Acute hepatic failure 
• Endotoxin shock or, suspected 
• Hepatic necrosis 
 
 
 

 
10 
Table 3 Acceptance criteria for causality between adverse events and Takecab Tablets 
Rating 
Acceptance criteria 
Related 
A temporal correlation (including post-discontinuation courses) is found. 
Alternatively, although other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures, may also 
be involved, the event is attributable to the study drug. 
Unrelated 
No temporal correlation with the drug is found. Alternatively, the event is 
reasonably attributable to other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures. 
Indeterminable 
Information essential for assessments, such as temporal correlations 
(including post-discontinuation courses), primary disease, complications, 
concomitant drugs, and concomitant procedures, are lacking. 
 
10.0 
Analysis items and methods 
10.1 Items concerning study population composition 
Number of patients enrolled, number of patients from whom the surveillance form (electronic) 
has been collected, numbers of patients included in the safety and efficacy analysis sets, number 
of patients excluded from analysis and reasons for removal, and other items will be tabulated. 
 
10.2 Patient demographics 
Data on patient demographics, including sex, age, predisposition to hypersensitivity, and 
complications, will be tabulated. 
 
10.3 Treatment details 
Data on the use of Takecab Tablets and the use of concomitant drugs will be tabulated. 
 
10.4 Matters concerning the safety 
Data for the safety analysis set will be tabulated as follows: AEs will be reworded using the 
MedDRA/J and summarized with Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Factors of onset of adverse events 
With regard to the adverse events occurring during the observation period, frequency data 
will be tabulated by type, onset time, seriousness, causality with Takecab Tablets, and other 
aspects. 
 
10.4.2 Factors that may affect the safety 
With regard to the adverse drug reactions occurring during the observation period, 
frequency data will be tabulated by target disease, patient demographic factors (sex, age, 
presence/absence of complicating renal dysfunction, presence/absence of complicating 
hepatic dysfunction, etc.), and treatment (use of Takecab Tablets and use of concomitant 
drugs). 

 
11 
 
10.5 Matters concerning the safety 
Data for the efficacy analysis set will be tabulated as follows: 
10.5.1 Endoscopic cure rate 
Data on endoscopic cure rates in patients with endoscopic findings available at the start of 
treatment with Takecab Tablets and the end of the surveillance* will be tabulated by target 
disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation 
 
10.5.2 Subjective symptom amelioration rate 
Data on subjective symptom amelioration rates in patients with severity findings available 
from the start of treatment with Takecab Tablets to the end of the surveillance* will be 
tabulated by target disease. 
*The time point will be Week 8 for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, 
and, if treatment with Takecab Tablets is discontinued before these times, at the time of treatment 
discontinuation. 
 
10.5.3 Factors that may affect the efficacy 
Data on endoscopic cure rates and subjective symptom amelioration rates will be tabulated 
by target disease, patient demographic factors (sex, age, presence/absence of complicating 
renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), and 
treatment (use of Takecab Tablets, use of concomitant drugs). 
 
11.0 
Surveillance information registry 
Takeda Pharmaceutical Company Limited will register information on this surveillance study 
prior to its start date with an open-access website. 
•Japan Pharmaceutical Information Center Clinical Trials Information 
 
12.0 
Organizational structure 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract research organization 
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12 
 
14.0 
Other requirements 
14.1 Protocol revisions 
Study progression, onset of adverse drug reactions and serious adverse drug reactions that are 
unexpected from the Precautions, presence/absence of increased incidences of particular 
adverse drug reactions, validity of survey items, etc. will be monitored during the survey period 
and, if necessary, this protocol will be reconsidered and revised. If partial changes in the dosage 
and administration or indications are approved during the surveillance period, the necessity for 
revising this protocol will be determined as required, and the protocol will be revised if 
necessary. 
 
14.2 Measures to be taken in the event of problematic or doubtful issues 
If any problematic finding is found regarding safety and efficacy, the data will be checked 
extensively, and appropriate countermeasures will be considered. 
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13 
Appendix: Schedule of observations 
Surveillance information entry times 
 
 
Items for surveillance 
Duration of observation 
At the time 
of patient 
enrollment 
At the 
start of 
treatment 
with 
Takecab 
Tablets 
 
 
Week 
2 
 
 
 
Week 
4  
 
 
Week 
6 
Note 1) 
 
 
Week 
8 
Note 2) 
At the time of 
treatment 
discontinuation 
Patient 
enrollment 
Date of prescribing Takecab 
Tablets 
○ 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
Initialized name of patient 
○ 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
Target disease for Takecab Tablets 
○ 
 
 
 
 
 
 
Exclusion criteria rating 
○ 
 
 
 
 
 
 
Patient 
demographic 
information 
Date of diagnosing the target 
disease 
 
○ 
 
 
 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
 
 
Complications 
 
○ 
 
 
 
 
 
Past medical history of gastric 
ulcer/duodenal ulcer/reflux 
esophagitis 
 
○ 
 
 
 
 
 
Height, weight 
 
○ 
 
 
 
 
 
Presence/absence of Helicobacter 
pylori infection 
 
○ 
 
 
 
 
 
Presence/absence of esophageal 
hiatal hernia 
 
○ 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
Treatment prior to starting 
Takecab Tablets 
 
○ 
 
 
 
 
 
Treatment 
information 
Use of Takecab Tablets 
 
○ 
○ 
Use of concomitant drugs 
 
○ 
○ 
Items for 
examination 
and 
observation 
 
 
Endoscopy 
 
○ 
Note 3) 
 
 
○ 
Note 4) 
○ 
Note 4) 
○ 
Note 4) 
Severity of subjective symptoms 
 
○ 
○ 
○ 
○ 
○ 
○ 
Liver function test 
 
○Note 5) 
○ 
Presence/absence of pregnancy 
(for women only) 
 
○ 
○ 
Adverse events 
 
○ 
○ 

 
14 
○ : Performed. 
○     : Performed throughout the surveillance period. 
Note 1) Gastric ulcer and reflux esophagitis are excluded. 
Note 2) Duodenal ulcer is excluded. 
Note 3) The time point will be essentially from 7 days before the start of treatment to the treatment 
start day. 
Note 4) The time point will be essentially until 14 days after the end of the surveillance (Week 8 
for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer, or at treatment 
discontinuation). 
Note 5) Within 1 month before the start of treatment to the end of the surveillance. 

 
 
 
 
 
Drug Use Surveillance Protocol 
Drug Use Surveillance for Takecab Tablets 
Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5001 
Version No. 
Version 3 
Preparation date 
January 7, 2016 
 

 
Table of Contents 
1.0 
Background ...................................................................................................................................................... 1 
2.0 
Objective .......................................................................................................................................................... 1 
3.0 
Planned sample size and justification .............................................................................................................. 1 
3.1 
Planned sample size .................................................................................................................................... 1 
3.2 
Justification ................................................................................................................................................ 1 
4.0 
Subject patients ................................................................................................................................................ 2 
5.0 
Dosage and administration ............................................................................................................................... 2 
6.0 
Planned number of medical institutions by department ................................................................................... 2 
7.0 
Methods ........................................................................................................................................................... 2 
7.1 
Duration of observation .............................................................................................................................. 2 
7.2 
Requests to, and agreements with, study sites ............................................................................................ 2 
7.3 
Patient registration ...................................................................................................................................... 3 
7.4 
Data entry in the surveillance form (electronic) and electronic signature .................................................. 3 
7.5 
Measures to be taken in case of serious adverse events ............................................................................. 3 
8.0 
Scheduled period.............................................................................................................................................. 4 
9.0 
Items for surveillance ....................................................................................................................................... 4 
9.1 
Patient enrollment ....................................................................................................................................... 4 
9.2 
Patient demographic information ............................................................................................................... 4 
9.3 
Treatment information ................................................................................................................................ 4 
9.4 
Items for examination and observation....................................................................................................... 5 
9.4.1 
Endoscopy ............................................................................................................................................. 5 
9.4.2 
Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early satiety, 
epigastralgia, epigastric burning, sensation of abdominal distention, nausea/vomiting, burping, 
anorexia)................................................................................................................................................ 5 
9.4.3 
Liver function test ................................................................................................................................. 6 
9.4.4 
Other items for observation ................................................................................................................... 6 
9.5 
Adverse events............................................................................................................................................ 6 
10.0 
Analysis items and methods........................................................................................................................... 10 
10.1 
Items concerning study population composition ...................................................................................... 10 
10.2 
Patient demographics................................................................................................................................ 10 
10.3 
Treatment details ...................................................................................................................................... 10 
10.4 
Matters concerning the safety ................................................................................................................... 10 
10.4.1 
Factors of onset of adverse events ....................................................................................................... 10 
10.4.2 
Factors that may affect the safety ........................................................................................................ 10 
10.5 
Matters concerning the safety ................................................................................................................... 11 
10.5.1 
Endoscopic cure rate ........................................................................................................................... 11 
10.5.2 
Subjective symptom amelioration rate ................................................................................................ 11 
10.5.3 
Factors that may affect the efficacy ..................................................................................................... 11 
11.0 
Surveillance information registry .................................................................................................................. 11 

 
12.0 
Organizational structure ................................................................................................................................. 11 
12.1 
Manager .................................................................................................................................................... 11 
13.0 
Contract research organization....................................................................................................................... 11 
14.0 
Other requirements ........................................................................................................................................ 12 
14.1 
Protocol revisions ..................................................................................................................................... 12 
14.2 
Measures to be taken in the event of problematic or doubtful issues ....................................................... 12 
 
Appendix Schedule of observations............................................................................................................................13 
 

 
1 
1.0 
Background 
The safety of Takecab Tablets 20 mg in the treatment of gastric ulcer, duodenal ulcer, and reflux 
esophagitis has been assessed in Japanese clinical studies in 244, 183, and 988 patients, 
respectively, showing no remarkable problems. In postmarketing routine practices, however, 
unlike in the clinical studies, the drug may be used in patients with various complications and 
patients receiving multiple concomitant drugs, which means that the possibility of onset of 
unexpected adverse drug reactions cannot be ruled out based on the results of the clinical studies. 
Hence, we planned a drug use surveillance (hereinafter referred to as this surveillance) study to 
assess the safety and efficacy of Takecab Tablets in the three acid-related diseases gastric ulcer, 
duodenal ulcer, and reflux esophagitis in actual routine practices. 
This surveillance will be conducted in compliance with the MHLW Ministerial Ordinance on 
GPSP and other related regulatory requirements. 
 
