Special Drug Use Surveillance of Takecab Tablets for "Maintenance Therapy of Reflux Esophagitis: Long-term Use"
Conditions: Reflux Esophagitis
Sponsor: Takeda

 
 
Title: Takecab Tablets Special Drug Use Surveillance “Maintenance therapy for reflux 
esophagitis: Long-term use” 
 
NCT Number: NCT03214081 
Protocol Approve Date: 02-Jun-2017 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
 
 
Special Drug Use Surveillance Protocol 
Takecab Tablets Special Drug Use Surveillance  
“Maintenance therapy for reflux esophagitis: 
Long-term use” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited  
Protocol Number  
Version Number 
Version 2 
Date of 
preparation 
June 2, 2017 
 

Table of Contents 
1.0 
Background ................................................................................................................................................. 1 
2.0 
Objectives ................................................................................................................................................... 1 
3.0 
Planned sample size and rationale .............................................................................................................. 1 
3.1 
Planned sample size ................................................................................................................................. 1 
3.2 
Rationale .................................................................................................................................................. 1 
4.0 
Surveillance population .............................................................................................................................. 1 
5.0 
Dosage and administration.......................................................................................................................... 2 
6.0 
Planned number of surveillance sites by specialty department ................................................................... 2 
7.0 
Methods ...................................................................................................................................................... 2 
7.1 
Duration of observation............................................................................................................................ 2 
7.2 
Request to and contract with medical institutions .................................................................................... 2 
7.3 
Patient enrollment method ....................................................................................................................... 2 
7.4 
Data entry to the survey form (electronic) and electronic signature ........................................................ 3 
7.5 
Actions taken for serious adverse events ................................................................................................. 3 
8.0 
Planned surveillance period ........................................................................................................................ 3 
9.0 
Surveillance items ....................................................................................................................................... 3 
9.1 
Patient enrollment .................................................................................................................................... 3 
9.2 
Patient demographics information ........................................................................................................... 4 
9.3 
Treatment information.............................................................................................................................. 4 
9.4 
Tests and observations .............................................................................................................................. 4 
9.4.1 
Endoscopy ........................................................................................................................................ 4 
9.4.2 
Subjective symptoms (heartburn, acid reflux, heavy stomach feeling, early satiety, epigastric pain, 
epigastric burning sensation, bloating, nausea/vomiting, belching, inappetence)............................ 4 
9.4.3 
Liver function tests ........................................................................................................................... 5 
9.4.4 
Serum gastrin.................................................................................................................................... 5 
9.4.5 
Other items of observations .............................................................................................................. 5 
9.5 
Adverse events ......................................................................................................................................... 5 
10.0 
Analysis items and methods ....................................................................................................................... 8 
10.1 
Disposition of patients.............................................................................................................................. 8 
10.2 
Patient demographics ............................................................................................................................... 8 
10.3 
Treatment details ...................................................................................................................................... 8 
10.4 
Safety data ................................................................................................................................................ 8 
10.4.1 
Incidence of adverse events .............................................................................................................. 8 
10.4.2 
Factors which may affect safety ....................................................................................................... 8 
10.5 
Efficacy data............................................................................................................................................. 8 
10.5.1 
Endoscopic relapse rate .................................................................................................................... 8 
10.5.2 
Change of the severity of subjective symptoms ............................................................................... 9 
10.5.3 
Factors which may affect efficacy .................................................................................................... 9 
11.0 
Registration of surveillance information .................................................................................................... 9 

12.0 
Administrative structure ............................................................................................................................. 9 
13.0 
Trustees ....................................................................................................................................................... 9 
14.0 
Other necessary items ................................................................................................................................. 9 
14.1 
Protocol amendments ............................................................................................................................... 9 
14.2 
Actions to be taken in response to detection of any issues or concerns ................................................. 10 
 
Appendix  Observation schedule..........................................................................................................................9 
 

1 
1.0 
Background 
Administration of Takecab Tablets as maintenance therapy for reflux esophagitis with repeated 
recurrences or relapses is anticipated to be continued long-term in routine clinical settings. 
Administration of Takecab Tablets 10 or 20 mg once daily as maintenance therapy for reflux 
esophagitis was evaluated for up to 24 weeks in 406 patients in a Japanese phase III 
double-blind comparative study and up to 52 weeks in 305 patients in a Japanese phase III 
long-term study, and raised no particular safety issues. However, it would be meaningful to 
verify the safety of Takecab Tablets used in routine clinical practice and the consistency of the 
long-term safety profile with the known safety profile of the drug. Thus, the present special 
drug use surveillance has been planned.  
This surveillance will be conducted in compliance with the Ministerial Ordinance on Good 
Post-Marketing Study Practice (GPSP) and relevant regulatory requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of long-term use of Takecab Tablets as maintenance 
therapy for reflux esophagitis in routine clinical practice.  
 
3.0 
Planned sample size and rationale 
3.1 Planned sample size 
1,000 patients 
 
3.2 Rationale 
The target sample size is set to 1000 for collection of 12-month therapy data from 300 
patients.  
Based on the results from Takepron (lansoprazole) post-marketing surveillance*, the 
percentage of patients given 12-month therapy is conservatively assumed to be 30%. Thus, a 
target sample size of 1000 would allow collection of 12-month therapy data from 300 patients.  
With the data collection from 300 patients, an adverse drug reaction (ADR) occurring with an 
incidence of 1% or more can be detected with a probability of at least 95%, which should 
allow determination of ADRs characteristic of long-term use of the drug.  
 
