Drug Use Surveillance of Takecab Tablets "Supplement to Helicobacter Pylori Eradication"
Conditions: Gastric/Duodenal Ulcer, Gastric MALT Lymphoma, Idiopathic Thrombocytopenic Purpura, or H. Pylori Gastritis, and Other
Sponsor: Takeda

Title: Drug use surveillance of Takecab tablets “Supplement to Helicobacter pylori 
eradication” 
NCT Number: NCT03219723 
Protocol Approve Date: 23-Feb-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. 

 
 
 
 
Protocol of drug use surveillance 
Drug use surveillance of Takecab tablets 
“Supplement to Helicobacter pylori eradication” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5002 
Version 
Version 5 
Date 
February 23, 2018 
 

Table of contents 
1.0 
Background of conduct ................................................................................................................................ 1 
2.0 
Objectives ..................................................................................................................................................... 1 
3.0 
Planned sample size and its rationale ........................................................................................................... 1 
3.1 
Sample size ............................................................................................................................................... 1 
3.2 
Rationale................................................................................................................................................... 1 
4.0 
Study population .......................................................................................................................................... 2 
4.1 
Inclusion criteria ....................................................................................................................................... 3 
4.2 
Exclusion criteria ...................................................................................................................................... 3 
5.0 
Dosage and administration ........................................................................................................................... 3 
6.0 
Number of medical institutions by departments where the survey is planned ............................................. 3 
7.0 
Method ......................................................................................................................................................... 3 
7.1 
Observational period ................................................................................................................................ 3 
7.2 
Request to and contract with the medical institutions .............................................................................. 4 
7.3 
Method of patient enrollment ................................................................................................................... 4 
7.4 
Data entry and electronic signature in the survey form (electronic) ........................................................ 4 
7.5 
Actions to take at the time of development of a serious adverse event .................................................... 4 
8.0 
Scheduled period of the survey .................................................................................................................... 5 
9.0 
Data to be collected ...................................................................................................................................... 5 
9.1 
Patient enrollment .................................................................................................................................... 5 
9.2 
Patient demographic information ............................................................................................................. 5 
9.3 
Information of treatment .......................................................................................................................... 5 
9.4 
Test/examination items ............................................................................................................................. 6 
9.4.1 
Determination of H. pylori eradication ............................................................................................ 6 
9.4.2 
Liver function test ............................................................................................................................ 6 
9.4.3 
Other examination items .................................................................................................................. 6 
9.5 
Adverse event ........................................................................................................................................... 6 
10.0 
Analysis items and method........................................................................................................................... 9 
10.1 
Items related to patient disposition ........................................................................................................... 9 
10.2 
Patient demographics ............................................................................................................................... 9 
10.3 
Details of treatment .................................................................................................................................. 9 
10.4 
Items related to safety............................................................................................................................... 9 
10.4.1 
Onset of adverse events .................................................................................................................... 9 
10.4.2 
Factors which may affect safety ....................................................................................................... 9 
10.5 
Items related to efficacy ........................................................................................................................... 9 
10.5.1 
Eradication rate of H. pylori............................................................................................................. 9 
10.5.2 
Factors which may affect efficacy ................................................................................................... 9 
11.0 
Registration of survey information ............................................................................................................. 10 
12.0 
Organization of this survey ........................................................................................................................ 10 
12.1 
Manager .................................................................................................................................................. 10 

13.0 
Clinical research organizations................................................................................................................... 10 
14.0 
Other required items ................................................................................................................................... 11 
14.1 
Revision of the protocol ......................................................................................................................... 11 
14.2 
Procedure when there is any issue or doubt ........................................................................................... 11 
 
Appendix: Observation schedule............................................................................................................................12 
 

1 
1.0 
Background of conduct 
In the domestic clinical studies of Helicobacter Pylori (H. pylori) eradication with Takecab 
Tablets in combination with antimicrobials, safety of triple therapy was evaluated: Takecab 
Tablets, amoxicillin and clarithromycin (first-line eradication) in 329 patients, and Takecab 
Tablets, amoxicillin and metronidazole (second-line eradication) in 50 patients, and the results 
showed no specific issue. 
The safety profile of the first-line eradication could be expected in view of the results of 
Takecab Tablets clinical studies in patients with acid-related diseases (gastric ulcer, duodenal 
ulcer and reflux oesophagitis) and information provided in the package inserts of 
antimicrobials. Most of the adverse reactions (ADRs) developed during the second-line 
eradication were also observed in the first-line eradication, and there was no substantial 
difference between them. Accordingly, the safety profile of the use of Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
The Drug use surveillance of Takecab Tablets (this survey) for the supplement to H. pylori 
eradication in first-line and second-line eradication in the routine clinical setting is planned to 
confirm validity of this estimation (whether there is a new safety concern or not). 
This survey is conducted in compliance with relevant regulatory requirements such as GPSP 
ministerial ordinance. 
 
2.0 
Objectives 
The objective of this survey is to evaluate the safety and efficacy of first-line and second-line 
eradication including Takecab Tablets (triple therapy) in the routine clinical setting. 
 
3.0 
Planned sample size and its rationale 
3.1 Sample size 
500 patients 
 
3.2 Rationale 
The safety profile of H. pylori eradication with a proton pump inhibitor (lansoprazole) in 
combination with antimicrobials (amoxicillin and clarithromycin) observed in the domestic 
clinical studies and the drug use surveillance could be expected from the results of the 
domestic clinical studies and the drug use surveillance of lansoprazole in patients with 
acid-related diseases (gastric ulcer, duodenal ulcer and reflux oesophagitis), and from the 
information provided in the package inserts of antimicrobials. 
The safety profile of the first-line eradication observed in the clinical studies for H. pylori 
eradication with Takecab Tablets in combination with antimicrobials could be expected from 

2 
the results of the clinical studies of Takecab Tablets in patients with acid-related diseases and 
information provided in the package inserts of antimicrobials. 
Based on the above, the safety profile of the first-line eradication with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
In addition, it has been confirmed that ADRs of H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and metronidazole) in the specific 
drug use surveillance of proton pump inhibitors (lansoprazole, omeprazole and rabeprazole) 
were mostly similar to the ADRs reported in H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and clarithromycin). Most of the 
ADRs developed during the second-line H. pylori eradication in the clinical study of Takecab 
Tablets in combination with antimicrobials were also observed in the first-line eradication. 
Therefore, it is estimated that ADRs developed in association with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication are not substantially different 
between first-line eradication and second-line eradication. In view of the above, the drug use 
surveillance of Takecab Tablets for supplement of H. pylori eradication is to be conducted for 
both first-line and second-line eradication. 
Accordingly, in this survey, data will be collected from 500 patients to whom Takecab Tablets 
is administered for supplement of H. pylori eradication, and will be compared with the safety 
information of Takecab Tablets collected in the drug use surveillance in patients with 
acid-related diseases (total 3,000 patients) and with information provided in the package 
inserts of antimicrobials, and it will be confirmed whether there is a new safety concern or not 
(please note that the sample size of 500 patients is not statistically calculated). 
In this survey, patients excluded from the clinical studies such as with gastric 
mucosa-associated lymphoid tissue (MALT) lymphoma, idiopathic thrombocytopenic purpura, 
stomach following endoscopic treatment of early gastric cancer, or H. pylori gastritis will be 
enrolled. 
 