2.0 
Objective 
To assess the safety and efficacy of Takecab Tablets in patients with gastric ulcer, duodenal ulcer, 
and reflux esophagitis in actual use settings and routine practices. 
 
3.0 
Planned sample size and justification 
3.1 Planned sample size 
3,000 Patients 
The sample size will not be less than 500 patients for each of gastric ulcer and duodenal ulcer, 
and will not be less than 1,000 patients for reflux esophagitis. 
 
3.2 Justification 
Gastric ulcer, duodenal ulcer, and reflux esophagitis all share the same pathologic feature that 
gastrointestinal mucosal injury is caused by gastric acid. Duration of treatment in Japanese 
clinical studies of Takecab Tablets in various patient populations with each disease was roughly 
the same for gastric ulcer and reflux esophagitis (up to 8 weeks) and duodenal ulcer (up to 6 
weeks), and incidences and severity of adverse drug reactions and safety profiles for adverse 
drug reactions with high incidences were similar. 
Based on the above facts, a drug use-results surveillance study will be conducted with a planned 
sample size of 3,000 patients with the three acid-related diseases of gastric ulcer, duodenal ulcer, 
and reflux esophagitis. With regard to the minimum sample size allowing the safety of Takecab 
Tablets to be assessed in patients with each disease, we have decided to enroll at least 500 
patients with gastric ulcer and duodenal ulcer. Since the number of patients with reflux 
esophagitis has been increasing rapidly year by year in Japan, and the disease is considered to 
affect the largest number of patients for whom Takecab Tablets is indicated, we have decided to 
enroll at least 1,000 patients with reflux esophagitis. Hence, incidences and severity of adverse 
drug reactions and differences in major adverse drug reactions in actual use settings and routine 
practices seem to be assessable by disease (the sample size was not statistically calculated). 

 
2 
 
4.0 
Subject patients 
Patients with gastric ulcer, duodenal ulcer, and reflux esophagitis will be enrolled. However, the 
subjects should not meet any of the exclusion criteria shown below. Refer to the Precautions in 
the package insert. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the subjects of this 
surveillance. 
1) Patients with a past medical history of hypersensitivity to any of the ingredients of 
Takecab Tablets 
2) Patients on treatment with atazanavir sulfate or rilpivirine hydrochloride 
3) When the target disease for Takecab Tablets is gastric ulcer or duodenal ulcer, patients 
whose endoscopic stage classification by Sakita and Miwa at the start of treatment with 
Takecab Tablets is the scarring stage (S1, S2) 
4) When the target disease for Takecab Tablets is reflux esophagitis, patients whose rating 
by the Los Angeles Classification of Gastroesophageal Reflux Disease (modified by 
Hoshihara) at the start of treatment with Takecab Tablets is Grade N or Grade M 
 
5.0 
Dosage and administration 
The usual adult dosage is 20 mg of vonoprazan administered orally once daily. Usually, the 
duration of treatment should be up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal 
ulcer. For reflux esophagitis, the duration of treatment should usually be up to 4 weeks; if the 
effect is insufficient, however, the drug can be administered for up to 8 weeks. Refer to the 
Precautions in the package insert. 
 
6.0 
Planned number of medical institutions by department 
Gastroenterology and other departments: About 500 medical institutions 
 
7.0 
Methods 
7.1 Duration of observation 
Duration of observation will be 8 weeks for gastric ulcer and reflux esophagitis and 6 weeks for 
duodenal ulcer. 
However, if treatment with Takecab Tablets is completed with the goal of treatment attained, or 
treatment with Takecab Tablets is discontinued for any reason, the surveillance will be ended at 
that time. 
 
7.2 Requests to, and agreements with, study sites 
Requests to, and agreements with, study sites will be made using a web-based electronic data 
collection system (
). Prior to starting this surveillance, an officer of Takeda 
Pharmaceutical Company Limited (hereinafter referred to as Takeda officer) will provide the 
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surveillance investigator with an explanation about the objective and contents of this 
surveillance, 
 operating procedures, electronic signature, user ID, and handling of 
passwords using the documents “Request for Your Cooperation in Drug Use-Results 
Surveillance,” “Implementation Guideline,” “Input Screen Image,” and “
 Operating 
Manual (Abridged Edition)” and conclude written agreements with the study site to ask it to 
conduct the surveillance within the specified surveillance period. 
 
7.3 Patient registration 
“Central registration” based on 
 will be used. For the patients with Takecab Tablets 
prescribed on or after the starting day of the period of agreements with the study site, the 
surveillance investigator or a person designated by the surveillance investigator will enter 
patient enrollment information (refer to Section 9.1) into 
 and the surveillance 
investigator will provide an electronic signature not later than 14 days after the day of 
prescribing Takecab Tablets (the prescribing day is defined as “Day 0” and the day after the 
prescribing day as “Day 1”). 
 
7.4 Data entry in the surveillance form (electronic) and electronic signature 
For all the patients enrolled, the surveillance investigator or a person designated by the 
surveillance investigator will enter patient characteristics information, treatment information, 
and other information into 
 and the surveillance investigator will provide an 
electronic signature generally within 1 month after the end of the observation period for each 
patient. If Takecab Tablets are not confirmed to have actually been taken, this fact will be entered 
(no other items need to be entered). 
For the patients who have discontinued Takecab Tablets for any reason during the observation 
period, the surveillance investigator or a person designated by the surveillance investigator will 
enter patient characteristics information, treatment information, and other information into 
 and the surveillance investigator will provide an electronic signature generally 
within 1 month after completion of the observations required. For the patients who have 
discontinued Takecab Tablets because of development of any adverse event, however, the 
surveillance investigator will continue observations until the adverse event resolves or remits 
whenever possible after treatment discontinuation, the surveillance investigator or a person 
designated by the surveillance investigator will enter the observation results into 
 
and the surveillance investigator will provide an electronic signature. 
 
7.5 Measures to be taken in case of serious adverse events 
If any serious adverse event develops during the observation period, the surveillance 
investigator will immediately notify this fact to a Takeda officer. Upon request from a Takeda 
officer, the surveillance investigator will separately provide detailed information. 
 
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8.0 
Scheduled period 
Surveillance period: March 2016 to April 30, 2018 
Accrual period: March 2016 to February 28, 2018Note) 
Note) Even for the patients with Takecab Tablets prescribed by February 28, 2018, patient 
enrollment (data entry in
) will not be accepted on and after March 1, 2018. 
If the number of enrolled patients reaches the planned sample size for this surveillance as a 
whole before February 28, 2018, registration will be terminated before the end of the patient 
accrual period. If the patient accrual period is shortened, the overall surveillance period will 
be changed in proportion to the shortage. 
In addition, enrollment may be subject to limitations for each target diseasebefore 
February 28, 2018 in view of the enrollment status for each target disease. 
 
9.0 
Items for surveillance 
The surveillance investigator or a person designated by the surveillance investigator will enter 
information on the items shown below into
: The schedule for this surveillance is 
shown in the Appendix. 
9.1 Patient enrollment 
1) Items for surveillance 
Date of prescribing Takecab Tablets, patient ID No., initialized patient name, sex, date of 
birth, target disease for Takecab Tablets, exclusion criteria ratings 
2) Surveillance times 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Items for surveillance 
Date of diagnosing the target disease, Inpatient/outpatient classification (from the start of 
treatment with Takecab Tablets), predisposition to hypersensitivity (presence/absence and 
details), complications (presence/absence and details), past medical history of gastric 
ulcer/duodenal ulcer/reflux esophagitis (presence/absence and details), height, body weight, 
presence/absence of Helicobacter pylori infection (from the start of treatment with Takecab 
Tablets), presence/absence of esophageal hiatal hernia, smoking history, drinking history, 
treatments prior to the start of Takecab Tablets [presence/absence, names of drugs, doses 
(excluding H2 blockers), and duration of treatment] 
2) Surveillance times 
At the start of treatment with Takecab Tablets 
 
9.3 Treatment information 
1) Items for surveillance 
Use of Takecab Tablets (daily dose, duration of treatment, and reason for treatment 
discontinuation), use of concomitant drugs (presence/absence, names of drugs, and purpose 
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of administration) 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance will 
be at the time of treatment discontinuation. 
 