* “Reflux esophagitis/maintenance therapy 3 to 6 months”: 6-month therapy in 57% 
“Suppression of ulcer recurrence on low-dose aspirin: Long-term use”: 12-month therapy in 79.1% 
“Suppression of ulcer recurrence on non-steroidal anti-inflammatory drugs: Long-term use”: 12-month 
therapy in 46.1% 
 
4.0 
Surveillance population 
This surveillance will enroll patients who require maintenance therapy for reflux esophagitis 
with repeated recurrences and relapses* and who do not meet the exclusion criteria specified 
below. The PRECAUTIONS section of the Takecab package insert should also be referenced.  
*Re-enrollment is prohibited for patients previously enrolled in this surveillance even if they receive 
re-administration for maintenance therapy.  

2 
 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded:  
(1) Patients diagnosed with Los Angeles classification (Hoshihara’s modification) grade A 
to D disease, based on endoscopy at initiation of maintenance therapy with Takecab 
Tablets 
(2) Patients with a history of hypersensitivity to any ingredients of Takecab Tablets 
(3) Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual adult dosage is 10 mg of vonoprazan administered orally once daily. If this is 
inadequately effective, the dosage may be increased to 20 mg orally once daily. The 
PRECAUTIONS section of the Takecab package insert should also be referenced.  
 
6.0 
Planned number of surveillance sites by specialty department  
Approximately 300 sites, including the internal medicine (gastroenterology) department  
 
7.0 
Methods 
7.1 Duration of observation 
12 months  
 
7.2 Request to and contract with medical institutions  
The surveillance implementation will use a Web-based electronic data capture system 
). Upon request, a medical representative of 
 
(hereinafter referred to as 
”) will explain to the potential surveillance investigator 
about the surveillance objectives and contents, as well as how to use 
 and enter the 
electronic signature and handling of the user ID and the password according to the 
“Surveillance Implementation Outline”, “
 Data Entry screen images” and 
“
 User Manual”. If the request is accepted, a written contract for the surveillance 
within the specified period will be made with the medical institution. 
 
7.3 Patient enrollment method  
Patients will be enrolled using a centralized enrollment method via 
. For patients 
prescribed Takecab Tablets on or after the first day of the contract period for the medical 
institution, the surveillance investigators will enter the patient information required for 
enrollment (see Section 9.1) and the electronic signature in 
within 14 days after 
the prescription of Takecab Tablets (with the day of prescription counted as zero and the day 
following prescription counted as “1 day after prescription”).  
 
PPD
PPD
CCI
CCI
CCI
CCI
CCI
CCI

3 
7.4 Data entry to the survey form (electronic) and electronic signature 
The surveillance investigator will enter data on patient demographics, treatment details, etc. 
and the electronic signature in 
, roughly within 1 month after the end of required 
observations at Month 12 of Takecab therapy. If administration of this drug could not be 
confirmed, this fact should be entered (no other data are required).  
 
For patients who discontinued treatment with Takecab Tablets for certain reasons during the 
observation period, the surveillance investigator will enter data on patient demographics, 
treatment details, etc. and the electronic signature in 
 roughly within 1 month after 
the end of required observations. However, for patients who discontinued Takecab therapy 
because of onset of an adverse event (AE), even after the discontinuation of this drug, the 
surveillance investigator will continue observation as far as possible up to resolution or 
improvement of the adverse event. The surveillance investigator will then enter the 
observation result and the electronic signature in 
.  
 
7.5 Actions taken for serious adverse events 
If any serious AE occurs during the observation period, the surveillance investigator will 
immediately report it to an 
. If requested by the 
 the surveillance 
investigator will provide detailed information separately.  
 
8.0 
Planned surveillance period 
Surveillance period: March 2016 to August 31, 2018 
Patient enrollment period: March 2016 to August 31, 2017 Note)  
Note) No patient enrolment (via 
) will be acceptable on or after September 1, 2017, 
even if Takecab is prescribed by August 31, 2017.  
If the total number of the enrolled patients in the entire surveillance reached the planned 
sample size before August 31, 2017, patient enrolment will be closed before the end of the 
patient enrollment period. If the patient enrollment period is shortened, the surveillance 
period will also be changed according to the shortened enrollment period. 
 
9.0 
Surveillance items 
The surveillance investigator will enter data of the following items into 
. The 
surveillance schedule is shown in the Appendix.  
 
9.1 Patient enrollment 
1) Surveillance items 
Date of prescription of Takecab Tablets for maintenance therapy, patient identification 
number, patient initials, sex, date of birth, assessment against the exclusion criteria 
2) Time of data collection 
At enrollment of the patient 
PPD
PPD
CCI
CCI
CCI
CCI
CCI

4 
 
9.2 Patient demographics information  
1) Surveillance items  
Time of initial onset of reflux esophagitis, inpatient/outpatient classification (at initiation of 
Takecab therapy), hypersensitive diathesis (presence or absence, and details), complication 
(presence or absence, and details), height, weight, presence or absence of Helicobacter 
pylori infection (at initiation of Takecab therapy), presence or absence of hiatus hernia, 
smoking history, drinking history, treatment (antacids) within 1 month before initiation of 
maintenance therapy for reflux esophagitis (presence or absence, name of drug, reason for 
use)  
2) Time of data collection 
At initiation of Takecab maintenance therapy 
 
9.3 Treatment information 
1) Surveillance items  
Takecab therapy details (daily dose, therapy dates, and reason for discontinuation), 
concomitant drug details (presence or absence, name of drug, reason for use)  
2) Time of data collection  
From initiation of Takecab maintenance therapy to Month 12 (or discontinuation of the 
therapy)  
 
9.4 Tests and observations 
9.4.1 Endoscopy 
1) Data items 
Endoscopy (performed or not, date of endoscopy, and gradeNote)  
Note) The Los Angeles classification (Hoshihara’s modification) grade of mucosal damage will be 
used. 
 