4.0 
Study population 
Patients with the diseases described below* will receive triple therapy for H. pylori eradication. 
However, patients should meet the inclusion criterion and should not meet the exclusion 
criterion described below. Refer to the Precautions section of the package insert. 
* If a patient’s first-line eradication is unsuccessful in this survey, the patient can be enrolled in the 
second-line eradication in this survey. 
Gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) 
lymphoma, idiopathic thrombocytopenic purpura, stomach following endoscopic 
treatment of early gastric cancer, or H. pylori gastritis 

3 
4.1 Inclusion criteria 
Patients who meet either of the following criteria will be included in the survey: 
[1] Patients receiving H. pylori eradication for the first time 
[2] Patients for whom H. pylori eradication with Takecab Tablets or proton pump inhibitor + 
amoxicillin + clarithromycin was found unsuccessful and who are to receive eradication 
treatment with amoxicillin and metronidazole 
 
4.2 Exclusion criteria 
Patients who meet either of the following criteria will not be included in the survey. Refer to 
the Contraindications and Precautions section of the package insert of antimicrobials used in 
the triple therapy. 
[1] Patients with previous history of hypersensitivity to ingredients in Takecab Tablets 
[2] Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual dose for adults is 20 mg of vonoprazan, 750 mg (potency) of amoxicillin hydrate, 
and 200 mg (potency) of clarithromycin. These three drugs will be orally administered at the 
same time, twice daily for 7 days. The dose of clarithromycin can be increased as clinically 
warranted. However, the dosage of clarithromycin should not exceed 400 mg (potency)/dose 
twice daily. 
If H. pylori eradication with a three-drug regimen comprising vonoprazan or proton pump 
inhibitor + amoxicillin hydrate + clarithromycin is unsuccessful, as an alternative treatment, 
the following three drugs will be orally administered to adults at the same time, twice daily for 
7 days: vonoprazan at a dose of 20 mg, amoxicillin hydrate at a dose of 750 mg (potency), and 
metronidazole at a dose of 250 mg. Refer to the Precautions section of the package insert of 
antimicrobials used in triple therapy. 
 
6.0 
Number of medical institutions by departments where the survey is planned 
Internal medicine department (such as gastrointestinal medicine department)
 
Approximately 150 medical institutions 
Hematology department 
Approximately 10 medical institutions 
 
7.0 
Method 
7.1 Observational period 
Triple therapy period (7 days) and the period from the completion of the triple therapy to the 
determination of H. pylori eradication 
Time frame of the H. pylori determination is approximately from 4 weeks* to 2 months after 
the triple therapy. 
* According to the “Guidelines for diagnosis and treatment of H. pylori infection” of the Japanese Society 
for Helicobacter Research, determination of H. pylori eradication should be conducted after 4 weeks 

4 
from discontinuation of eradication therapy. 
 
7.2 Request to and contract with the medical institutions 
Request to and contract with the medical institutions will be conducted using web-based 
electronic data collection system (
). The Medical Representative of 
 
will explain objectives and details of this survey, 
procedure, electronic signature, and handling of user ID and password of 
 to the 
surveillance investigator based on “Implementation guidance”, “Data entry screens of 
” and “
 operational manual” when this survey is requested. Thereafter, 
written contract is made with the medical institution and conduct of the survey will be 
requested within the prespecified duration of the survey. 
 
7.3 Method of patient enrollment 
Patients will be enrolled with “central enrollment method” using 
. The surveillance 
investigator will enter the information required for patient enrollment (see Section 9.1) and 
will provide his/her electronic signature in 
concerning patients to whom drugs of 
triple therapy (three drugs including Takecab Tablets) are prescribed within 5 days after 
prescription day of the three drugs including Takecab Tablets (the prescription day is defined 
as “Day 0”, and the day after prescription as “Day 1”) after term of contract with the medical 
institution is started. 
 
7.4 Data entry and electronic signature in the survey form (electronic) 
The surveillance investigator will enter the information of patient demographics and treatment 
and will provide electronic signature in 
 for all patients enrolled in this survey by 
one month after completion of the observational period of each patient. If receipt of Takecab 
Tablets was not confirmed, it will be entered so in 
 (it is not required to enter other 
data). 
For the patients who discontinued triple therapy including Takecab Tablets for any reason 
during the observational period, the surveillance investigator will enter the information of 
patient demographics and treatment and will provide his/her electronic signature in 
 
by one month after completion of required observation. However, for patients who 
discontinued triple therapy including Takecab Tablets due to development of an AE, 
observation will be continued as much as possible until resolve or resolving from the AE even 
after the treatment is discontinued, and the observation results will be entered in 
 
with his/her electronic signature. 
 
7.5 Actions to take at the time of development of a serious adverse event 
The surveillance investigator will immediately communicate 
 on development of a 
serious adverse event during the observational period. In addition, the surveillance investigator 
will provide detailed information separately if requested by 
 
PPD
PPD
PPD
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

5 
 
8.0 
Scheduled period of the survey 
Duration of the survey: September 2015 to April 30, 2017 
Patient enrollment period: September 2015 to February 28, 2017 Note) 
Note) Patients will not be enrolled in this survey (or entered in 
) on or after March 1, 
2017 even if Takecab Tablets is prescribed on or before February 28, 2017. 
If enrollment of the planned number of patients of this survey is completed prior to 
February 28, 2017, the patient enrollment will be discontinued prior to the end of the 
patient enrollment period. When the patient enrollment period is shortened, the duration of 
the survey is to be changed according to the shortened period. 
 
9.0 
Data to be collected 
The surveillance investigator will enter the information of the following items in 
. 
The schedule of this survey is presented in the Appendix. 
9.1 Patient enrollment 
1) Data to be collected 
Prescription date of the three drugs including Takecab Tablets used in the triple therapy; 
patient identification number; patient initials; sex; date of birth; target disease of H. pylori 
eradication; assessment of inclusion and exclusion criteria 
2) Data collection period 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Data to be collected 
Inpatient/outpatient classification (at the time when triple therapy is started); predisposition 
of hypersensitivity (presence/absence and details); complication (presence/absence and 
details); details of previous H. pylori eradication (in patients with a history of unsuccessful 
H. pylori eradication with Takecab Tablets or a proton pump inhibitor with amoxicillin and 
clarithromycin); height; weight; smoking history; drinking history; diagnosis of H. pylori 
infection (time of diagnosis and testing method) 
2) Data collection period 
At the start of triple therapy 
 
9.3 Information of treatment 
1) Data to be collected 
Treatment compliance to Takecab Tablets and antimicrobials used for triple therapy (name 
of drugs; daily dose; duration of triple therapy and reason for discontinuation of the triple 
therapy); treatment compliance to concomitant drugs (excluding antimicrobials used for the 
triple therapy) (presence/absence; drug name(s), and indication(s)) 
2) Data collection period 
CCI
CCI

6 
Duration from the start to the completion (or the discontinuation) of triple therapy 
 
9.4 Test/examination items 
9.4.1 Determination of H. pylori eradication 
1) Test items 
Conduct of tests (presence/absence; reason if test is not conducted; testing method; date 
and result of determination) 
2) Testing period 
At the time of determination of H. pylori eradication* 
*  Time frame of the H. pylori determination is approximately from 4 weeks to 2 months after the triple 
therapy. 
 
9.4.2 Liver function test 
1) Test items 
Aspartate aminotransferase (AST); alanine aminotransferase (ALT); γ-glutamyl 
transpeptidase (γ-GTP); alkaline phosphatase (ALP); total bilirubin; lactate 
dehydrogenase (LDH) 
2) Testing period 
Duration from the start of triple therapy* to the determination of H. pylori eradication (or the 
discontinuation of triple therapy) 
* Within 1 month before starting triple therapy 
 
9.4.3 Other examination items 
1) Examination items 
Presence/absence of pregnancy during the observational period (only female patients) 
If pregnancy is confirmed during the observational period, the information is immediately 
communicated to 
. The surveillance investigator provides detailed information 
(including information until delivery, e.g., pregnancy outcome such as premature delivery, 
as much as possible) separately when 
 requests it. 
2) Examination period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
9.5 Adverse event 
1) Data to be collected 
Presence/absence of adverse event (AE) (See Table 1); AE term; onset date; seriousness 
and reason for seriousness (See Table 2); cause of discontinuation of triple therapy; 
outcome date; outcome; causality* with triple therapy (See Table 3) 
Follow-up survey will be conducted as much as possible when outcome is not resolved or 
unknown and causality is determined as unassessable. 
PPD
PPD

7 
Detailed information (e.g., clinical course and results of tests conducted for diagnosis) 
will be collected as much as possible when onset of hepatic function disorder or 
gastrointestinal infection of clostridium difficile is observed. 
* Following information will be collected: rationale of assessment when causality is assessed as not 
related, and reason when causality is determined as unassessable. 
Note) A point to consider concerning adverse events 
Abnormal exacerbation of the target disease, i.e., exacerbation worse than the expected natural 
course of the disease, will be handled as an adverse event. 
2) Data collection period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
Table 1 
Definition of adverse event 
Adverse event (AE) is any unfavorable medical occurrence in a patient administered a pharmaceutical 
product. It does not necessarily need to have a causal relationship with the pharmaceutical product. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including abnormal 
laboratory values), symptom, or disease occurring at the use of a pharmaceutical product, whether or not 
considered related to the pharmaceutical product. 
Following cases should also be handled as adverse events. 
 