9.4 Items for examination and observation 
9.4.1 Endoscopy 
1) Items for examination 
Endoscopy (check date and findings*1) 
*1: Gastric ulcer and duodenal ulcer will be assessed using the endoscopic stage classification by 
Sakita and Miwa, and reflux esophagitis will be assessed using the classification of mucosal 
injuries according to the Los Angeles Classification of Gastroesophageal Reflux Disease 
(modified by Hoshihara). 
2) Surveillance times 
Examination time points at the start of treatment with Takecab Tablets*2 and the end of the 
surveillance*3 
*2: The time point will be essentially between 7 days before the start of treatment and the day of the 
start of treatment. 
*3: The time point will be essentially until 14 days after Week 8 for gastric ulcer and reflux esophagitis 
and after Week 6 for duodenal ulcer. If Takecab Tablets are discontinued before these times, the 
time point will be essentially until 14 days after treatment discontinuation. 
 
9.4.2 Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early 
satiety, epigastralgia, epigastric burning, sensation of abdominal distention, 
nausea/vomiting, burping, anorexia) 
1) Items for observation 
Subjective symptoms (presence/absence and severity*) 
*Mild: Occasionally or slightly symptomatic. 
Moderate: Considerably symptomatic. 
Severe: Unendurably symptomatic. 
2) Surveillance times 
Interview time points at the start of treatment with Takecab Tablets, at Week 2, at Week 4, 
and at the end of the surveillance*. 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
6 
9.4.3 Liver function test 
1) Parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Surveillance times 
Examination time points from the start of treatment with Takecab Tablets*1 to the end of 
the surveillance*2 
*1: Within 1 month before the start of treatment. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.4 Other items for observation 
1) Items for observation 
Presence/absence of pregnancy during the observation period (for women only) 
If the subject is found to be pregnant during the observation period, this fact should 
immediately be notified to a Takeda officer. Upon request by the Takeda officer, the 
surveillance investigator will provide detailed information (including information up to 
delivery, including details of premature birth and other outcomes) separately using a 
pregnant-woman sheet. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.5 Adverse events 
1) Items for surveillance 
Presence/absence of adverse events (see Table 1), names of adverse events, onset days, 
seriousness and rationale for the seriousness rating (see Table 2), cause of discontinuation 
of Takecab Tablets, outcome determination day, outcome, causality with Takecab Tablets* 
(see Table 3). 
If the outcome is “unresolved” or “unknown” and if the causality is indeterminable, a 
follow-up surveillance will be performed whenever possible. 
In the event of manifested hepatic dysfunction or gastrointestinal infections with 
Clostridium difficile, detailed information (clinical courses, results of tests performed for 
diagnostic purposes, etc.) will be collected as much as possible. 
*If the rating of causality with Takecab Tablets is “unrelated”, information on the justification for the 
rating will be collected. If the rating is “indeterminable”, the reason will be recorded. 

 
7 
Note) Matters to be taken into account with regard to adverse events 
Abnormal exacerbations of the target disease, including those exceeding the foreseeable 
spontaneous course of the condition, will be handled as adverse events. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
8 
Table 1 Definition of an adverse event 
An adverse event (AE) refers to any unwanted medical event appearing in a patient receiving a drug. 
An AE does not always represent an event for which causality with administration of the drug is 
evident. 
Hence, an adverse event refers to any unwanted or unintended sign (including abnormal laboratory 
values), symptom, or disease that has occurred in a subject receiving the test drug, irrespective of 
the presence/absence of causality with the drug. 
The following cases will also be handled as adverse events: 
•Symptoms etc. that have developed in infants breastfed by mothers on treatment with the drug 
•Unwanted symptoms etc. that have developed in children receiving the drug 
•Symptoms etc. that have developed with occupational exposure to the drug 
•Symptoms etc. that have developed with administration of a false drug imitating an ethical drug 
marketed by our company 
•Unwanted symptoms that have developed in persons using the drug and have become known by a 
lawsuit or any other legal act 
 
 
 

 
9 
Table 2 Seriousness rating criteria 
If any of the following criteria applies, the event will be rated as “serious.” 
1. Results in death (death) 
2. Life-threatening (possible death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (hospital admission 
or prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disorders) 
5. Causes congenital anomalies 
6. Medically important states secondary to Items 1 to 5 AEs included in the “Takeda Medically 
Significant AE List” will be included in this section 
 
Takeda Medically Significant AE List 
• Acute respiratory insufficiency/acute 
respiratory distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsades de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizures (including 
convulsions and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperpyrexia 
• Aplastic anemia 
• Spontaneous abortions/stillbirths and fetal deaths 
• Toxic epidermal 
necrolysis/oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of drug-
mediated infection 
• Acute hepatic failure 
• Endotoxin shock or, suspected 
• Hepatic necrosis 
 
 
 

 
10 
Table 3 Acceptance criteria for causality between adverse events and Takecab Tablets 
Rating 
Acceptance criteria 
Related 
A temporal correlation (including post-discontinuation courses) is found. 
Alternatively, although other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures, may also 
be involved, the event is attributable to the study drug. 
Unrelated 
No temporal correlation with the drug is found. Alternatively, the event is 
reasonably attributable to other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures. 
Indeterminable 
Information essential for assessments, such as temporal correlations 
(including post-discontinuation courses), primary disease, complications, 
concomitant drugs, and concomitant procedures, are lacking. 
 
10.0 
Analysis items and methods 
10.1 Items concerning study population composition 
Number of patients enrolled, number of patients from whom the surveillance form (electronic) 
has been collected, numbers of patients included in the safety and efficacy analysis sets, number 
of patients excluded from analysis and reasons for removal, and other items will be tabulated. 
 
10.2 Patient demographics 
Data on patient demographics, including sex, age, predisposition to hypersensitivity, and 
complications, will be tabulated. 
 
10.3 Treatment details 
Data on the use of Takecab Tablets and the use of concomitant drugs will be tabulated. 
 
10.4 Matters concerning the safety 
Data for the safety analysis set will be tabulated as follows: AEs will be reworded using the 
MedDRA/J and summarized with Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Factors of onset of adverse events 
With regard to the adverse events occurring during the observation period, frequency data will 
be tabulated by type, onset time, seriousness, causality with Takecab Tablets, and other aspects. 
 
10.4.2 Factors that may affect the safety 
With regard to the adverse drug reactions occurring during the observation period, frequency 
data will be tabulated by target disease, patient demographic factors (sex, age, presence/absence 
of complicating renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), 
and treatment (use of Takecab Tablets and use of concomitant drugs). 
 

 
11 
10.5 Matters concerning the safety 
Data for the efficacy analysis set will be tabulated as follows: 
10.5.1 Endoscopic cure rate 
Data on endoscopic cure rates in patients with endoscopic findings available at the start of 
treatment with Takecab Tablets and the end of the surveillance will be tabulated by target 
disease. 
 
10.5.2 Subjective symptom amelioration rate 
Data on subjective symptom amelioration rates in patients with severity findings available 
from the start of treatment with Takecab Tablets to the end of the surveillance will be 
tabulated by target disease. 
 
10.5.3 Factors that may affect the efficacy 
Data on endoscopic cure rates and subjective symptom amelioration rates will be tabulated 
by target disease, patient demographic factors (sex, age, presence/absence of complicating 
renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), and 
treatment (use of Takecab Tablets, use of concomitant drugs). 
 
11.0 
Surveillance information registry 
Takeda Pharmaceutical Company Limited will register information on this surveillance study 
prior to its start date with an open-access website. 
•Japan Pharmaceutical Information Center Clinical Trials Information 
 
12.0 
Organizational structure 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract research organization 
 
PPD
PPD

 
12 
14.0 
Other requirements 
14.1 Protocol revisions 
Study progression, onset of adverse drug reactions and serious adverse drug reactions that are 
unexpected from the Precautions, presence/absence of increased incidences of particular 
adverse drug reactions, validity of survey items, etc. will be monitored during the survey period 
and, if necessary, this protocol will be reconsidered and revised. If partial changes in the dosage 
and administration or indications are approved during the surveillance period, the necessity for 
revising this protocol will be determined as required, and the protocol will be revised if 
necessary. 
 
14.2 Measures to be taken in the event of problematic or doubtful issues 
If any problematic finding is found regarding safety and efficacy, the data will be checked 
extensively, and appropriate countermeasures will be considered. 

 
13 
Appendix: Schedule of observations 
Surveillance information entry times 
 
 
Items for surveillance 
Duration of observation 
At the time 
of patient 
enrollment 
At the 
start of 
treatment 
with 
Takecab 
Tablets 
 
 
Week 
2 
 
 
 
Week 
4  
 
 
Week 
6 
Note 1) 
 
 
Week 
8 
Note 2) 
At the time of 
treatment 
discontinuation 
Patient 
enrollment 
Date of prescribing Takecab 
Tablets 
○ 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
Initialized name of patient 
○ 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
Target disease for Takecab 
Tablets 
○ 
 
 
 
 
 
 
Exclusion criteria rating 
○ 
 
 
 
 
 
 
Patient 
demographic 
information 
Date of diagnosing the target 
disease 
 
○ 
 
 
 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
 
 
Complications 
 
○ 
 
 
 
 
 
Past medical history of gastric 
ulcer/duodenal ulcer/reflux 
esophagitis 
 
○ 
 
 
 
 
 
Height, weight 
 
○ 
 
 
 
 
 
Presence/absence of 
Helicobacter pylori infection 
 
○ 
 
 
 
 
 
Presence/absence of esophageal 
hiatal hernia 
 
○ 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
Treatment prior to starting 
Takecab Tablets 
 
○ 
 
 
 
 
 
Treatment 
information 
Use of Takecab Tablets 
 
○ 
○ 
Use of concomitant drugs 
 
○ 
○ 
Items for 
examination 
and 
observation 
 
 
Endoscopy 
 
○ 
Note 3) 
 
 
○ 
Note 4) 
○ 
Note 4) 
○ 
Note 4) 
Severity of subjective 
symptoms 
 
○ 
○ 
○ 
○ 
○ 
○ 
Liver function test 
 
 
○Note 5) 
○ 
Presence/absence of pregnancy 
(for women only) 
 
○ 
○ 
Adverse events 
 
○ 
○ 
○ : Performed. 