2) Time of data collection  
At time points of endoscopy from initiation of Takecab maintenance therapy to Month 12 
(or discontinuation of the therapy)  
 
9.4.2 Subjective symptoms (heartburn, acid reflux, heavy stomach feeling, early satiety, 
epigastric pain, epigastric burning sensation, bloating, nausea/vomiting, belching, 
inappetence)  
1) Data items 
Subjective symptoms (presence or absence and severity)  
2) Time of data collection  
At medical interviews at initiation of Takecab maintenance therapy, Month 6, and Month 
12 (or discontinuation of the therapy) 

5 
 
9.4.3 Liver function tests 
1) Test parameters  
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate dehydrogenase 
(LDH)  
2) Time of data collection  
At the testing from initiation of Takecab maintenance therapy* to Month 12 (or 
discontinuation of the therapy)  
*Within 1 month before initiation of Takecab maintenance therapy  
 
9.4.4 Serum gastrin 
1) Test parameter 
Serum gastrin level 
2) Time of data collection  
At the testing from initiation of Takecab maintenance therapy* to Month 12 (or 
discontinuation of the therapy) 
*Within 1 month before initiation of Takecab maintenance therapy 
 
9.4.5 Other items of observations 
1) Observation items 
Presence or absence of pregnancy during the observation period (only in women)  
Any pregnancy found during the observation period should be immediately notified to an 
. In response to a request by an 
, the surveillance investigator will 
provide detailed information (wherever possible up to the outcome of pregnancy, such as 
premature delivery).  
2) Time of data collection  
From initiation of Takecab maintenance therapy to Month 12 (or discontinuation of the 
therapy) 
 
9.5 Adverse events 
1) Surveillance items  
Presence or absence of AEs (see Table 1), AE term, date of onset, seriousness and reason 
for the assessment as serious (see Table 2), reason for discontinuation of Takecab, 
outcome assessment date, outcome, causal relationship to Takecab* (see Table 3)  
If the outcome is “not resolved” or “unknown”, or if the causal relationship is 
“unassessable”, the event should be followed as far as possible.  
Detailed event information should be collected as much as possible in the event of hepatic 
function disorder, fracture, gastrointestinal infection with Clostridium difficile, or 
neuroendocrine tumor.  
PPD
PPD

6 
*If the causal relationship to Takecab is “Not related”, the basis for the assessment should be recorded. If 
the causal relationship to Takecab is “Unassessable”, the reason should be recorded.  
Note) Special guidance about reporting of AEs:  
Abnormal worsening of the target disease, e.g., outside the predictable range of the natural course 
of the disease, is regarded as an AE.  
Serum gastrin can increase due to the pharmacological action of Takecab. However, if Takecab therapy 
is discontinued because of increased serum gastrin, this event should be handled as an AE.  
2) Time of data collection  
From initiation of Takecab maintenance therapy to Month 12 (or discontinuation of the 
therapy)  
 
Table 1  Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment.  
An adverse event can therefore be any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product. 
Note that the following events will also be handled as adverse events:  
 Any manifestation in an infant breastfed by a mother taking this drug  
 Any untoward manifestation in a child given this drug  
 Any manifestation due to occupational exposure to this drug 
 Any manifestation due to a counterfeit product of a prescription drug marketed by Takeda 
 Any untoward manifestation in a patient given this drug revealed by a lawsuit or any other legal 
action 
 

7 
Table 2  Criteria for Serious Adverse Events 
An adverse event is assessed as “serious” if it results in any of the following outcomes:  
1. results in death (Death),  
2. is life-threatening (Life-threatening),  
3. requires hospitalization or prolongation of existing hospitalization (Hospitalization/Prolongation of 
hospitalization),  
4. results in persistent or significant disability/incapacity (Disability),  
5. leads to a congenital anomaly or birth defect (Congenital anomaly), or 
6. is any other important medical event that does not fulfil 1 to 5 above.  
Serious adverse events include events described in the “Takeda Medically Significant AE List”.  
 
Takeda Medically Significant AE List 
- Acute respiratory failure /Acute respiratory 
distress syndrome (ARDS)  
- Anaphylactic shock 
- Torsade de pointes / Ventricular fibrillation / 
Ventricular tachycardia 
- Acute renal failure 
- Malignant hypertension 
- Pulmonary hypertension 
- Convulsive seizure (including convulsion 
and epilepsy)  
- Pulmonary fibrosis (including interstitial 
pneumonia)  
- Agranulocytosis 
- Neuroleptic malignant syndrome/ Malignant 
hyperthermia  
- Aplastic anaemia 
- Spontaneous abortion / Stillbirth and fetal death 
- Toxic epidermal necrolysis / 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
- Confirmed or suspected transmission of infectious 
agent by a medicinal product 
- Hepatic necrosis 
- Confirmed or suspected endotoxin shock 
- Acute hepatic failure 
 
 
Table 3  Assessment of the causal relationship between an adverse event and Takecab 
Causality classification 
Definition 
Related 
An adverse event that follows a temporal sequence from 
administration of this drug (including the course after withdrawal 
of the drug), or for which possible involvement of this drug can be 
considered, although factors other than this drug, such as the 
primary disease, complication, concomitant drugs or concurrent 
treatments, may also be responsible. 
Not related 
An adverse event that does not follow a temporal sequence from 
administration of this drug or that can reasonably be explained by 
other factors, such as the primary disease, complication, 
concomitant drugs or concurrent treatments.  
Unassessable 
The causality cannot be assessed because of insufficiency of 

8 
required information, such as temporal sequence of the event onset 
relative to administration of this drug (including the course after 
withdrawal of the drug), primary disease, complication, 
concomitant drugs, and concurrent treatments. 
 