Symptoms developed in an infant breastfed by a mother receiving the pharmaceutical product 
 
Unfavorable symptoms, etc. developed in a child after administration of the pharmaceutical product 
 
Symptoms developed after occupational exposure to the pharmaceutical product 
 
Symptoms developed due to the use of a counterfeit of a pharmaceutical product 
manufactured/marketed by Takeda Pharmaceutical Company Limited 
 
Unfavorable symptoms developed in a user of the pharmaceutical product which information was 
obtained through litigation or other legal actions 
 

8 
Table 2 
Seriousness assessment criteria 
An event meeting any of the following criteria is assessed as “serious”: 
1. Fatal (death) 
2. Life-threatening (life-threatening) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolongation of hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Congenital anomaly/birth defect (congenital anomaly) 
6. Other medically important condition than 1-5. Events listed in “Takeda Medically Significant AE 
List” are included in this criterion. 
 
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/hyperthermia malignant 
 
Aplastic anaemia 
 
Abortion spontaneous/stillbirth and dead foetus 
 
Toxic epidermal necrolysis/oculomucocutaneous syndrome (Stevens-Johnson syndrome) 
 
Transmission or suspected transmission of infection via a medicinal product 
 
Hepatic necrosis 
 
Endotoxic shock or suspected endotoxic shock 
 
Acute hepatic failure 
 
Table 3 
Causality assessment criteria for adverse events and triple therapy 
Assessment 
Assessment criteria 
Related 
There is temporal relationship (including the clinical course after the 
discontinuation of the triple therapy). Or, while other factors such as 
underlying disease, complication, concomitant drug or concomitant 
procedure could be presumed, the AE is possibly related to triple 
therapy. 
Not related 
There is no temporal relationship with the triple therapy. Or, other 
factors such as underlying disease, complication, concomitant drug or 
concomitant procedure are quite considerable as the cause. 
Unassessable 
Information required for causality assessment, such as temporal 
relationship (including the clinical course after the discontinuation of 
the triple therapy), underlying disease, complication, concomitant 
drug, and concomitant procedure is insufficient. 
 

9 
10.0 
Analysis items and method 
10.1 Items related to patient disposition 
Following data will be accumulated: number of patients enrolled; number of patients whose 
survey form (electronic) have been collected; number of patients in the safety analysis set and 
the efficacy analysis set; number of patients excluded from analysis and reasons for exclusion 
 
10.2 Patient demographics 
Patient demographic data including sex, age, hypersensitivity predisposition and complication 
will be accumulated. 
 
10.3 Details of treatment 
Treatment compliance to Takecab Tablets and antimicrobials used for the triple therapy and 
concomitant drugs (other than antimicrobials used for the triple therapy) will be accumulated. 
 
10.4 Items related to safety 
Following data will be accumulated for the safety analysis set. Adverse events are coded with 
MedDRA/J, and accumulated by Preferred Term (PT) and System Organ Class (SOC). 
The patients enrolled to this survey in both first-line and second-line eradication cases will be 
accumulated separately. 
10.4.1 Onset of adverse events 
Frequencies of adverse events which developed during the observational period will be 
accumulated by type, onset period, seriousness, and causality with the triple therapy. 
 
10.4.2 Factors which may affect safety 
Frequencies of adverse reactions which developed during the observational period will be 
accumulated by subgroups of patient demographic factors (e.g., sex; age; target disease of 
H. pylori eradication; presence/absence of renal disorder complication; and 
presence/absence of liver disorder complication) and details of treatment (first-line and 
second-line eradication). 
 
10.5 Items related to efficacy 
Following data will be accumulated for the efficacy analysis set. 
10.5.1 Eradication rate of H. pylori 
In patients who have the result of determination of eradication, proportion of patients with 
H. pylori negative (eradication rate) will be accumulated by first-line and second-line 
eradication. 
 
10.5.2 Factors which may affect efficacy 
The eradication rates of H. pylori will be accumulated by subgroup of patient demographic 
factors (e.g., sex; age; target disease of H. pylori eradication; complication). 

10 
 
11.0 
Registration of survey information 
Takeda Pharmaceutical Company Limited will register information of this survey on the 
public websites before starting this survey. 
 Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization of this survey 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
Post-marketing surveillance manager 
 
13.0 
Clinical research organizations 
 
PPD

11 
14.0 
Other required items 
14.1 Revision of the protocol 
During the period of conducting this survey, following information will be captured: 
development of ADRs not expectable from Precautions for Use and onset of serious ADRs; 
whether there is increased frequency of specific ADRs or not; validity of the survey items. The 
protocol will be reviewed and revised if it is considered necessary. In addition, if a 
supplemental approval of a new dosage and administration or a new indication is granted 
during the period of conducting this survey, necessity of revision of the protocol will be 
examined if needed, and the protocol will be revised if needed. 
 
14.2 Procedure when there is any issue or doubt 
If there is any safety or efficacy issue, data will be closely examined, and action will be 
considered. 

12 
Appendix: Observation schedule 
Period of survey/data entry 
 
 
 
 
Data to be collected 
Observational period 
At the time of patient 
enrollment 
At the start of triple 
therapy 
At the completion of 
triple therapy 
At the time of 
determination of H. 
pylori eradication Note 1) 
At the time of 
discontinuation of 
triple therapy 
Patient 
enrollment 
Prescription date of 3 drugs 
including Takecab Tablets in triple 
therapy 
○ 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
Patient initials 
○ 
 
 
 
 
Sex 
○ 
 
 
 
 
Date of birth 
○ 
 
 
 
 
Target disease of H. pylori eradication 
○ 
 
 
 
 
Assessment of inclusion criteria 
○ 
 
 
 
 
Assessment of exclusion criteria 
○ 
 
 
 
 
Patient 
demographic 
information 
Inpatient/outpatient classification 
 
○ 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
Complication 
 
○ 
 
 
 
Previous H. pylori eradication Note 2) 
 
○ 
 
 
 
Height, weight 
 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
Drinking history 
 
○ 
 
 
 
Diagnosis of H. pylori infection 
 
○ 
 
 
 
Information 
of treatment 
Treatment compliance to Takecab 
Tablets and antimicrobials 
 
○ 
 
○ 
Treatment compliance to 
concomitant drugs (excluding 
antimicrobials) 
 
 
○ 
 
○ 
Test/ 
examination 
items 
Determination of H. pylori 
eradication 
 
 
 
○ 
 
Liver function test 
 
   ○Note 3) 
○ 
Presence/absence of pregnancy 
(only female patients) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○ 
: To be conducted 
○ 
: To be conducted throughout the period 
Note 1) Approximately from 4 weeks to 2 months after the triple therapy is completed 
Note 2) In patients with a history of unsuccessful H. pylori eradication with Takecab Tablets or a proton 
pump inhibitor in combination with amoxicillin and clarithromycin 
Note 3) From within one month before the start of triple therapy to determination of H. pylori 
eradication 