 
14 
○     : Performed throughout the surveillance period. 
Note 1) Gastric ulcer and reflux esophagitis are excluded. 
Note 2) Duodenal ulcer is excluded. 
Note 3) The time point will be essentially from 7 days before the start of treatment to the treatment 
start day. 
Note 4) The time point will be essentially until 14 days after the end of the surveillance (Week 8 
for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer) or treatment 
discontinuation. 
Note 5) Within 1 month before the start of treatment to the end of the surveillance. 

 
 
 
 
 
Drug Use Surveillance Protocol 
Drug Use Surveillance for Takecab Tablets 
Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5001 
Version No. 
Version 2 
Preparation date 
June 22, 2015 
 

 
Table of Contents 
1.0 
Background ...................................................................................................................................................... 1 
2.0 
Objective .......................................................................................................................................................... 1 
3.0 
Planned sample size and justification .............................................................................................................. 1 
3.1 
Planned sample size .................................................................................................................................... 1 
3.2 
Justification ................................................................................................................................................ 1 
4.0 
Subject patients ................................................................................................................................................ 2 
5.0 
Dosage and administration ............................................................................................................................... 2 
6.0 
Planned number of medical institutions by department ................................................................................... 2 
7.0 
Methods ........................................................................................................................................................... 2 
7.1 
Duration of observation .............................................................................................................................. 2 
7.2 
Requests to, and agreements with, study sites ............................................................................................ 2 
7.3 
Patient registration ...................................................................................................................................... 3 
7.4 
Data entry in the surveillance form (electronic) and electronic signature .................................................. 3 
7.5 
Measures to be taken in case of serious adverse events ............................................................................. 3 
8.0 
Scheduled period.............................................................................................................................................. 3 
9.0 
Items for surveillance ....................................................................................................................................... 4 
9.1 
Patient enrollment ....................................................................................................................................... 4 
9.2 
Patient demographic information ............................................................................................................... 4 
9.3 
Treatment information ................................................................................................................................ 4 
9.4 
Items for examination and observation....................................................................................................... 5 
9.4.1 
Endoscopy ............................................................................................................................................. 5 
9.4.2 
Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early satiety, 
epigastralgia, epigastric burning, sensation of abdominal distention, nausea/vomiting, burping, 
anorexia)................................................................................................................................................ 5 
9.4.3 
Liver function test ................................................................................................................................. 5 
9.4.4 
Other items for observation ................................................................................................................... 6 
9.5 
Adverse events............................................................................................................................................ 6 
10.0 
Analysis items and methods........................................................................................................................... 10 
10.1 
Items concerning study population composition ...................................................................................... 10 
10.2 
Patient demographics................................................................................................................................ 10 
10.3 
Treatment details ...................................................................................................................................... 10 
10.4 
Matters concerning the safety ................................................................................................................... 10 
10.4.1 
Factors of onset of adverse events ....................................................................................................... 10 
10.4.2 
Factors that may affect the safety ........................................................................................................ 10 
10.5 
Matters concerning the safety ................................................................................................................... 11 
10.5.1 
Endoscopic cure rate ........................................................................................................................... 11 
10.5.2 
Subjective symptom amelioration rate ................................................................................................ 11 
10.5.3 
Factors that may affect the efficacy ..................................................................................................... 11 
11.0 
Surveillance information registry .................................................................................................................. 11 

 
12.0 
Organizational structure ................................................................................................................................. 11 
12.1 
Manager .................................................................................................................................................... 11 
13.0 
Contract research organization....................................................................................................................... 11 
14.0 
Other requirements ........................................................................................................................................ 12 
14.1 
Protocol revisions ..................................................................................................................................... 12 
14.2 
Measures to be taken in the event of problematic or doubtful issues ....................................................... 12 
 
Appendix Schedule of observations...........................................................................................................................13 

 
1 
1.0 
Background 
The safety of Takecab Tablets 20 mg in the treatment of gastric ulcer, duodenal ulcer, and reflux 
esophagitis has been assessed in Japanese clinical studies in 244, 183, and 988 patients, 
respectively, showing no remarkable problems. In postmarketing routine practices, however, 
unlike in the clinical studies, the drug may be used in patients with various complications and 
patients receiving multiple concomitant drugs, which means that the possibility of onset of 
unexpected adverse drug reactions cannot be ruled out based on the results of the clinical studies. 
Hence, we planned a drug use surveillance (hereinafter referred to as this surveillance) study to 
assess the safety and efficacy of Takecab Tablets in the three acid-related diseases gastric ulcer, 
duodenal ulcer, and reflux esophagitis in actual routine practices. 
This surveillance will be conducted in compliance with the MHLW Ministerial Ordinance on 
GPSP and other related regulatory requirements. 
 
2.0 
Objective 
To assess the safety and efficacy of Takecab Tablets in patients with gastric ulcer, duodenal ulcer, 
and reflux esophagitis in actual use settings and routine practices. 
 
3.0 
Planned sample size and justification 
3.1 Planned sample size 
3,000 Patients 
The sample size will not be less than 500 patients for each of gastric ulcer and duodenal ulcer, 
and will not be less than 1,000 patients for reflux esophagitis. 
 
3.2 Justification 
Gastric ulcer, duodenal ulcer, and reflux esophagitis all share the same pathologic feature that 
gastrointestinal mucosal injury is caused by gastric acid. Duration of treatment in Japanese 
clinical studies of Takecab Tablets in various patient populations with each disease was roughly 
the same for gastric ulcer and reflux esophagitis (up to 8 weeks) and duodenal ulcer (up to 6 
weeks), and incidences and severity of adverse drug reactions and safety profiles for adverse 
drug reactions with high incidences were similar. 
Based on the above facts, a drug use-results surveillance study will be conducted with a planned 
sample size of 3,000 patients with the three acid-related diseases of gastric ulcer, duodenal ulcer, 
and reflux esophagitis. With regard to the minimum sample size allowing the safety of Takecab 
Tablets to be assessed in patients with each disease, we have decided to enroll at least 500 
patients with gastric ulcer and duodenal ulcer. Since the number of patients with reflux 
esophagitis has been increasing rapidly year by year in Japan, and the disease is considered to 
affect the largest number of patients for whom Takecab Tablets is indicated, we have decided to 
enroll at least 1,000 patients with reflux esophagitis. Hence, incidences and severity of adverse 
drug reactions and differences in major adverse drug reactions in actual use settings and routine 
practices seem to be assessable by disease (the sample size was not statistically calculated). 

 
2 
 
4.0 
Subject patients 
Patients with gastric ulcer, duodenal ulcer, and reflux esophagitis will be enrolled. However, the 
subjects should not meet any of the exclusion criteria shown below. Refer to the Precautions in 
the package insert. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the subjects of this 
surveillance. 
1) Patients with a past medical history of hypersensitivity to any of the ingredients of 
Takecab Tablets 
2) Patients on treatment with atazanavir sulfate or rilpivirine hydrochloride 
3) When the target disease for Takecab Tablets is gastric ulcer or duodenal ulcer, patients 
whose endoscopic stage classification by Sakita and Miwa at the start of treatment with 
Takecab Tablets is the scarring stage (S1, S2) 
4) When the target disease for Takecab Tablets is reflux esophagitis, patients whose rating 
by the Los Angeles Classification of Gastroesophageal Reflux Disease (modified by 
Hoshihara) at the start of treatment with Takecab Tablets is Grade N or Grade M 
 
5.0 
Dosage and administration 
The usual adult dosage is 20 mg of vonoprazan administered orally once daily. Usually, the 
duration of treatment should be up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal 
ulcer. For reflux esophagitis, the duration of treatment should usually be up to 4 weeks; if the 
effect is insufficient, however, the drug can be administered for up to 8 weeks. Refer to the 
Precautions in the package insert. 
 
6.0 
Planned number of medical institutions by department 
Gastroenterology and other departments: About 500 medical institutions 
 
7.0 
Methods 
7.1 Duration of observation 
Duration of observation will be 8 weeks for gastric ulcer and reflux esophagitis and 6 weeks for 
duodenal ulcer. 
However, if treatment with Takecab Tablets is completed with the goal of treatment attained, or 
treatment with Takecab Tablets is discontinued for any reason, the surveillance will be ended at 
that time. 
 
7.2 Requests to, and agreements with, study sites 
Requests to, and agreements with, study sites will be made using a web-based electronic data 
collection system (
). Prior to starting this surveillance, an officer of Takeda 
Pharmaceutical Company Limited (hereinafter referred to as Takeda officer) will provide the 
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surveillance investigator with an explanation about the objective and contents of this 
surveillance, 
 operating procedures, electronic signature, user ID, and handling of 
passwords using the documents “Request for Your Cooperation in Drug Use-Results 
Surveillance,” “Implementation Guideline,” “Input Screen Image,” and “
 Operating 
Manual (Abridged Edition)” and conclude written agreements with the study site to ask it to 
conduct the surveillance within the specified surveillance period. 
 