10.0 
Analysis items and methods 
10.1 Disposition of patients 
Number of patients enrolled, number of patients with collected survey forms (electronic), 
numbers of patients for safety and efficacy analyses, number of patients excluded from 
analysis, reason for exclusion, etc. will be summarized.  
 
10.2 Patient demographics 
Patient demographic data such as sex, age, hypersensitive diathesis, and complication will be 
summarized.  
 
10.3 Treatment details 
Detailed use of Takecab and concomitant drugs will be summarized.  
 
10.4 Safety data 
The following data will be summarized using the safety analysis set. AEs will be coded using 
the MedDRA/J, and summarized by Preferred Term (PT) and System Organ Class (SOC).  
10.4.1 Incidence of adverse events 
AEs occurring during the observation period will be summarized using frequency count by 
event type, time of onset, seriousness, causal relationship to Takecab, etc.  
 
10.4.2 Factors which may affect safety 
ADRs occurring during the observation period will be summarized using frequency count, 
with stratification of patients according to patient demographic factors (e.g., sex, age, any 
renal impairment, any hepatic impairment) and treatment details (e.g., detailed use of 
Takecab, detailed use of concomitant drugs). 
 
10.5 Efficacy data 
The following data will be summarized using the efficacy analysis set.  
10.5.1 Endoscopic relapse rate 
The endoscopic relapse rate (i.e., the percentage of patients assessed as having Los Angeles 
classification grade A to D disease) will be calculated among patients with recorded 
endoscopic findings at initiation of Takecab maintenance therapy, during the therapy, and at 
Month 12 (or discontinuation of the therapy). 
 

9 
10.5.2 Change of the severity of subjective symptoms  
The change of the severity of subjective symptoms will be summarized among patients 
with recorded severity of subjective symptoms at initiation of Takecab maintenance therapy 
and at each time point of observation after administration.  
 
10.5.3 Factors which may affect efficacy  
The endoscopic relapse rate will be summarized with stratification of patients according to 
patient demographic factors (e.g., sex, age, complication) and treatment details (e.g., 
detailed use of Takecab, detailed use of concomitant drugs ).  
 
11.0 
Registration of surveillance information 
Before initiation of the surveillance, Takeda Pharmaceutical Company Limited will register 
the surveillance information with an online public clinical trials registry:  
- Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information:  
Japan Pharmaceutical Information Center-Clinical Trials Information 
12.0 
Administrative structure 
Responsible Manager 
Post-marketing surveillance manager, Takeda Pharmaceutical Company Limited  
 
13.0 
Trustees 
 
14.0 
Other necessary items 
14.1 Protocol amendments  
During the surveillance period, monitoring will be performed regarding the progress of the 
PPD

10 
surveillance, occurrence of ADRs unexpected from the PRECAUTIONS and serious ADRs, 
any increase in the incidence of particular ADRs, validity of the surveillance items, etc., and 
the protocol will be reviewed and amended as necessary. If any partial change to the DOSAGE 
AND ADMINISTRATION, INDICATIONS, etc. is approved during the surveillance period, 
whether or not the protocol should be amended will be examined, and the protocol will be 
amended as necessary. 
 
14.2 Actions to be taken in response to detection of any issues or concerns 
Whenever an issue is found regarding the safety or efficacy, the data will be investigated in 
detail, and necessary actions will be determined.  

11 
Appendix  Observation schedule 
 
         Time of data collection/entry 
 
 
 Surveillance items  
Observation period  
At 
enrollmen
t 
Start of 
Takecab 
maintenan
ce therapy 
Month 6 
Month 12  
Discontin
uation of 
Takecab 
maintenan
ce therapy 
Patient enrollment 
Date of prescription of Takecab 
Tablets for maintenance therapy 
○ 
 
 
 
 
Patient identification number 
○ 
 
Patient initials 
○ 
 
Sex  
○ 
 
Date of birth  
○ 
 
Assessment against exclusion 
criteria 
○ 
 
 
 
 
Patient demographics 
Time of initial onset of reflux 
esophagitis 
 
○ 
 
 
 
Inpatient/outpatient classification 
○ 
 
 
Hypersensitive diathesis 
○ 
 
 
Complication 
○ 
 
 
Height, weight 
 
○ 
 
 
H. pylori infection 
 
○ 
 
 
 
Hiatus hernia 
 
○ 
 
 
 
Smoking history  
 
○ 
 
 
Drinking history 
 
○ 
 
 
Treatment (antacids) within 1 
month of maintenance therapy 
for reflux esophagitis  
 
○ 
 
 
 
Treatment 
details 
Detailed use of Takecab  
○ 
○ 
Detailed use of concomitant drugs 
○ 
○ 
Assessments 
Endoscopy 
○ 
○ 
Subjective symptoms  
○ 
○ 
○ 
○ 
Liver function tests 
 