 
 
 
 
Protocol of drug use surveillance 
Drug use surveillance of Takecab tablets 
“Supplement to Helicobacter pylori eradication” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5002 
Version 
Version 4 
Date 
June 2, 2017 
 

Table of contents 
1.0 
Background of conduct ................................................................................................................................ 1 
2.0 
Objectives ..................................................................................................................................................... 1 
3.0 
Planned sample size and its rationale ........................................................................................................... 1 
3.1 
Sample size ............................................................................................................................................... 1 
3.2 
Rationale................................................................................................................................................... 1 
4.0 
Study population .......................................................................................................................................... 2 
4.1 
Inclusion criteria ....................................................................................................................................... 3 
4.2 
Exclusion criteria ...................................................................................................................................... 3 
5.0 
Dosage and administration ........................................................................................................................... 3 
6.0 
Number of medical institutions by departments where the survey is planned ............................................. 3 
7.0 
Method ......................................................................................................................................................... 3 
7.1 
Observational period ................................................................................................................................ 3 
7.2 
Request to and contract with the medical institutions .............................................................................. 4 
7.3 
Method of patient enrollment ................................................................................................................... 4 
7.4 
Data entry and electronic signature in the survey form (electronic) ........................................................ 4 
7.5 
Actions to take at the time of development of a serious adverse event .................................................... 4 
8.0 
Scheduled period of the survey .................................................................................................................... 5 
9.0 
Data to be collected ...................................................................................................................................... 5 
9.1 
Patient enrollment .................................................................................................................................... 5 
9.2 
Patient demographic information ............................................................................................................. 5 
9.3 
Information of treatment .......................................................................................................................... 5 
9.4 
Test/examination items ............................................................................................................................. 6 
9.4.1 
Determination of H. pylori eradication ............................................................................................ 6 
9.4.2 
Liver function test ............................................................................................................................ 6 
9.4.3 
Other examination items .................................................................................................................. 6 
9.5 
Adverse event ........................................................................................................................................... 6 
10.0 
Analysis items and method........................................................................................................................... 9 
10.1 
Items related to patient disposition ........................................................................................................... 9 
10.2 
Patient demographics ............................................................................................................................... 9 
10.3 
Details of treatment .................................................................................................................................. 9 
10.4 
Items related to safety............................................................................................................................... 9 
10.4.1 
Onset of adverse events .................................................................................................................... 9 
10.4.2 
Factors which may affect safety ....................................................................................................... 9 
10.5 
Items related to efficacy ........................................................................................................................... 9 
10.5.1 
Eradication rate of H. pylori............................................................................................................. 9 
10.5.2 
Factors which may affect efficacy ................................................................................................... 9 
11.0 
Registration of survey information ............................................................................................................. 10 
12.0 
Organization of this survey ........................................................................................................................ 10 
12.1 
Manager .................................................................................................................................................. 10 

13.0 
Clinical research organizations................................................................................................................... 10 
14.0 
Other required items ................................................................................................................................... 10 
14.1 
Revision of the protocol ......................................................................................................................... 10 
14.2 
Procedure when there is any issue or doubt ........................................................................................... 11 
 
Appendix: Observation schedule............................................................................................................................12 
 

1 
1.0 
Background of conduct 
In the domestic clinical studies of Helicobacter Pylori (H. pylori) eradication with Takecab 
Tablets in combination with antimicrobials, safety of triple therapy was evaluated: Takecab 
Tablets, amoxicillin and clarithromycin (first-line eradication) in 329 patients, and Takecab 
Tablets, amoxicillin and metronidazole (second-line eradication) in 50 patients, and the results 
showed no specific issue. 
The safety profile of the first-line eradication could be expected in view of the results of 
Takecab Tablets clinical studies in patients with acid-related diseases (gastric ulcer, duodenal 
ulcer and reflux oesophagitis) and information provided in the package inserts of 
antimicrobials. Most of the adverse reactions (ADRs) developed during the second-line 
eradication were also observed in the first-line eradication, and there was no substantial 
difference between them. Accordingly, the safety profile of the use of Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
The Drug use surveillance of Takecab Tablets (this survey) for the supplement to H. pylori 
eradication in first-line and second-line eradication in the routine clinical setting is planned to 
confirm validity of this estimation (whether there is a new safety concern or not). 
This survey is conducted in compliance with relevant regulatory requirements such as GPSP 
ministerial ordinance. 
 
2.0 
Objectives 
The objective of this survey is to evaluate the safety and efficacy of first-line and second-line 
eradication including Takecab Tablets (triple therapy) in the routine clinical setting. 
 
3.0 
Planned sample size and its rationale 
3.1 Sample size 
500 patients 
 
3.2 Rationale 
The safety profile of H. pylori eradication with a proton pump inhibitor (lansoprazole) in 
combination with antimicrobials (amoxicillin and clarithromycin) observed in the domestic 
clinical studies and the drug use surveillance could be expected from the results of the 
domestic clinical studies and the drug use surveillance of lansoprazole in patients with 
acid-related diseases (gastric ulcer, duodenal ulcer and reflux oesophagitis), and from the 
information provided in the package inserts of antimicrobials. 
The safety profile of the first-line eradication observed in the clinical studies for H. pylori 
eradication with Takecab Tablets in combination with antimicrobials could be expected from 

2 
the results of the clinical studies of Takecab Tablets in patients with acid-related diseases and 
information provided in the package inserts of antimicrobials. 
Based on the above, the safety profile of the first-line eradication with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
In addition, it has been confirmed that ADRs of H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and metronidazole) in the specific 
drug use surveillance of proton pump inhibitors (lansoprazole, omeprazole and rabeprazole) 
were mostly similar to the ADRs reported in H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and clarithromycin). Most of the 
ADRs developed during the second-line H. pylori eradication in the clinical study of Takecab 
Tablets in combination with antimicrobials were also observed in the first-line eradication. 
Therefore, it is estimated that ADRs developed in association with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication are not substantially different 
between first-line eradication and second-line eradication. In view of the above, the drug use 
surveillance of Takecab Tablets for supplement of H. pylori eradication is to be conducted for 
both first-line and second-line eradication. 
Accordingly, in this survey, data will be collected from 500 patients to whom Takecab Tablets 
is administered for supplement of H. pylori eradication, and will be compared with the safety 
information of Takecab Tablets collected in the drug use surveillance in patients with 
acid-related diseases (total 3,000 patients) and with information provided in the package 
inserts of antimicrobials, and it will be confirmed whether there is a new safety concern or not 
(please note that the sample size of 500 patients is not statistically calculated). 
In this survey, patients excluded from the clinical studies such as with gastric 
mucosa-associated lymphoid tissue (MALT) lymphoma, idiopathic thrombocytopenic purpura, 
stomach following endoscopic treatment of early gastric cancer, or H. pylori gastritis will be 
enrolled. 
 