7.3 Patient registration 
“Central registration” based on 
 will be used. For the patients with Takecab Tablets 
prescribed on or after the starting day of the period of agreements with the study site, the 
surveillance investigator will enter patient enrollment information (refer to Section 9.1) into 
 and provide an electronic signature not later than 14 days after the day of prescribing 
Takecab Tablets (the prescribing day is defined as “Day 0” and the day after the prescribing day 
as “Day 1”). 
 
7.4 Data entry in the surveillance form (electronic) and electronic signature 
For all the patients enrolled, the surveillance investigator will enter patient characteristics 
information, treatment information, and other information into 
 and provide an 
electronic signature generally within 1 month after the end of the observation period for each 
patient. If Takecab Tablets are not confirmed to have actually been taken, this fact will be entered 
(no other items need to be entered). 
For the patients who have discontinued Takecab Tablets for any reason during the observation 
period, the surveillance investigator will enter patient characteristics information, treatment 
information, and other information into 
 and provide an electronic signature 
generally within 1 month after completion of the observations required. For the patients who 
have discontinued Takecab Tablets because of development of any adverse event, however, the 
surveillance investigator will continue observations until the adverse event resolves or remits 
whenever possible after treatment discontinuation, enter the observation results into 
 
and provide an electronic signature. 
 
7.5 Measures to be taken in case of serious adverse events 
If any serious adverse event develops during the observation period, the surveillance 
investigator will immediately notify this fact to a Takeda officer. Upon request from a Takeda 
officer, the surveillance investigator will separately provide detailed information. 
 
8.0 
Scheduled period 
Surveillance period: March 2016 to April 30, 2018 
Accrual period: March 2016 to February 28, 2018Note) 
Note) Even for the patients with Takecab Tablets prescribed by February 28, 2018, patient 
enrollment (data entry in 
 will not be accepted on and after March 1, 2018. 
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If the number of enrolled patients reaches the planned sample size for this surveillance as a 
whole before February 28, 2018, registration will be terminated before the end of the patient 
accrual period. If the patient accrual period is shortened, the overall surveillance period will 
be changed in proportion to the shortage. 
In addition, enrollment may be subject to limitations for each target disease before 
February 28, 2018 in view of the enrollment status for each target disease. 
 
9.0 
Items for surveillance 
The surveillance investigator will enter information on the items shown below into
: 
The schedule for this surveillance is shown in the Appendix. 
9.1 Patient enrollment 
1) Items for surveillance 
Date of prescribing Takecab Tablets, patient ID No., initialized patient name, sex, date of 
birth, target disease for Takecab Tablets, exclusion criteria ratings 
2) Surveillance times 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Items for surveillance 
Date of diagnosing the target disease, Inpatient/outpatient classification (from the start of 
treatment with Takecab Tablets), predisposition to hypersensitivity (presence/absence and 
details), complications (presence/absence and details), past medical history of gastric 
ulcer/duodenal ulcer/reflux esophagitis (presence/absence and details), height, body weight, 
presence/absence of Helicobacter pylori infection (from the start of treatment with Takecab 
Tablets), presence/absence of esophageal hiatal hernia, smoking history, drinking history, 
treatments prior to the start of Takecab Tablets [presence/absence, names of drugs, doses 
(excluding H2 blockers), and duration of treatment] 
2) Surveillance times 
At the start of treatment with Takecab Tablets 
 
9.3 Treatment information 
1) Items for surveillance 
Use of Takecab Tablets (daily dose, duration of treatment, and reason for treatment 
discontinuation), use of concomitant drugs (presence/absence, names of drugs, and purpose 
of administration) 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance will 
be at the time of treatment discontinuation. 
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9.4 Items for examination and observation 
9.4.1 Endoscopy 
1) Items for examination 
Endoscopy (check date and findings*1) 
*1: Gastric ulcer and duodenal ulcer will be assessed using the endoscopic stage classification by 
Sakita and Miwa, and reflux esophagitis will be assessed using the classification of mucosal 
injuries according to the Los Angeles Classification of Gastroesophageal Reflux Disease 
(modified by Hoshihara). 
2) Surveillance times 
Examination time points at the start of treatment with Takecab Tablets*2 and the end of the 
surveillance*3 
*2: The time point will be essentially between 7 days before the start of treatment and the day of the 
start of treatment. 
*3: The time point will be essentially until 14 days after Week 8 for gastric ulcer and reflux esophagitis 
and after Week 6 for duodenal ulcer. If Takecab Tablets are discontinued before these times, the 
time point will be essentially until 14 days after treatment discontinuation. 
 
9.4.2 Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early 
satiety, epigastralgia, epigastric burning, sensation of abdominal distention, 
nausea/vomiting, burping, anorexia) 
1) Items for observation 
Subjective symptoms (presence/absence and severity*) 
*Mild: Occasionally or slightly symptomatic. 
Moderate: Considerably symptomatic. 
Severe: Unendurably symptomatic. 
2) Surveillance times 
Interview time points at the start of treatment with Takecab Tablets, at Week 2, at Week 4, 
and at the end of the surveillance*. 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.3 Liver function test 
1) Parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Surveillance times 
Examination time points from the start of treatment with Takecab Tablets*1 to the end of 

 
6 
the surveillance*2 
*1: Within 1 month before the start of treatment. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.4 Other items for observation 
1) Items for observation 
Presence/absence of pregnancy during the observation period (for women only) 
If the subject is found to be pregnant during the observation period, this fact should 
immediately be notified to a Takeda officer. Upon request by the Takeda officer, the 
surveillance investigator will provide detailed information (including information up to 
delivery, including details of premature birth and other outcomes) separately using a 
pregnant-woman sheet. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.5 Adverse events 
1) Items for surveillance 
Presence/absence of adverse events (see Table 1), names of adverse events, onset days, 
seriousness and rationale for the seriousness rating (see Table 2), cause of discontinuation 
of Takecab Tablets, outcome determination day, outcome, causality with Takecab Tablets* 
(see Table 3). 
If the outcome is “unresolved” or “unknown” and if the causality is indeterminable, a 
follow-up surveillance will be performed whenever possible. 
In the event of manifested hepatic dysfunction or gastrointestinal infections with 
Clostridium difficile, detailed information (clinical courses, results of tests performed for 
diagnostic purposes, etc.) will be collected as much as possible. 
*If the rating of causality with Takecab Tablets is “unrelated”, information on the justification for the 
rating will be collected. If the rating is “indeterminable”, the reason will be recorded. 
Note) Matters to be taken into account with regard to adverse events 
Abnormal exacerbations of the target disease, including those exceeding the foreseeable 
spontaneous course of the condition, will be handled as adverse events, whereas foreseeable 
exacerbations of the target disease will not be handled as adverse events. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 

 
7 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
8 
Table 1 Definition of an adverse event 
An adverse event (AE) refers to any unwanted medical event appearing in a patient receiving a drug. 
An AE does not always represent an event for which causality with administration of the drug is 
evident. 
Hence, an adverse event refers to any unwanted or unintended sign (including abnormal laboratory 
values), symptom, or disease that has occurred in a subject receiving the test drug, irrespective of 
the presence/absence of causality with the drug. 
The following cases will also be handled as adverse events: 
•Symptoms etc. that have developed in infants breastfed by mothers on treatment with the drug 
•Unwanted symptoms etc. that have developed in children receiving the drug 
•Symptoms etc. that have developed with occupational exposure to the drug 
•Symptoms etc. that have developed with administration of a false drug imitating an ethical drug 
marketed by our company 
•Unwanted symptoms that have developed in persons using the drug and have become known by a 
lawsuit or any other legal act 
 
 
 

 
9 
Table 2 Seriousness rating criteria 
If any of the following criteria applies, the event will be rated as “serious.” 
1. Results in death (death) 
2. Life-threatening (possible death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (hospital admission 
or prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disorders) 
5. Causes congenital anomalies 
6. Medically important states secondary to Items 1 to 5 AEs included in the “Takeda Medically 
Significant AE List” will be included in this section 
 
Takeda Medically Significant AE List 
• Acute respiratory insufficiency/acute 
respiratory distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsades de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizures (including 
convulsions and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperpyrexia 
• Aplastic anemia 
• Spontaneous abortions/stillbirths and fetal deaths 
• Toxic epidermal 
necrolysis/oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of drug-
mediated infection 
• Acute hepatic failure 
• Endotoxin shock or, suspected 
• Hepatic necrosis 
 
 
 
 
 

 
10 
Table 3 Acceptance criteria for causality between adverse events and Takecab Tablets 
Rating 
Acceptance criteria 
Related 
A temporal correlation (including post-discontinuation courses) is found. 
Alternatively, although other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures, may also 
be involved, the event is attributable to the study drug. 
Unrelated 
No temporal correlation with the drug is found. Alternatively, the event is 
reasonably attributable to other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures. 
Indeterminable 
Information essential for assessments, such as temporal correlations 
(including post-discontinuation courses), primary disease, complications, 
concomitant drugs, and concomitant procedures, are lacking. 
 
10.0 
Analysis items and methods 
10.1 Items concerning study population composition 
Number of patients enrolled, number of patients from whom the surveillance form (electronic) 
has been collected, numbers of patients included in the safety and efficacy analysis sets, number 
of patients excluded from analysis and reasons for removal, and other items will be tabulated. 
 
10.2 Patient demographics 
Data on patient demographics, including sex, age, predisposition to hypersensitivity, and 
complications, will be tabulated. 
 