  ○Note)  
○ 
Serum gastrin 
 
  ○Note)  
○ 
Pregnancy (women only)  
○ 
○ 
AE monitoring 
○ 
○ 
○    : Performed 
○    : Performed throughout the period  
Note) From ≤1 month before initiation of Takecab maintenance therapy to Month 12 

 
 
 
Special Drug Use Surveillance Protocol 
Takecab Tablets Special Drug Use Surveillance  
“Maintenance therapy for reflux esophagitis: 
Long-term use” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited  
Protocol Number Vonoprazan-5003 
Version Number 
Version 1 
Date of 
preparation 
January 7, 2016 
 

Table of Contents 
1.0 
Background ................................................................................................................................................. 1 
2.0 
Objectives ................................................................................................................................................... 1 
3.0 
Planned sample size and rationale .............................................................................................................. 1 
3.1 
Planned sample size ................................................................................................................................. 1 
3.2 
Rationale .................................................................................................................................................. 1 
4.0 
Surveillance population .............................................................................................................................. 1 
5.0 
Dosage and administration.......................................................................................................................... 2 
6.0 
Planned number of surveillance sites by specialty department ................................................................... 2 
7.0 
Methods ...................................................................................................................................................... 2 
7.1 
Duration of observation............................................................................................................................ 2 
7.2 
Request to and contract with medical institutions .................................................................................... 2 
7.3 
Patient enrollment method ....................................................................................................................... 2 
7.4 
Data entry to the survey form (electronic) and electronic signature ........................................................ 3 
7.5 
Actions taken for serious adverse events ................................................................................................. 3 
8.0 
Planned surveillance period ........................................................................................................................ 3 
9.0 
Surveillance items ....................................................................................................................................... 3 
9.1 
Patient enrollment .................................................................................................................................... 3 
9.2 
Patient demographics information ........................................................................................................... 4 
9.3 
Treatment information.............................................................................................................................. 4 
9.4 
Tests and observations .............................................................................................................................. 4 
9.4.1 
Endoscopy ........................................................................................................................................ 4 
9.4.2 
Subjective symptoms (heartburn, acid reflux, heavy stomach feeling, early satiety, epigastric pain, 
epigastric burning sensation, bloating, nausea/vomiting, belching, inappetence)............................ 4 
9.4.3 
Liver function tests ........................................................................................................................... 5 
9.4.4 
Serum gastrin.................................................................................................................................... 5 
9.4.5 
Other items of observations .............................................................................................................. 5 
9.5 
Adverse events ......................................................................................................................................... 5 
10.0 
Analysis items and methods ....................................................................................................................... 8 
10.1 
Disposition of patients.............................................................................................................................. 8 
10.2 
Patient demographics ............................................................................................................................... 8 
10.3 
Treatment details ...................................................................................................................................... 8 
10.4 
Safety data ................................................................................................................................................ 8 
10.4.1 
Incidence of adverse events .............................................................................................................. 8 
10.4.2 
Factors which may affect safety ....................................................................................................... 8 
10.5 
Efficacy data............................................................................................................................................. 8 
10.5.1 
Endoscopic relapse rate .................................................................................................................... 8 
10.5.2 
Change of the severity of subjective symptoms ............................................................................... 9 
10.5.3 
Factors which may affect efficacy .................................................................................................... 9 
11.0 
Registration of surveillance information .................................................................................................... 9 

12.0 
Administrative structure ............................................................................................................................. 9 
13.0 
Trustees ....................................................................................................................................................... 9 
14.0 
Other necessary items ................................................................................................................................. 9 
14.1 
Protocol amendments ............................................................................................................................... 9 
14.2 
Actions to be taken in response to detection of any issues or concerns ................................................. 10 
 
Appendix  Observation schedule..........................................................................................................................9 
 

1 
1.0 
Background 
Administration of Takecab Tablets as maintenance therapy for reflux esophagitis with repeated 
recurrences or relapses is anticipated to be continued long-term in routine clinical settings. 
Administration of Takecab Tablets 10 or 20 mg once daily as maintenance therapy for reflux 
esophagitis was evaluated for up to 24 weeks in 406 patients in a Japanese phase III 
double-blind comparative study and up to 52 weeks in 305 patients in a Japanese phase III 
long-term study, and raised no particular safety issues. However, it would be meaningful to 
verify the safety of Takecab Tablets used in routine clinical practice and the consistency of the 
long-term safety profile with the known safety profile of the drug. Thus, the present special 
drug use surveillance has been planned.  
This surveillance will be conducted in compliance with the Ministerial Ordinance on Good 
Post-Marketing Study Practice (GPSP) and relevant regulatory requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of long-term use of Takecab Tablets as maintenance 
therapy for reflux esophagitis in routine clinical practice.  
 
3.0 
Planned sample size and rationale 
3.1 Planned sample size 
1,000 patients 
 
3.2 Rationale 
The target sample size is set to 1000 for collection of 12-month therapy data from 300 
patients.  
Based on the results from Takepron (lansoprazole) post-marketing surveillance*, the 
percentage of patients given 12-month therapy is conservatively assumed to be 30%. Thus, a 
target sample size of 1000 would allow collection of 12-month therapy data from 300 patients.  
With the data collection from 300 patients, an adverse drug reaction (ADR) occurring with an 
incidence of 1% or more can be detected with a probability of at least 95%, which should 
allow determination of ADRs characteristic of long-term use of the drug.  
 