4.0 
Study population 
Patients with the diseases described below* will receive triple therapy for H. pylori eradication. 
However, patients should meet the inclusion criterion and should not meet the exclusion 
criterion described below. Refer to the Precautions section of the package insert. 
* If a patient’s first-line eradication is unsuccessful in this survey, the patient can be enrolled in the 
second-line eradication in this survey. 
Gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) 
lymphoma, idiopathic thrombocytopenic purpura, stomach following endoscopic 
treatment of early gastric cancer, or H. pylori gastritis 

3 
4.1 Inclusion criteria 
Patients who meet either of the following criteria will be included in the survey: 
[1] Patients receiving H. pylori eradication for the first time 
[2] Patients for whom H. pylori eradication with Takecab Tablets or proton pump inhibitor + 
amoxicillin + clarithromycin was found unsuccessful and who are to receive eradication 
treatment with amoxicillin and metronidazole 
 
4.2 Exclusion criteria 
Patients who meet either of the following criteria will not be included in the survey. Refer to 
the Contraindications and Precautions section of the package insert of antimicrobials used in 
the triple therapy. 
[1] Patients with previous history of hypersensitivity to ingredients in Takecab Tablets 
[2] Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual dose for adults is 20 mg of vonoprazan, 750 mg (potency) of amoxicillin hydrate, 
and 200 mg (potency) of clarithromycin. These three drugs will be orally administered at the 
same time, twice daily for 7 days. The dose of clarithromycin can be increased as clinically 
warranted. However, the dosage of clarithromycin should not exceed 400 mg (potency)/dose 
twice daily. 
If H. pylori eradication with a three-drug regimen comprising vonoprazan or proton pump 
inhibitor + amoxicillin hydrate + clarithromycin is unsuccessful, as an alternative treatment, 
the following three drugs will be orally administered to adults at the same time, twice daily for 
7 days: vonoprazan at a dose of 20 mg, amoxicillin hydrate at a dose of 750 mg (potency), and 
metronidazole at a dose of 250 mg. Refer to the Precautions section of the package insert of 
antimicrobials used in triple therapy. 
 
6.0 
Number of medical institutions by departments where the survey is planned 
Internal medicine department (such as gastrointestinal medicine department)
 
Approximately 150 medical institutions 
Hematology department 
Approximately 10 medical institutions 
 
7.0 
Method 
7.1 Observational period 
Triple therapy period (7 days) and the period from the completion of the triple therapy to the 
determination of H. pylori eradication 
Time frame of the H. pylori determination is approximately from 4 weeks* to 2 months after 
the triple therapy. 
* According to the “Guidelines for diagnosis and treatment of H. pylori infection” of the Japanese Society 
for Helicobacter Research, determination of H. pylori eradication should be conducted after 4 weeks 

4 
from discontinuation of eradication therapy. 
 
7.2 Request to and contract with the medical institutions 
Request to and contract with the medical institutions will be conducted using web-based 
electronic data collection system (
). The Medical Representative of 
 
will explain objectives and details of this survey, 
procedure, electronic signature, and handling of user ID and password of 
 to the 
surveillance investigator based on “Implementation guidance”, “Data entry screens of 
” and “
 operational manual” when this survey is requested. Thereafter, 
written contract is made with the medical institution and conduct of the survey will be 
requested within the prespecified duration of the survey. 
 
7.3 Method of patient enrollment 
Patients will be enrolled with “central enrollment method” using 
 The surveillance 
investigator will enter the information required for patient enrollment (see Section 9.1) and 
will provide his/her electronic signature in 
 concerning patients to whom drugs of 
triple therapy (three drugs including Takecab Tablets) are prescribed within 5 days after 
prescription day of the three drugs including Takecab Tablets (the prescription day is defined 
as “Day 0”, and the day after prescription as “Day 1”) after term of contract with the medical 
institution is started. 
 
7.4 Data entry and electronic signature in the survey form (electronic) 
The surveillance investigator will enter the information of patient demographics and treatment 
and will provide electronic signature in 
 for all patients enrolled in this survey by 
one month after completion of the observational period of each patient. If receipt of Takecab 
Tablets was not confirmed, it will be entered so in 
 (it is not required to enter other 
data). 
For the patients who discontinued triple therapy including Takecab Tablets for any reason 
during the observational period, the surveillance investigator will enter the information of 
patient demographics and treatment and will provide his/her electronic signature in 
 
by one month after completion of required observation. However, for patients who 
discontinued triple therapy including Takecab Tablets due to development of an AE, 
observation will be continued as much as possible until resolve or resolving from the AE even 
after the treatment is discontinued, and the observation results will be entered in 
 
with his/her electronic signature. 
 
7.5 Actions to take at the time of development of a serious adverse event 
The surveillance investigator will immediately communicate 
 on development of a 
serious adverse event during the observational period. In addition, the surveillance investigator 
will provide detailed information separately if requested by 
 
PPD
PPD
PPD
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

5 
 
8.0 
Scheduled period of the survey 
Duration of the survey: September 2015 to April 30, 2017 
Patient enrollment period: September 2015 to February 28, 2017 Note) 
Note) Patients will not be enrolled in this survey (or entered in 
) on or after March 1, 
2017 even if Takecab Tablets is prescribed on or before February 28, 2017. 
If enrollment of the planned number of patients of this survey is completed prior to 
February 28, 2017, the patient enrollment will be discontinued prior to the end of the 
patient enrollment period. When the patient enrollment period is shortened, the duration of 
the survey is to be changed according to the shortened period. 
 
9.0 
Data to be collected 
The surveillance investigator will enter the information of the following items in 
. 
The schedule of this survey is presented in the Appendix. 
9.1 Patient enrollment 
1) Data to be collected 
Prescription date of the three drugs including Takecab Tablets used in the triple therapy; 
patient identification number; patient initials; sex; date of birth; target disease of H. pylori 
eradication; assessment of inclusion and exclusion criteria 
2) Data collection period 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Data to be collected 
Inpatient/outpatient classification (at the time when triple therapy is started); predisposition 
of hypersensitivity (presence/absence and details); complication (presence/absence and 
details); details of previous H. pylori eradication (in patients with a history of unsuccessful 
H. pylori eradication with Takecab Tablets or a proton pump inhibitor with amoxicillin and 
clarithromycin); height; weight; smoking history; drinking history; diagnosis of H. pylori 
infection (time of diagnosis and testing method) 
2) Data collection period 
At the start of triple therapy 
 
9.3 Information of treatment 
1) Data to be collected 
Treatment compliance to Takecab Tablets and antimicrobials used for triple therapy (name 
of drugs; daily dose; duration of triple therapy and reason for discontinuation of the triple 
therapy); treatment compliance to concomitant drugs (excluding antimicrobials used for the 
triple therapy) (presence/absence; drug name(s), and indication(s)) 
2) Data collection period 
CCI
CCI

6 
Duration from the start to the completion (or the discontinuation) of triple therapy 
 
9.4 Test/examination items 
9.4.1 Determination of H. pylori eradication 
1) Test items 
Conduct of tests (presence/absence; reason if test is not conducted; testing method; date 
and result of determination) 
2) Testing period 
At the time of determination of H. pylori eradication* 
* Time frame of the H. pylori determination is approximately from 4 weeks to 2 months after the triple 
therapy. 
 
9.4.2 Liver function test 
1) Test items 
Aspartate aminotransferase (AST); alanine aminotransferase (ALT); γ-glutamyl 
transpeptidase (γ-GTP); alkaline phosphatase (ALP); total bilirubin; lactate 
dehydrogenase (LDH) 
2) Testing period 
Duration from the start of triple therapy* to the determination of H. pylori eradication (or the 
discontinuation of triple therapy) 
* Within 1 month before starting triple therapy 
 
9.4.3 Other examination items 
1) Examination items 
Presence/absence of pregnancy during the observational period (only female patients) 
If pregnancy is confirmed during the observational period, the information is immediately 
communicated to 
. The surveillance investigator provides detailed information 
(including information until delivery, e.g., pregnancy outcome such as premature delivery, 
as much as possible) separately when 
 requests it. 
2) Examination period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
9.5 Adverse event 
1) Data to be collected 
Presence/absence of adverse event (AE) (See Table 1); AE term; onset date; seriousness 
and reason for seriousness (See Table 2); cause of discontinuation of triple therapy; 
outcome date; outcome; causality* with triple therapy (See Table 3) 
Follow-up survey will be conducted as much as possible when outcome is not resolved or 
unknown and causality is determined as unassessable. 
PPD
PPD

7 
Detailed information (e.g., clinical course and results of tests conducted for diagnosis) 
will be collected as much as possible when onset of hepatic function disorder or 
gastrointestinal infection of clostridium difficile is observed. 
* Following information will be collected: rationale of assessment when causality is assessed as not 
related, and reason when causality is determined as unassessable. 
Note) A point to consider concerning adverse events 
Abnormal exacerbation of the target disease, i.e., exacerbation worse than the expected natural 
course of the disease, will be handled as an adverse event. 
2) Data collection period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
Table 1 
Definition of adverse event 
Adverse event (AE) is any unfavorable medical occurrence in a patient administered a pharmaceutical 
product. It does not necessarily need to have a causal relationship with the pharmaceutical product. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including abnormal 
laboratory values), symptom, or disease occurring at the use of a pharmaceutical product, whether or not 
considered related to the pharmaceutical product. 
Following cases should also be handled as adverse events. 
 