10.3 Treatment details 
Data on the use of Takecab Tablets and the use of concomitant drugs will be tabulated. 
 
10.4 Matters concerning the safety 
Data for the safety analysis set will be tabulated as follows: AEs will be reworded using the 
MedDRA/J and summarized with Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Factors of onset of adverse events 
With regard to the adverse events occurring during the observation period, frequency data 
will be tabulated by type, onset time, seriousness, causality with Takecab Tablets, and other 
aspects. 
 
10.4.2 Factors that may affect the safety 
With regard to the adverse drug reactions occurring during the observation period, 
frequency data will be tabulated by target disease, patient demographic factors (sex, age, 
presence/absence of complicating renal dysfunction, presence/absence of complicating 
hepatic dysfunction, etc.), and treatment (use of Takecab Tablets and use of concomitant 
drugs). 

 
11 
 
10.5 Matters concerning the safety 
Data for the efficacy analysis set will be tabulated as follows: 
10.5.1 Endoscopic cure rate 
Data on endoscopic cure rates in patients with endoscopic findings available at the start of 
treatment with Takecab Tablets and the end of the surveillance will be tabulated by target 
disease. 
 
10.5.2 Subjective symptom amelioration rate 
Data on subjective symptom amelioration rates in patients with severity findings available 
from the start of treatment with Takecab Tablets to the end of the surveillance will be 
tabulated by target disease. 
 
10.5.3 Factors that may affect the efficacy 
Data on endoscopic cure rates and subjective symptom amelioration rates will be tabulated 
by target disease, patient demographic factors (sex, age, presence/absence of complicating 
renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), and 
treatment (use of Takecab Tablets, use of concomitant drugs). 
 
11.0 
Surveillance information registry 
Takeda Pharmaceutical Company Limited will register information on this surveillance study 
prior to its start date with an open-access website. 
•Japan Pharmaceutical Information Center Clinical Trials Information 
 
12.0 
Organizational structure 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract research organization 
 
PPD
PPD

 
12 
14.0 
Other requirements 
14.1 Protocol revisions 
Study progression, onset of adverse drug reactions and serious adverse drug reactions that are 
unexpected from the Precautions, presence/absence of increased incidences of particular 
adverse drug reactions, validity of survey items, etc. will be monitored during the survey period 
and, if necessary, this protocol will be reconsidered and revised. If partial changes in the dosage 
and administration or indications are approved during the surveillance period, the necessity for 
revising this protocol will be determined as required, and the protocol will be revised if 
necessary. 
 
14.2 Measures to be taken in the event of problematic or doubtful issues 
If any problematic finding is found regarding safety and efficacy, the data will be checked 
extensively, and appropriate countermeasures will be considered. 

 
13 
Appendix: Schedule of observations 
Surveillance information entry times 
 
 
Items for surveillance 
Duration of observation 
At the time 
of patient 
enrollment 
At the 
start of 
treatment 
with 
Takecab 
Tablets 
 
 
Week 
2 
 
 
 
Week 
4  
 
 
Week 
6 
Note 1) 
 
 
Week 
8 
Note 2) 
At the time of 
treatment 
discontinuation 
Patient 
enrollment 
Date of prescribing Takecab 
Tablets 
○ 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
Initialized name of patient 
○ 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
Target disease for Takecab Tablets 
○ 
 
 
 
 
 
 
Exclusion criteria rating 
○ 
 
 
 
 
 
 
Patient 
demographic 
information 
Date of diagnosing the target 
disease 
 
○ 
 
 
 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
 
 
Complications 
 
○ 
 
 
 
 
 
Past medical history of gastric 
ulcer/duodenal ulcer/reflux 
esophagitis 
 
○ 
 
 
 
 
 
Height, weight 
 
○ 
 
 
 
 
 
Presence/absence of Helicobacter 
pylori infection 
 
○ 
 
 
 
 
 
Presence/absence of esophageal 
hiatal hernia 
 
○ 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
Treatment prior to starting 
Takecab Tablets 
 
○ 
 
 
 
 
 
Treatment 
information 
Use of Takecab Tablets 
 
○ 
○ 
Use of concomitant drugs 
 
○ 
○ 
Items for 
examination 
and 
observation 
 
 
Endoscopy 
 
○ 
Note 3) 
 
 
○ 
Note 4) 
○ 
Note 4) 
○ 
Note 4) 
Severity of subjective symptoms 
 
○ 
○ 
○ 
○ 
○ 
○ 
Liver function test 
 
○Note 5) 
○ 
Presence/absence of pregnancy 
(for women only) 
 
○ 
○ 
Adverse events 
 
○ 
○ 

 
14 
○ : Performed. 
○     : Performed throughout the surveillance period. 
Note 1) Gastric ulcer and reflux esophagitis are excluded. 
Note 2) Duodenal ulcer is excluded. 
Note 3) The time point will be essentially from 7 days before the start of treatment to the treatment 
start day. 
Note 4) The time point will be essentially until 14 days after the end of the surveillance (Week 8 
for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer) or treatment 
discontinuation. 
Note 5) Within 1 month before the start of treatment to the end of the surveillance. 

 
 
 
 
 
Drug Use Surveillance Protocol 
Drug Use Surveillance for Takecab Tablets 
Gastric Ulcer, Duodenal Ulcer, and Reflux Esophagitis 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5001 
Version No. 
Version 1 
Preparation date 
December 26, 2014 
 

 
Table of Contents 
1.0 
Background ...................................................................................................................................................... 1 
2.0 
Objective .......................................................................................................................................................... 1 
3.0 
Planned sample size and justification .............................................................................................................. 1 
3.1 
Planned sample size .................................................................................................................................... 1 
3.2 
Justification ................................................................................................................................................ 1 
4.0 
Subject patients ................................................................................................................................................ 2 
5.0 
Dosage and administration ............................................................................................................................... 2 
6.0 
Planned number of medical institutions by department ................................................................................... 2 
7.0 
Methods ........................................................................................................................................................... 2 
7.1 
Duration of observation .............................................................................................................................. 2 
7.2 
Requests to, and agreements with, study sites ............................................................................................ 2 
7.3 
Patient registration ...................................................................................................................................... 3 
7.4 
Data entry in the surveillance form (electronic) and electronic signature .................................................. 3 
7.5 
Measures to be taken in case of serious adverse events ............................................................................. 3 
8.0 
Scheduled period.............................................................................................................................................. 3 
9.0 
Items for surveillance ....................................................................................................................................... 4 
9.1 
Patient enrollment ....................................................................................................................................... 4 
9.2 
Patient demographic information ............................................................................................................... 4 
9.3 
Treatment information ................................................................................................................................ 4 
9.4 
Items for examination and observation....................................................................................................... 5 
9.4.1 
Endoscopy ............................................................................................................................................. 5 
9.4.2 
Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early satiety, 
epigastralgia, epigastric burning, sensation of abdominal distention, nausea/vomiting, burping, 
anorexia)................................................................................................................................................ 5 
9.4.3 
Liver function test ................................................................................................................................. 5 
9.4.4 
Other items for observation ................................................................................................................... 6 
9.5 
Adverse events............................................................................................................................................ 6 
10.0 
Analysis items and methods........................................................................................................................... 10 
10.1 
Items concerning study population composition ...................................................................................... 10 
10.2 
Patient demographics................................................................................................................................ 10 
10.3 
Treatment details ...................................................................................................................................... 10 
10.4 
Matters concerning the safety ................................................................................................................... 10 
10.4.1 
Factors of onset of adverse events ....................................................................................................... 10 
10.4.2 
Factors that may affect the safety ........................................................................................................ 10 
10.5 
Matters concerning the safety ................................................................................................................... 11 
10.5.1 
Endoscopic cure rate ........................................................................................................................... 11 
10.5.2 
Subjective symptom amelioration rate ................................................................................................ 11 
10.5.3 
Factors that may affect the efficacy ..................................................................................................... 11 
11.0 
Surveillance information registry .................................................................................................................. 11 

 
12.0 
Organizational structure ................................................................................................................................. 11 
12.1 
Manager .................................................................................................................................................... 11 
13.0 
Contract research organization....................................................................................................................... 11 
14.0 
Other requirements ........................................................................................................................................ 11 
14.1 
Protocol revisions ..................................................................................................................................... 11 
14.2 
Measures to be taken in the event of problematic or doubtful issues ....................................................... 12 
 
Appendix Schedule of observations............................................................................................................................12 

 
1 
1.0 
Background 
The safety of Takecab Tablets 20 mg in the treatment of gastric ulcer, duodenal ulcer, and reflux 
esophagitis has been assessed in Japanese clinical studies in 244, 183, and 988 patients, 
respectively, showing no remarkable problems. In postmarketing routine practices, however, 
unlike in the clinical studies, the drug may be used in patients with various complications and 
patients receiving multiple concomitant drugs, which means that the possibility of onset of 
unexpected adverse drug reactions cannot be ruled out based on the results of the clinical studies. 
Hence, we planned a drug use surveillance (hereinafter referred to as this surveillance) study to 
assess the safety and efficacy of Takecab Tablets in the three acid-related diseases gastric ulcer, 
duodenal ulcer, and reflux esophagitis in actual routine practices. 
This surveillance will be conducted in compliance with the MHLW Ministerial Ordinance on 
GPSP and other related regulatory requirements. 
 
2.0 
Objective 
To assess the safety and efficacy of Takecab Tablets in patients with gastric ulcer, duodenal ulcer, 
and reflux esophagitis in actual use settings and routine practices. 
 
3.0 
Planned sample size and justification 
3.1 Planned sample size 
3,000 Patients 
The sample size will not be less than 500 patients for each of gastric ulcer and duodenal ulcer, 
and will not be less than 1,000 patients for reflux esophagitis. 
 