* “Reflux esophagitis/maintenance therapy 3 to 6 months”: 6-month therapy in 57% 
“Suppression of ulcer recurrence on low-dose aspirin: Long-term use”: 12-month therapy in 79.1% 
“Suppression of ulcer recurrence on non-steroidal anti-inflammatory drugs: Long-term use”: 12-month 
therapy in 46.1% 
 
4.0 
Surveillance population 
This surveillance will enroll patients who require maintenance therapy for reflux esophagitis 
with repeated recurrences and relapses* and who do not meet the exclusion criteria specified 
below. The PRECAUTIONS section of the Takecab package insert should also be referenced.  
*Re-enrollment is prohibited for patients previously enrolled in this surveillance even if they receive 
re-administration for maintenance therapy.  

2 
 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded:  
(1) Patients diagnosed with Los Angeles classification (Hoshihara’s modification) grade A 
to D disease, based on endoscopy at initiation of maintenance therapy with Takecab 
Tablets 
(2) Patients with a history of hypersensitivity to any ingredients of Takecab Tablets 
(3) Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual adult dosage is 10 mg of vonoprazan administered orally once daily. If this is 
inadequately effective, the dosage may be increased to 20 mg orally once daily. The 
PRECAUTIONS section of the Takecab package insert should also be referenced.  
 
6.0 
Planned number of surveillance sites by specialty department  
Approximately 300 sites, including the internal medicine (gastroenterology) department  
 
7.0 
Methods 
7.1 Duration of observation 
12 months  
 
7.2 Request to and contract with medical institutions  
The surveillance implementation will use a Web-based electronic data capture system 
(
). Upon request, a medical representative of 
 
(hereinafter referred to as “
”) will explain to the potential surveillance investigator 
about the surveillance objectives and contents, as well as how to use 
 and enter the 
electronic signature and handling of the user ID and the password according to the 
“Surveillance Implementation Outline”, “
 Data Entry screen images” and 
“
 User Manual”. If the request is accepted, a written contract for the surveillance 
within the specified period will be made with the medical institution. 
 
7.3 Patient enrollment method  
Patients will be enrolled using a centralized enrollment method via 
. For patients 
prescribed Takecab Tablets on or after the first day of the contract period for the medical 
institution, the surveillance investigators will enter the patient information required for 
enrollment (see Section 9.1) and the electronic signature in 
 within 14 days after 
the prescription of Takecab Tablets (with the day of prescription counted as zero and the day 
following prescription counted as “1 day after prescription”).  
 
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7.4 Data entry to the survey form (electronic) and electronic signature 
The surveillance investigator will enter data on patient demographics, treatment details, etc. 
and the electronic signature in 
, roughly within 1 month after the end of the 
required observations at Month 12 of Takecab therapy. If administration of this drug could not 
be confirmed, this fact should be entered (no other data are required).  
 
For patients who discontinued treatment with Takecab Tablets for certain reasons during the 
observation period, the surveillance investigator will enter data on patient demographics, 
treatment details, etc. and the electronic signature in 
 roughly within 1 month after 
the end of required observations. However, for patients who discontinued Takecab therapy 
because of onset of an adverse event (AE), even after the discontinuation of this drug, the 
surveillance investigator will continue observation as far as possible up to resolution or 
improvement of the adverse event. The surveillance investigator will then enter the 
observation result and the electronic signature in 
.  
 
7.5 Actions taken for serious adverse events 
If any serious AE occurs during the observation period, the surveillance investigator will 
immediately report it to an 
 If requested by the 
 the surveillance 
investigator will provide detailed information separately.  
 
8.0 
Planned surveillance period 
Surveillance period: March 2016 to August 31, 2018 
Patient enrollment period: March 2016 to August 31, 2017 Note)  
Note) No patient enrolment (via 
) will be acceptable on or after September 1, 2017, 
even if Takecab is prescribed by August 31, 2017.  
If the total number of the enrolled patients in the entire surveillance reached the planned 
sample size before August 31, 2017, patient enrolment will be closed before the end of the 
patient enrollment period. If the patient enrollment period is shortened, the surveillance 
period will also be changed according to the shortened enrollment period. 
 
9.0 
Surveillance items 
The surveillance investigator will enter data of the following items into 
. The 
surveillance schedule is shown in the Appendix.  
 
9.1 Patient enrollment 
1) Surveillance items 
Date of prescription of Takecab Tablets for maintenance therapy, patient identification 
number, patient initials, sex, date of birth, assessment against the exclusion criteria 
2) Time of data collection 
At enrollment of the patient 
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9.2 Patient demographics information  
1) Surveillance items  
Time of initial onset of reflux esophagitis, inpatient/outpatient classification (at initiation of 
Takecab therapy), hypersensitive diathesis (presence or absence, and details), complication 
(presence or absence, and details), height, weight, presence or absence of Helicobacter 
pylori infection (at initiation of Takecab therapy), presence or absence of hiatus hernia, 
smoking history, drinking history, treatment (antacids) within 1 month before initiation of 
maintenance therapy for reflux esophagitis (presence or absence, name of drug, reason for 
use)  
2) Time of data collection 
At initiation of Takecab maintenance therapy 
 
9.3 Treatment information 
1) Surveillance items  
Takecab therapy details (daily dose, therapy dates, and reason for discontinuation), 
concomitant drug details (presence or absence, name of drug, reason for use)  
2) Time of data collection  
From initiation of Takecab maintenance therapy to Month 12 (or discontinuation of the 
therapy)  
 
9.4 Tests and observations 
9.4.1 Endoscopy 
1) Data items 
Endoscopy (performed or not, date of endoscopy, and gradeNote)  
Note) The Los Angeles classification (Hoshihara’s modification) grade of mucosal damage will be 
used. 
 