Symptoms developed in an infant breastfed by a mother receiving the pharmaceutical product 
 
Unfavorable symptoms, etc. developed in a child after administration of the pharmaceutical product 
 
Symptoms developed after occupational exposure to the pharmaceutical product 
 
Symptoms developed due to the use of a counterfeit of a pharmaceutical product 
manufactured/marketed by Takeda Pharmaceutical Company Limited 
 
Unfavorable symptoms developed in a user of the pharmaceutical product which information was 
obtained through litigation or other legal actions 
 

8 
Table 2 
Seriousness assessment criteria 
An event meeting any of the following criteria is assessed as “serious”: 
1. Fatal (death) 
2. Life-threatening (life-threatening) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolongation of hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Congenital anomaly/birth defect (congenital anomaly) 
6. Other medically important condition than 1-5. Events listed in “Takeda Medically Significant AE 
List” are included in this criterion. 
 
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/hyperthermia malignant 
 
Aplastic anaemia 
 
Abortion spontaneous/stillbirth and dead foetus 
 
Toxic epidermal necrolysis/oculomucocutaneous syndrome (Stevens-Johnson syndrome) 
 
Transmission or suspected transmission of infection via a medicinal product 
 
Hepatic necrosis 
 
Endotoxic shock or suspected endotoxic shock 
 
Acute hepatic failure 
 
Table 3 
Causality assessment criteria for adverse events and triple therapy 
Assessment 
Assessment criteria 
Related 
There is temporal relationship (including the clinical course after the 
discontinuation of the triple therapy). Or, while other factors such as 
underlying disease, complication, concomitant drug or concomitant 
procedure could be presumed, the AE is possibly related to triple 
therapy. 
Not related 
There is no temporal relationship with the triple therapy. Or, other 
factors such as underlying disease, complication, concomitant drug or 
concomitant procedure are quite considerable as the cause. 
Unassessable 
Information required for causality assessment, such as temporal 
relationship (including the clinical course after the discontinuation of 
the triple therapy), underlying disease, complication, concomitant 
drug, and concomitant procedure is insufficient. 
 

9 
10.0 
Analysis items and method 
10.1 Items related to patient disposition 
Following data will be accumulated: number of patients enrolled; number of patients whose 
survey form (electronic) have been collected; number of patients in the safety analysis set and 
the efficacy analysis set; number of patients excluded from analysis and reasons for exclusion 
 
10.2 Patient demographics 
Patient demographic data including sex, age, hypersensitivity predisposition and complication 
will be accumulated. 
 
10.3 Details of treatment 
Treatment compliance to Takecab Tablets and antimicrobials used for the triple therapy and 
concomitant drugs (other than antimicrobials used for the triple therapy) will be accumulated. 
 
10.4 Items related to safety 
Following data will be accumulated for the safety analysis set. Adverse events are coded with 
MedDRA/J, and accumulated by Preferred Term (PT) and System Organ Class (SOC). 
The patients enrolled to this survey in both first-line and second-line eradication cases will be 
accumulated separately. 
10.4.1 Onset of adverse events 
Frequencies of adverse events which developed during the observational period will be 
accumulated by type, onset period, seriousness, and causality with the triple therapy. 
 
10.4.2 Factors which may affect safety 
Frequencies of adverse reactions which developed during the observational period will be 
accumulated by subgroups of patient demographic factors (e.g., sex; age; target disease of 
H. pylori eradication; presence/absence of renal disorder complication; and 
presence/absence of liver disorder complication) and details of treatment (first-line and 
second-line eradication). 
 
10.5 Items related to efficacy 
Following data will be accumulated for the efficacy analysis set. 
10.5.1 Eradication rate of H. pylori 
In patients who have the result of determination of eradication, proportion of patients with 
H. pylori negative (eradication rate) will be accumulated by first-line and second-line 
eradication. 
 
10.5.2 Factors which may affect efficacy 
The eradication rates of H. pylori will be accumulated by subgroup of patient demographic 
factors (e.g., sex; age; target disease of H. pylori eradication; complication). 

10 
 
11.0 
Registration of survey information 
Takeda Pharmaceutical Company Limited will register information of this survey on the 
public websites before starting this survey. 
 Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization of this survey 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
Post-marketing surveillance manager 
 
13.0 
Clinical research organizations 
 
14.0 
Other required items 
14.1 Revision of the protocol 
During the period of conducting this survey, following information will be captured: 
development of ADRs not expectable from Precautions for Use and onset of serious ADRs; 
whether there is increased frequency of specific ADRs or not; validity of the survey items. The 
protocol will be reviewed and revised if it is considered necessary. In addition, if a 
supplemental approval of a new dosage and administration or a new indication is granted 
PPD

11 
during the period of conducting this survey, necessity of revision of the protocol will be 
examined if needed, and the protocol will be revised if needed. 
 
14.2 Procedure when there is any issue or doubt 
If there is any safety or efficacy issue, data will be closely examined, and action will be 
considered. 

12 
Appendix: Observation schedule 
Period of survey/data entry 
 
 
 
 
Data to be collected 
Observational period 
At the time of patient 
enrollment 
At the start of triple 
therapy 
At the completion of 
triple therapy 
At the time of 
determination of H. 
pylori eradication Note 1) 
At the time of 
discontinuation of 
triple therapy 
Patient 
enrollment 
Prescription date of 3 drugs 
including Takecab Tablets in triple 
therapy 
○ 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
Patient initials 
○ 
 
 
 
 
Sex 
○ 
 
 
 
 
Date of birth 
○ 
 
 
 
 
Target disease of H. pylori eradication 
○ 
 
 
 
 
Assessment of inclusion criteria 
○ 
 
 
 
 
Assessment of exclusion criteria 
○ 
 
 
 
 
Patient 
demographic 
information 
Inpatient/outpatient classification 
 
○ 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
Complication 
 
○ 
 
 
 
Previous H. pylori eradication Note 2) 
 
○ 
 
 
 
Height, weight 
 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
Drinking history 
 
○ 
 
 
 
Diagnosis of H. pylori infection 
 
○ 
 
 
 
Information 
of treatment 
Treatment compliance to Takecab 
Tablets and antimicrobials 
 
○ 
 
○ 
Treatment compliance to 
concomitant drugs (excluding 
antimicrobials) 
 
 
○ 
 
○ 
Test/ 
examination 
items 
Determination of H. pylori 
eradication 
 
 
 
○ 
 
Liver function test 
 
   ○Note 3) 
○ 
Presence/absence of pregnancy 
(only female patients) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○ 
: To be conducted 
○ 
: To be conducted throughout the period 
Note 1) Approximately from 4 weeks to 2 months after the triple therapy is completed 
Note 2) In patients with a history of unsuccessful H. pylori eradication with Takecab Tablets or a proton 
pump inhibitor in combination with amoxicillin and clarithromycin 
Note 3) From within one month before the start of triple therapy to determination of H. pylori 
eradication 

 
 
 
 
Protocol of drug use surveillance 
Drug use surveillance of Takecab tablets 
“Supplement to Helicobacter pylori eradication” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5002 
Version 
Version 3 
Date 
July 24, 2015 
 