3.2 Justification 
Gastric ulcer, duodenal ulcer, and reflux esophagitis all share the same pathologic feature that 
gastrointestinal mucosal injury is caused by gastric acid. Duration of treatment in Japanese 
clinical studies of Takecab Tablets in various patient populations with each disease was roughly 
the same for gastric ulcer and reflux esophagitis (up to 8 weeks) and duodenal ulcer (up to 6 
weeks), and incidences and severity of adverse drug reactions and safety profiles for adverse 
drug reactions with high incidences were similar. 
Based on the above facts, a drug use-results surveillance study will be conducted with a planned 
sample size of 3,000 patients with the three acid-related diseases of gastric ulcer, duodenal ulcer, 
and reflux esophagitis. With regard to the minimum sample size allowing the safety of Takecab 
Tablets to be assessed in patients with each disease, we have decided to enroll at least 500 
patients with gastric ulcer and duodenal ulcer. Since the number of patients with reflux 
esophagitis has been increasing rapidly year by year in Japan, and the disease is considered to 
affect the largest number of patients for whom Takecab Tablets is indicated, we have decided to 
enroll at least 1,000 patients with reflux esophagitis. Hence, incidences and severity of adverse 
drug reactions and differences in major adverse drug reactions in actual use settings and routine 
practices seem to be assessable by disease (the sample size was not statistically calculated). 

 
2 
 
4.0 
Subject patients 
Patients with gastric ulcer, duodenal ulcer, and reflux esophagitis will be enrolled. However, the 
subjects should not meet any of the exclusion criteria shown below. Refer to the Precautions in 
the package insert. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the subjects of this 
surveillance. 
1) Patients with a past medical history of hypersensitivity to any of the ingredients of 
Takecab Tablets 
2) Patients on treatment with atazanavir sulfate or rilpivirine hydrochloride 
3) When the target disease for Takecab Tablets is gastric ulcer or duodenal ulcer, patients 
whose endoscopic stage classification by Sakita and Miwa at the start of treatment with 
Takecab Tablets is the scarring stage (S1, S2) 
4) When the target disease for Takecab Tablets is reflux esophagitis, patients whose rating 
by the Los Angeles Classification of Gastroesophageal Reflux Disease (modified by 
Hoshihara) at the start of treatment with Takecab Tablets is Grade N or Grade M 
 
5.0 
Dosage and administration 
The usual adult dosage is 20 mg of vonoprazan administered orally once daily. Usually, the 
duration of treatment should be up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal 
ulcer. For reflux esophagitis, the duration of treatment should usually be up to 4 weeks; if the 
effect is insufficient, however, the drug can be administered for up to 8 weeks. Refer to the 
Precautions in the package insert. 
 
6.0 
Planned number of medical institutions by department 
Gastroenterology and other departments: About 500 medical institutions 
 
7.0 
Methods 
7.1 Duration of observation 
Duration of observation will be 8 weeks for gastric ulcer and reflux esophagitis and 6 weeks for 
duodenal ulcer. 
However, if treatment with Takecab Tablets is completed with the goal of treatment attained, or 
treatment with Takecab Tablets is discontinued for any reason, the surveillance will be ended at 
that time. 
 
7.2 Requests to, and agreements with, study sites 
Requests to, and agreements with, study sites will be made using a web-based electronic data 
collection system (
). Prior to starting this surveillance, a medical representative of 
Takeda Pharmaceutical Company Limited (hereinafter referred to as Takeda MR) will provide 
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3 
the surveillance investigator with an explanation about the objective and contents of this 
surveillance, 
 operating procedures, electronic signature, user ID, and handling of 
passwords using the documents “Request for Your Cooperation in Drug Use-Results 
Surveillance,” “Implementation Guideline,” “Input Screen Image,” and “
 Operating 
Manual (Abridged Edition)” and conclude written agreements with the study site to ask it to 
conduct the surveillance within the specified surveillance period. 
 
7.3 Patient registration 
“Central registration” based on 
 will be used. For the patients with Takecab Tablets 
prescribed on or after the starting day of the period of agreement with the study site, the 
surveillance investigator will enter patient enrollment information (refer to Section 9.1) into 
 and provide an electronic signature not later than 14 days after the day of prescribing 
Takecab Tablets (the prescribing day is defined as “Day 0” and the day after the prescribing day 
as “Day 1”). 
 
7.4 Data entry in the surveillance form (electronic) and electronic signature 
For all the patients enrolled, the surveillance investigator will enter patient characteristics 
information, treatment information, and other information into 
 and provide an 
electronic signature generally within 1 month after the end of the observation period for each 
patient. If Takecab Tablets are not confirmed to have actually been taken, this fact will be entered 
(no other items need to be entered). 
For the patients who have discontinued Takecab Tablets for any reason during the observation 
period, the surveillance investigator will enter patient characteristics information, treatment 
information, and other information into 
 and provide an electronic signature 
generally within 1 month after completion of the observations required. For the patients who 
have discontinued Takecab Tablets because of development of any adverse event, however, the 
surveillance investigator will continue observations until the adverse event resolves or remits 
whenever possible after treatment discontinuation, enter the observation results into 
 
and provide an electronic signature. 
 
7.5 Measures to be taken in case of serious adverse events 
If any serious adverse event develops during the observation period, the surveillance 
investigator will immediately notify this fact to a Takeda MR. Upon request from a Takeda MR, 
the surveillance investigator will separately provide detailed information. 
 
8.0 
Scheduled period 
Surveillance period: September 2015 to October 31, 2017 
Accrual period: September 2015 to August 31, 2017Note) 
Note) Even for the patients with Takecab Tablets prescribed by August 31, 2017, patient 
enrollment (data entry in
) will not be accepted on and after September 1, 2017. 
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If the number of enrolled patients reaches the planned sample size for this surveillance as a 
whole before August 31, 2017, registration will be terminated before the end of the patient 
accrual period. If the patient accrual period is shortened, the overall surveillance period will 
be changed in proportion to the shortage. 
In addition, enrollment may be subject to limitations for each target disease before 
August 31, 2017 in view of the enrollment status for each target disease. 
 
9.0 
Items for surveillance 
The surveillance investigator will enter information on the items shown below into
: 
The schedule for this surveillance is shown in the Appendix. 
9.1 Patient enrollment 
1) Items for surveillance 
Date of prescribing Takecab Tablets, patient ID No., initialized patient name, sex, date of 
birth, target disease for Takecab Tablets, exclusion criteria ratings 
2) Surveillance times 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Items for surveillance 
Date of diagnosing the target disease, Inpatient/outpatient classification (from the start of 
treatment with Takecab Tablets), predisposition to hypersensitivity (presence/absence and 
details), complications (presence/absence and details), past medical history of gastric 
ulcer/duodenal ulcer/reflux esophagitis (presence/absence and details), height, body weight, 
presence/absence of Helicobacter pylori infection (from the start of treatment with Takecab 
Tablets), presence/absence of esophageal hiatal hernia, smoking history, drinking history, 
treatments prior to the start of Takecab Tablets [presence/absence, names of drugs, doses 
(excluding H2 blockers), and duration of treatment] 
2) Surveillance times 
At the start of treatment with Takecab Tablets 
 
9.3 Treatment information 
1) Items for surveillance 
Use of Takecab Tablets (daily dose, duration of treatment, and reason for treatment 
discontinuation), use of concomitant drugs (presence/absence, names of drugs, and purpose 
of administration) 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance will 
be at the time of treatment discontinuation. 
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5 
 
9.4 Items for examination and observation 
9.4.1 Endoscopy 
1) Items for examination 
Endoscopy (check date and findings*1) 
*1: Gastric ulcer and duodenal ulcer will be assessed using the endoscopic stage classification by 
Sakita and Miwa, and reflux esophagitis will be assessed using the classification of mucosal 
injuries according to the Los Angeles Classification of Gastroesophageal Reflux Disease 
(modified by Hoshihara). 
2) Surveillance times 
Examination time points at the start of treatment with Takecab Tablets*2 and the end of the 
surveillance*3 
*2: The time point will be essentially between 7 days before the start of treatment and the day of the 
start of treatment. 
*3: The time point will be essentially until 14 days after Week 8 for gastric ulcer and reflux esophagitis 
and after Week 6 for duodenal ulcer. If Takecab Tablets are discontinued before these times, the 
time point will be essentially until 14 days after treatment discontinuation. 
 