2) Time of data collection  
At time points of endoscopy from initiation of Takecab maintenance therapy to Month 12 
(or discontinuation of the therapy)  
 
9.4.2 Subjective symptoms (heartburn, acid reflux, heavy stomach feeling, early satiety, 
epigastric pain, epigastric burning sensation, bloating, nausea/vomiting, belching, 
inappetence)  
1) Data items 
Subjective symptoms (presence or absence and severity)  
2) Time of data collection  
At medical interviews at initiation of Takecab maintenance therapy, Month 6, and Month 
12 (or discontinuation of the therapy) 

5 
 
9.4.3 Liver function tests 
1) Test parameters  
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate dehydrogenase 
(LDH)  
2) Time of data collection  
At the testing from initiation of Takecab maintenance therapy* to Month 12 (or 
discontinuation of the therapy)  
*Within 1 month before initiation of Takecab maintenance therapy  
 
9.4.4 Serum gastrin 
1) Test parameter 
Serum gastrin level 
2) Time of data collection  
At the testing from initiation of Takecab maintenance therapy* to Month 12 (or 
discontinuation of the therapy) 
*Within 1 month before initiation of Takecab maintenance therapy 
 
9.4.5 Other items of observations 
1) Observation items 
Presence or absence of pregnancy during the observation period (only in women)  
Any pregnancy found during the observation period should be immediately notified to an 
. In response to a request by an 
 the surveillance investigator will 
provide detailed information (wherever possible up to the outcome of pregnancy, such as 
premature delivery).  
2) Time of data collection  
From initiation of Takecab maintenance therapy to Month 12 (or discontinuation of the 
therapy) 
 
9.5 Adverse events 
1) Surveillance items  
Presence or absence of AEs (see Table 1), AE term, date of onset, seriousness and reason 
for the assessment as serious (see Table 2), reason for discontinuation of Takecab, 
outcome assessment date, outcome, causal relationship to Takecab* (see Table 3)  
If the outcome is “not resolved” or “unknown”, or if the causal relationship is 
“unassessable”, the event should be followed as far as possible.  
Detailed event information should be collected as much as possible in the event of hepatic 
function disorder, fracture, gastrointestinal infection with Clostridium difficile, or 
neuroendocrine tumor.  
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*If the causal relationship to Takecab is “Not related”, the basis for the assessment should be recorded. If 
the causal relationship to Takecab is “Unassessable”, the reason should be recorded.  
Note) Special guidance about reporting of AEs:  
Abnormal worsening of the target disease, e.g., outside the predictable range of the natural course 
of the disease, is regarded as an AE.  
Serum gastrin can increase due to the pharmacological action of Takecab. However, if Takecab therapy 
is discontinued because of increased serum gastrin, this event should be handled as an AE.  
2) Time of data collection  
From initiation of Takecab maintenance therapy to Month 12 (or discontinuation of the 
therapy)  
 
Table 1  Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment.  
An adverse event can therefore be any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product. 
Note that the following events will also be handled as adverse events:  
 Any manifestation in an infant breastfed by a mother taking this drug  
 Any untoward manifestation in a child given this drug  
 Any manifestation due to occupational exposure to this drug 
 Any manifestation due to a counterfeit product of a prescription drug marketed by Takeda 
 Any untoward manifestation in a patient given this drug revealed by a lawsuit or any other legal 
action 
 

7 
Table 2  Criteria for Serious Adverse Events 
An adverse event is assessed as “serious” if it results in any of the following outcomes:  
1. results in death (Death),  
2. is life-threatening (Life-threatening),  
3. requires hospitalization or prolongation of existing hospitalization (Hospitalization/Prolongation of 
hospitalization),  
4. results in persistent or significant disability/incapacity (Disability),  
5. leads to a congenital anomaly or birth defect (Congenital anomaly), or 
6. is any other important medical event that does not fulfil 1 to 5 above.  
Serious adverse events include events described in the “Takeda Medically Significant AE List”.  
 
Takeda Medically Significant AE List 
- Acute respiratory failure /Acute respiratory 
distress syndrome (ARDS)  
- Anaphylactic shock 
- Torsade de pointes / Ventricular fibrillation / 
Ventricular tachycardia 
- Acute renal failure 
- Malignant hypertension 
- Pulmonary hypertension 
- Convulsive seizure (including convulsion 
and epilepsy)  
- Pulmonary fibrosis (including interstitial 
pneumonia)  
- Agranulocytosis 
- Neuroleptic malignant syndrome/ Malignant 
hyperthermia  
- Aplastic anaemia 
- Spontaneous abortion / Stillbirth and fetal death 
- Toxic epidermal necrolysis / 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
- Confirmed or suspected transmission of infectious 
agent by a medicinal product 
- Hepatic necrosis 
- Confirmed or suspected endotoxin shock 
- Acute hepatic failure 
 
 
Table 3  Assessment of the causal relationship between an adverse event and Takecab 
Causality classification 
Definition 
Related 
An adverse event that follows a temporal sequence from 
administration of this drug (including the course after withdrawal 
of the drug), or for which possible involvement of this drug can be 
considered, although factors other than this drug, such as the 
primary disease, complication, concomitant drugs or concurrent 
treatments, may also be responsible. 
Not related 
An adverse event that does not follow a temporal sequence from 
administration of this drug or that can reasonably be explained by 
other factors, such as the primary disease, complication, 
concomitant drugs or concurrent treatments.  
Unassessable 
The causality cannot be assessed because of insufficiency of 

8 
required information, such as temporal sequence of the event onset 
relative to administration of this drug (including the course after 
withdrawal of the drug), primary disease, complication, 
concomitant drugs, and concurrent treatments. 
 