Table of contents 
1.0 
Background of conduct ................................................................................................................................ 1 
2.0 
Objectives ..................................................................................................................................................... 1 
3.0 
Planned sample size and its rationale ........................................................................................................... 1 
3.1 
Sample size ............................................................................................................................................... 1 
3.2 
Rationale................................................................................................................................................... 1 
4.0 
Study population .......................................................................................................................................... 2 
4.1 
Inclusion criteria ....................................................................................................................................... 3 
4.2 
Exclusion criteria ...................................................................................................................................... 3 
5.0 
Dosage and administration ........................................................................................................................... 3 
6.0 
Number of medical institutions by departments where the survey is planned ............................................. 3 
7.0 
Method ......................................................................................................................................................... 3 
7.1 
Observational period ................................................................................................................................ 3 
7.2 
Request to and contract with the medical institutions .............................................................................. 4 
7.3 
Method of patient enrollment ................................................................................................................... 4 
7.4 
Data entry and electronic signature in the survey form (electronic) ........................................................ 4 
7.5 
Actions to take at the time of development of a serious adverse event .................................................... 4 
8.0 
Scheduled period of the survey .................................................................................................................... 5 
9.0 
Data to be collected ...................................................................................................................................... 5 
9.1 
Patient enrollment .................................................................................................................................... 5 
9.2 
Patient demographic information ............................................................................................................. 5 
9.3 
Information of treatment .......................................................................................................................... 5 
9.4 
Test/examination items ............................................................................................................................. 6 
9.4.1 
Determination of H. pylori eradication ............................................................................................ 6 
9.4.2 
Liver function test ............................................................................................................................ 6 
9.4.3 
Other examination items .................................................................................................................. 6 
9.5 
Adverse event ........................................................................................................................................... 6 
10.0 
Analysis items and method........................................................................................................................... 9 
10.1 
Items related to patient disposition ........................................................................................................... 9 
10.2 
Patient demographics ............................................................................................................................... 9 
10.3 
Details of treatment .................................................................................................................................. 9 
10.4 
Items related to safety............................................................................................................................... 9 
10.4.1 
Onset of adverse events .................................................................................................................... 9 
10.4.2 
Factors which may affect safety ....................................................................................................... 9 
10.5 
Items related to efficacy ........................................................................................................................... 9 
10.5.1 
Eradication rate of H. pylori............................................................................................................. 9 
10.5.2 
Factors which may affect efficacy ................................................................................................... 9 
11.0 
Registration of survey information ............................................................................................................. 10 
12.0 
Organization of this survey ........................................................................................................................ 10 
12.1 
Manager .................................................................................................................................................. 10 

13.0 
Clinical research organizations................................................................................................................... 10 
14.0 
Other required items ................................................................................................................................... 10 
14.1 
Revision of the protocol ......................................................................................................................... 10 
14.2 
Procedure when there is any issue or doubt ........................................................................................... 10 
 
Appendix: Observation schedule............................................................................................................................11 
 

1 
1.0 
Background of conduct 
In the domestic clinical studies of Helicobacter Pylori (H. pylori) eradication with Takecab 
Tablets in combination with antimicrobials, safety of triple therapy was evaluated: Takecab 
Tablets, amoxicillin and clarithromycin (first-line eradication) in 329 patients, and Takecab 
Tablets, amoxicillin and metronidazole (second-line eradication) in 50 patients, and the results 
showed no specific issue. 
The safety profile of the first-line eradication could be expected in view of the results of 
Takecab Tablets clinical studies in patients with acid-related diseases (gastric ulcer, duodenal 
ulcer and reflux oesophagitis) and information provided in the package inserts of 
antimicrobials. Most of the adverse reactions (ADRs) developed during the second-line 
eradication were also observed in the first-line eradication, and there was no substantial 
difference between them. Accordingly, the safety profile of the use of Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
The Drug use surveillance of Takecab Tablets (this survey) for the supplement to H. pylori 
eradication in first-line and second-line eradication in the routine clinical setting is planned to 
confirm validity of this estimation (whether there is a new safety concern or not). 
This survey is conducted in compliance with relevant regulatory requirements such as GPSP 
ministerial ordinance. 
 
2.0 
Objectives 
The objective of this survey is to evaluate the safety and efficacy of first-line and second-line 
eradication including Takecab Tablets (triple therapy) in the routine clinical setting. 
 
3.0 
Planned sample size and its rationale 
3.1 Sample size 
500 patients 
 
3.2 Rationale 
The safety profile of H. pylori eradication with a proton pump inhibitor (lansoprazole) in 
combination with antimicrobials (amoxicillin and clarithromycin) observed in the domestic 
clinical studies and the drug use surveillance could be expected from the results of the 
domestic clinical studies and the drug use surveillance of lansoprazole in patients with 
acid-related diseases (gastric ulcer, duodenal ulcer and reflux oesophagitis), and from the 
information provided in the package inserts of antimicrobials. 
The safety profile of the first-line eradication observed in the clinical studies for H. pylori 
eradication with Takecab Tablets in combination with antimicrobials could be expected from 

2 
the results of the clinical studies of Takecab Tablets in patients with acid-related diseases and 
information provided in the package inserts of antimicrobials. 
Based on the above, the safety profile of the first-line eradication with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
In addition, it has been confirmed that ADRs of H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and metronidazole) in the specific 
drug use surveillance of proton pump inhibitors (lansoprazole, omeprazole and rabeprazole) 
were mostly similar to the ADRs reported in H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and clarithromycin). Most of the 
ADRs developed during the second-line H. pylori eradication in the clinical study of Takecab 
Tablets in combination with antimicrobials were also observed in the first-line eradication. 
Therefore, it is estimated that ADRs developed in association with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication are not substantially different 
between first-line eradication and second-line eradication. In view of the above, the drug use 
surveillance of Takecab Tablets for supplement of H. pylori eradication is to be conducted for 
both first-line and second-line eradication. 
Accordingly, in this survey, data will be collected from 500 patients to whom Takecab Tablets 
is administered for supplement of H. pylori eradication, and will be compared with the safety 
information of Takecab Tablets collected in the drug use surveillance in patients with 
acid-related diseases (total 3,000 patients) and with information provided in the package 
inserts of antimicrobials, and it will be confirmed whether there is a new safety concern or not 
(please note that the sample size of 500 patients is not statistically calculated). 
In this survey, patients excluded from the clinical studies such as with gastric 
mucosa-associated lymphoid tissue (MALT) lymphoma, idiopathic thrombocytopenic purpura, 
stomach following endoscopic treatment of early gastric cancer, or H. pylori gastritis will be 
enrolled. 
 
4.0 
Study population 
Patients with the diseases described below* will receive triple therapy for H. pylori eradication. 
However, patients should meet the inclusion criterion and should not meet the exclusion 
criterion described below. Refer to the Precautions section of the package insert. 
* If a patient’s first-line eradication is unsuccessful in this survey, the patient can be enrolled in the 
second-line eradication in this survey. 
Gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) 
lymphoma, idiopathic thrombocytopenic purpura, stomach following endoscopic 
treatment of early gastric cancer, or H. pylori gastritis 

3 
4.1 Inclusion criteria 
Patients who meet either of the following criteria will be included in the survey: 
[1] Patients receiving H. pylori eradication for the first time 
[2] Patients for whom H. pylori eradication with Takecab Tablets or proton pump inhibitor + 
amoxicillin + clarithromycin was found unsuccessful and who are to receive eradication 
treatment with amoxicillin and metronidazole 
 
4.2 Exclusion criteria 
Patients who meet either of the following criteria will not be included in the survey. Refer to 
the Contraindications and Precautions section of the package insert of antimicrobials used in 
the triple therapy. 
[1] Patients with previous history of hypersensitivity to ingredients in Takecab Tablets 
[2] Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual dose for adults is 20 mg of vonoprazan, 750 mg (potency) of amoxicillin hydrate, 
and 200 mg (potency) of clarithromycin. These three drugs will be orally administered at the 
same time, twice daily for 7 days. The dose of clarithromycin can be increased as clinically 
warranted. However, the dosage of clarithromycin should not exceed 400 mg (potency)/dose 
twice daily. 
If H. pylori eradication with a three-drug regimen comprising vonoprazan or proton pump 
inhibitor + amoxicillin hydrate + clarithromycin is unsuccessful, as an alternative treatment, 
the following three drugs will be orally administered to adults at the same time, twice daily for 
7 days: vonoprazan at a dose of 20 mg, amoxicillin hydrate at a dose of 750 mg (potency), and 
metronidazole at a dose of 250 mg. Refer to the Precautions section of the package insert of 
antimicrobials used in triple therapy. 
 