9.4.2 Subjective symptoms (heartburns, acid reflux, postprandial heavy stomach feeling, early 
satiety, epigastralgia, epigastric burning, sensation of abdominal distention, 
nausea/vomiting, burping, anorexia) 
1) Items for observation 
Subjective symptoms (presence/absence and severity*) 
*Mild: Occasionally or slightly symptomatic. 
Moderate: Considerably symptomatic. 
Severe: Unendurably symptomatic. 
2) Surveillance times 
Interview time points at the start of treatment with Takecab Tablets, at Week 2, at Week 4, 
and at the end of the surveillance*. 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.3 Liver function test 
1) Parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Surveillance times 
Examination time points from the start of treatment with Takecab Tablets*1 to the end of 

 
6 
the surveillance*2 
*1: Within 1 month before the start of treatment. 
*2: The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 
for duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.4.4 Other items for observation 
1) Items for observation 
Presence/absence of pregnancy during the observation period (for women only) 
If the subject is found to be pregnant during the observation period, this fact should 
immediately be notified to a Takeda MR. Upon request by the Takeda MR, the 
surveillance investigator will provide detailed information (including information up to 
delivery, including details of premature birth and other outcomes) separately using a 
pregnant-woman sheet. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 
9.5 Adverse events 
1) Items for surveillance 
Presence/absence of adverse events (see Table 1), names of adverse events, onset days, 
seriousness and rationale for the seriousness rating (see Table 2), cause of discontinuation 
of Takecab Tablets, outcome determination day, outcome, causality with Takecab Tablets* 
(see Table 3). 
If the outcome is “unresolved” or “unknown” and if the causality is indeterminable, a 
follow-up surveillance will be performed whenever possible. 
In the event of manifested hepatic dysfunction or gastrointestinal infections with 
Clostridium difficile, detailed information (clinical courses, results of tests performed for 
diagnostic purposes, etc.) will be collected as much as possible. 
*If the rating of causality with Takecab Tablets is “unrelated”, information on the justification for the 
rating will be collected. If the rating is “indeterminable”, the reason will be recorded. 
Note) Matters to be taken into account with regard to adverse events 
Abnormal exacerbations of the target disease, including those exceeding the foreseeable 
spontaneous course of the condition, will be handled as adverse events, whereas foreseeable 
exacerbations of the target disease will not be handled as adverse events. 
2) Surveillance times 
From the start of treatment with Takecab Tablets to the end of the surveillance* 
*The end of the surveillance will be at Week 8 for gastric ulcer and reflux esophagitis and Week 6 for 

 
7 
duodenal ulcer. If Takecab Tablets are discontinued before these times, the end of the surveillance 
will be at the time of treatment discontinuation. 
 

 
8 
Table 1 Definition of an adverse event 
An adverse event (AE) refers to any unwanted medical event appearing in a patient receiving a drug. 
An AE does not always represent an event for which causality with administration of the drug is 
evident. 
Hence, an adverse event refers to any unwanted or unintended sign (including abnormal laboratory 
values), symptom, or disease that has occurred in a subject receiving the test drug, irrespective of 
the presence/absence of causality with the drug. 
The following cases will also be handled as adverse events: 
•Symptoms etc. that have developed in infants breastfed by mothers on treatment with the drug 
•Symptoms etc. that have developed in children receiving the drug 
•Symptoms etc. that have developed with occupational exposure to the drug 
•Symptoms etc. that have developed with administration of a false drug imitating an ethical drug 
marketed by our company 
 
 
 

 
9 
Table 2 Seriousness rating criteria 
If any of the following criteria applies, the event will be rated as “serious.” 
1. Results in death (death) 
2. Life-threatening (possible death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (hospital admission 
or prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disorders) 
5. Causes congenital anomalies 
6. Medically important states secondary to Items 1 to 5 AEs included in the “Takeda Medically 
Significant AE List” will be included in this section 
 
Takeda Medically Significant AE List 
• Acute respiratory insufficiency/acute 
respiratory distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsades de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizures (including 
convulsions and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperpyrexia 
• Aplastic anemia 
• Spontaneous abortions/stillbirths and fetal deaths 
• Toxic epidermal 
necrolysis/oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of drug-
mediated infection 
• Acute hepatic failure 
• Endotoxin shock or, suspected 
• Hepatic necrosis 
 
 
 

 
10 
Table 3 Acceptance criteria for causality between adverse events and Takecab Tablets 
Rating 
Acceptance criteria 
Related 
A temporal correlation (including post-discontinuation courses) is found. 
Alternatively, although other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures, may also 
be involved, the event is attributable to the study drug. 
Unrelated 
No temporal correlation with the drug is found. Alternatively, the event is 
reasonably attributable to other factors, such as primary disease, 
complications, concomitant drugs, and concomitant procedures. 
Indeterminable 
Information essential for assessments, such as temporal correlations 
(including post-discontinuation courses), primary disease, complications, 
concomitant drugs, and concomitant procedures, are lacking. 
 
10.0 
Analysis items and methods 
10.1 Items concerning study population composition 
Number of patients enrolled, number of patients from whom the surveillance form (electronic) 
has been collected, numbers of patients included in the safety and efficacy analysis sets, number 
of patients excluded from analysis and reasons for removal, and other items will be tabulated. 
 
10.2 Patient demographics 
Data on patient demographics, including sex, age, predisposition to hypersensitivity, and 
complications, will be tabulated. 
 
10.3 Treatment details 
Data on the use of Takecab Tablets and the use of concomitant drugs will be tabulated. 
 
10.4 Matters concerning the safety 
Data for the safety analysis set will be tabulated as follows: AEs will be reworded using the 
MedDRA/J and summarized with Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Factors of onset of adverse events 
With regard to the adverse events occurring during the observation period, frequency data 
will be tabulated by type, onset time, seriousness, causality with Takecab Tablets, and other 
aspects. 
 
10.4.2 Factors that may affect the safety 
With regard to the adverse drug reactions occurring during the observation period, 
frequency data will be tabulated by target disease, patient demographic factors (sex, age, 
presence/absence of complicating renal dysfunction, presence/absence of complicating 
hepatic dysfunction, etc.), and treatment (use of Takecab Tablets and use of concomitant 
drugs). 

 
11 
 
10.5 Matters concerning the safety 
Data for the efficacy analysis set will be tabulated as follows: 
10.5.1 Endoscopic cure rate 
Data on endoscopic cure rates in patients with endoscopic findings available at the start of 
treatment with Takecab Tablets and the end of the surveillance will be tabulated by target 
disease. 
 
10.5.2 Subjective symptom amelioration rate 
Data on subjective symptom amelioration rates in patients with severity findings available 
from the start of treatment with Takecab Tablets to the end of the surveillance will be 
tabulated by target disease. 
 
10.5.3 Factors that may affect the efficacy 
Data on endoscopic cure rates and subjective symptom amelioration rates will be tabulated 
by target disease, patient demographic factors (sex, age, presence/absence of complicating 
renal dysfunction, presence/absence of complicating hepatic dysfunction, etc.), and 
treatment (use of Takecab Tablets, use of concomitant drugs). 
 
11.0 
Surveillance information registry 
Takeda Pharmaceutical Company Limited will register information on this surveillance study 
prior to its start date with an open-access website. 
•Japan Pharmaceutical Information Center Clinical Trials Information 
•US National Institutes of Health (NIH) Clinical Study Registration System: ClinicalTrials.gov 
 
12.0 
Organizational structure 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract research organization 
 
14.0 
Other requirements 
14.1 Protocol revisions 
Study progression, onset of adverse drug reactions and serious adverse drug reactions that are 
unexpected from the Precautions, presence/absence of increased incidences of particular 
adverse drug reactions, validity of survey items, etc. will be monitored during the survey period 
and, if necessary, this protocol will be reconsidered and revised. If partial changes in the dosage 
PPD
PPD

 
12 
and administration or indications are approved during the surveillance period, the necessity for 
revising this protocol will be determined as required, and the protocol will be revised if 
necessary. 
 
14.2 Measures to be taken in the event of problematic or doubtful issues 
If any problematic finding is found regarding safety and efficacy, the data will be checked 
extensively, and appropriate countermeasures will be considered. 

 
13 
Appendix: Schedule of observations 
Surveillance information entry times 
 
 
Items for surveillance 
Duration of observation 
At the time 
of patient 
enrollment 
At the 
start of 
treatment 
with 
Takecab 
Tablets 
 
 
Week 
2 
 
 
 
Week 
4  
 
 
Week 
6 
Note 1) 
 
 
Week 
8 
Note 2) 
At the time of 
treatment 
discontinuation 
Patient 
enrollment 
Date of prescribing Takecab 
Tablets 
○ 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
Initialized name of patient 
○ 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
Target disease for Takecab Tablets 
○ 
 
 
 
 
 
 
Exclusion criteria rating 
○ 
 
 
 
 
 
 
Patient 
demographic 
information 
Date of diagnosing the target 
disease 
 
○ 
 
 
 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
 
 
Complications 
 
○ 
 
 
 
 
 
Past medical history of gastric 
ulcer/duodenal ulcer/reflux 
esophagitis 
 
○ 
 
 
 
 
 
Height, weight 
 
○ 
 
 
 
 
 
Presence/absence of Helicobacter 
pylori infection 
 
○ 
 
 
 
 
 
Presence/absence of esophageal 
hiatal hernia 
 
○ 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
 
Treatment prior to starting 
Takecab Tablets 
 
○ 
 
 
 
 
 
Treatment 
information 
Use of Takecab Tablets 
 
○ 
○ 
Use of concomitant drugs 
 
○ 
○ 
Items for 
examination 
and 
observation 
Endoscopy 
 
○ 
Note 3) 
 
 
○ 
Note 4) 
○ 
Note 4) 
○ 
Note 4) 
Severity of subjective symptoms 
 
○ 
○ 
○ 
○ 
○ 
○ 
Liver function test 
 
○Note 5) 
○ 
Presence/absence of pregnancy 
(for women only) 
 
○ 
○ 
Adverse events 
 
○ 
○ 

 
14 
○ : Performed. 
○     : Performed throughout the surveillance period. 
Note 1) Gastric ulcer and reflux esophagitis are excluded. 
Note 2) Duodenal ulcer is excluded. 
Note 3) The time point will be essentially from 7 days before the start of treatment to the treatment 
start day. 
Note 4) The time point will be essentially until 14 days after the end of the surveillance (Week 8 
for gastric ulcer and reflux esophagitis and Week 6 for duodenal ulcer) or treatment 
discontinuation. 
Note 5) Within 1 month before the start of treatment to the end of the surveillance.