10.0 
Analysis items and methods 
10.1 Disposition of patients 
Number of patients enrolled, number of patients with collected survey forms (electronic), 
numbers of patients for safety and efficacy analyses, number of patients excluded from 
analysis, reason for exclusion, etc. will be summarized.  
 
10.2 Patient demographics 
Patient demographic data such as sex, age, hypersensitive diathesis, and complication will be 
summarized.  
 
10.3 Treatment details 
Detailed use of Takecab and concomitant drugs will be summarized.  
 
10.4 Safety data 
The following data will be summarized using the safety analysis set. AEs will be coded using 
the MedDRA/J, and summarized by Preferred Term (PT) and System Organ Class (SOC).  
10.4.1 Incidence of adverse events 
AEs occurring during the observation period will be summarized using frequency count by 
event type, time of onset, seriousness, causal relationship to Takecab, etc.  
 
10.4.2 Factors which may affect safety 
ADRs occurring during the observation period will be summarized using frequency count, 
with stratification of patients according to patient demographic factors (e.g., sex, age, any 
renal impairment, any hepatic impairment) and treatment details (e.g., detailed use of 
Takecab, detailed use of concomitant drugs). 
 
10.5 Efficacy data 
The following data will be summarized using the efficacy analysis set.  
10.5.1 Endoscopic relapse rate 
The endoscopic relapse rate (i.e., the percentage of patients assessed as having Los Angeles 
classification grade A to D disease) will be calculated among patients with recorded 
endoscopic findings at initiation of Takecab maintenance therapy, during the therapy, and at 
Month 12 (or discontinuation of the therapy). 
 

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10.5.2 Change of the severity of subjective symptoms  
The change of the severity of subjective symptoms will be summarized among patients 
with recorded severity of subjective symptoms at initiation of Takecab maintenance therapy 
and at each time point of observation after administration.  
 
10.5.3 Factors which may affect efficacy  
The endoscopic relapse rate will be summarized with stratification of patients according to 
patient demographic factors (e.g., sex, age, complication) and treatment details (e.g., 
detailed use of Takecab, detailed use of concomitant drugs ).  
 
11.0 
Registration of surveillance information 
Before initiation of the surveillance, Takeda Pharmaceutical Company Limited will register 
the surveillance information with an online public clinical trials registry:  
- Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information:  
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Administrative structure 
Responsible Manager 
Post-marketing surveillance manager, Takeda Pharmaceutical Company Limited  
 
13.0 
Trustees 
 
 
14.0 
Other necessary items 
14.1 Protocol amendments  
During the surveillance period, monitoring will be performed regarding the progress of the 
surveillance, occurrence of ADRs unexpected from the PRECAUTIONS and serious ADRs, 
any increase in the incidence of particular ADRs, validity of the surveillance items, etc., and 
the protocol will be reviewed and amended as necessary. If any partial change to the DOSAGE 
AND ADMINISTRATION, INDICATIONS, etc. is approved during the surveillance period, 
whether or not the protocol should be amended will be examined, and the protocol will be 
amended as necessary. 
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14.2 Actions to be taken in response to detection of any issues or concerns 
Whenever an issue is found regarding the safety or efficacy, the data will be investigated in 
detail, and necessary actions will be determined.  

11 
Appendix  Observation schedule 
 
         Time of data collection/entry 
 
 
 Surveillance items  
Observation period  
At 
enrollment 
Start of 
Takecab 
maintenance 
therapy 
Month 6 
Month 12  
Discontinuat
ion of 
Takecab 
maintenance 
therapy 
Patient enrollment 
Date of prescription of Takecab 
Tablets for maintenance therapy 
○ 
 
 
 
 
Patient identification number 
○ 
 
Patient initials 
○ 
 
Sex  
○ 
 
Date of birth  
○ 
 
Assessment against exclusion 
criteria 
○ 
 
 
 
 
Patient demographics 
Time of initial onset of reflux 
esophagitis 
 
○ 
 
 
 
Inpatient/outpatient classification 
○ 
 
 
Hypersensitive diathesis 
○ 
 
 
Complication 
○ 
 
 
Height, weight 
 
○ 
 
 
H. pylori infection 
 
○ 
 
 
 
Hiatus hernia 
 
○ 
 
 
 
Smoking history  
 
○ 
 
 
Drinking history 
 
○ 
 
 
Treatment (antacids) within 1 
month of maintenance therapy 
for reflux esophagitis  
 
○ 
 
 
 
Treatment 
details 
Detailed use of Takecab  
○ 
○ 
Detailed use of concomitant drugs 
 
○ 
○ 
Assessments 
Endoscopy 
○ 
○ 
Subjective symptoms  
○ 
○ 
○ 
○ 
Liver function tests 
 
  ○Note)  
○ 
Serum gastrin 
 
  ○Note)  
○ 
Pregnancy (women only)  
○ 
○ 
AE monitoring 
○ 
○ 
○    : Performed 
○    : Performed throughout the period  
Note) From ≤1 month before initiation of Takecab maintenance therapy to Month 12