6.0 
Number of medical institutions by departments where the survey is planned 
Internal medicine department (such as gastrointestinal medicine department)
 
Approximately 150 medical institutions 
Hematology department 
Approximately 10 medical institutions 
 
7.0 
Method 
7.1 Observational period 
Triple therapy period (7 days) and the period from the completion of the triple therapy to the 
determination of H. pylori eradication 
Time frame of the H. pylori determination is approximately from 4 weeks* to 2 months after 
the triple therapy. 
*  According to the “Guidelines for diagnosis and treatment of H. pylori infection” of the Japanese Society 
for Helicobacter Research, determination of H. pylori eradication should be conducted after 4 weeks 

4 
from discontinuation of eradication therapy. 
 
7.2 Request to and contract with the medical institutions 
Request to and contract with the medical institutions will be conducted using web-based 
electronic data collection system (
). The Medical Representative of 
 
 will explain objectives and details of this survey, 
procedure, electronic signature, and handling of user ID and password of 
 to the 
surveillance investigator based on “Implementation guidance”, “Data entry screens of 
” and “
 operational manual” when this survey is requested. Thereafter, 
written contract is made with the medical institution and conduct of the survey will be 
requested within the prespecified duration of the survey. 
 
7.3 Method of patient enrollment 
Patients will be enrolled with “central enrollment method” using 
. The surveillance 
investigator will enter the information required for patient enrollment (see Section 9.1) and 
will provide his/her electronic signature in 
 concerning patients to whom drugs of 
triple therapy (three drugs including Takecab Tablets) are prescribed within 5 days after 
prescription day of the three drugs including Takecab Tablets (the prescription day is defined 
as “Day 0”, and the day after prescription as “Day 1”) after term of contract with the medical 
institution is started. 
 
7.4 Data entry and electronic signature in the survey form (electronic) 
The surveillance investigator will enter the information of patient demographics and treatment 
and will provide electronic signature in 
 for all patients enrolled in this survey by 
one month after completion of the observational period of each patient. If receipt of Takecab 
Tablets was not confirmed, it will be entered so in 
 (it is not required to enter other 
data). 
For the patients who discontinued triple therapy including Takecab Tablets for any reason 
during the observational period, the surveillance investigator will enter the information of 
patient demographics and treatment and will provide his/her electronic signature in 
 
by one month after completion of required observation. However, for patients who 
discontinued triple therapy including Takecab Tablets due to development of an AE, 
observation will be continued as much as possible until resolve or resolving from the AE even 
after the treatment is discontinued, and the observation results will be entered in 
 
with his/her electronic signature. 
 
7.5 Actions to take at the time of development of a serious adverse event 
The surveillance investigator will immediately communicate 
 on development of a 
serious adverse event during the observational period. In addition, the surveillance investigator 
will provide detailed information separately if requested by 
. 
PPD
PPD
PPD
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

5 
 
8.0 
Scheduled period of the survey 
Duration of the survey: September 2015 to April 30, 2017 
Patient enrollment period: September 2015 to February 28, 2017 Note) 
Note) Patients will not be enrolled in this survey (or entered in 
) on or after March 1, 
2017 even if Takecab Tablets is prescribed on or before February 28, 2017. 
If enrollment of the planned number of patients of this survey is completed prior to 
February 28, 2017, the patient enrollment will be discontinued prior to the end of the 
patient enrollment period. When the patient enrollment period is shortened, the duration of 
the survey is to be changed according to the shortened period. 
 
9.0 
Data to be collected 
The surveillance investigator will enter the information of the following items in 
 
The schedule of this survey is presented in the Appendix. 
9.1 Patient enrollment 
1) Data to be collected 
Prescription date of the three drugs including Takecab Tablets used in the triple therapy; 
patient identification number; patient initials; sex; date of birth; target disease of H. pylori 
eradication; assessment of inclusion and exclusion criteria 
2) Data collection period 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Data to be collected 
Inpatient/outpatient classification (at the time when triple therapy is started); predisposition 
of hypersensitivity (presence/absence and details); complication (presence/absence and 
details); details of previous H. pylori eradication (in patients with a history of unsuccessful 
H. pylori eradication with Takecab Tablets or a proton pump inhibitor with amoxicillin and 
clarithromycin); height; weight; smoking history; drinking history; diagnosis of H. pylori 
infection (time of diagnosis and testing method) 
2) Data collection period 
At the start of triple therapy 
 
9.3 Information of treatment 
1) Data to be collected 
Treatment compliance to Takecab Tablets and antimicrobials used for triple therapy (name 
of drugs; daily dose; duration of triple therapy and reason for discontinuation of the triple 
therapy); treatment compliance to concomitant drugs (excluding antimicrobials used for the 
triple therapy) (presence/absence; drug name(s), and indication(s)) 
2) Data collection period 
CCI
CCI

6 
Duration from the start to the completion (or the discontinuation) of triple therapy 
 
9.4 Test/examination items 
9.4.1 Determination of H. pylori eradication 
1) Test items 
Conduct of tests (presence/absence; reason if test is not conducted; testing method; date 
and result of determination) 
2) Testing period 
At the time of determination of H. pylori eradication* 
* Time frame of the H. pylori determination is approximately from 4 weeks to 2 months after the triple 
therapy. 
 
9.4.2 Liver function test 
1) Test items 
Aspartate aminotransferase (AST); alanine aminotransferase (ALT); γ-glutamyl 
transpeptidase (γ-GTP); alkaline phosphatase (ALP); total bilirubin; lactate 
dehydrogenase (LDH) 
2) Testing period 
Duration from the start of triple therapy* to the determination of H. pylori eradication (or the 
discontinuation of triple therapy) 
* Within 1 month before starting triple therapy 
 
9.4.3 Other examination items 
1) Examination items 
Presence/absence of pregnancy during the observational period (only female patients) 
If pregnancy is confirmed during the observational period, the information is immediately 
communicated to 
 The surveillance investigator provides detailed information 
(including information until delivery, e.g., pregnancy outcome such as premature delivery, 
as much as possible) separately when 
 requests it. 
2) Examination period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
9.5 Adverse event 
1) Data to be collected 
Presence/absence of adverse event (AE) (See Table 1); AE term; onset date; seriousness 
and reason for seriousness (See Table 2); cause of discontinuation of triple therapy; 
outcome date; outcome; causality* with triple therapy (See Table 3) 
Follow-up survey will be conducted as much as possible when outcome is not resolved or 
unknown and causality is determined as unassessable. 
PPD
PPD

7 
Detailed information (e.g., clinical course, and results of tests conducted for diagnosis) 
will be collected as much as possible when onset of hepatic function disorder or 
gastrointestinal infection of clostridium difficile is observed. 
* Following information will be collected: rationale of assessment when causality is assessed as not 
related, and reason when causality is determined as unassessable. 
Note) A point to consider concerning adverse events 
Abnormal exacerbation of the target disease, i.e., exacerbation worse than the expected natural 
course of the disease, will be handled as an adverse event. 
2) Data collection period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
Table 1 
Definition of adverse event 
Adverse event (AE) is any unfavorable medical occurrence in a patient administered a pharmaceutical 
product. It does not necessarily need to have a causal relationship with the pharmaceutical product. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including abnormal 
laboratory values), symptom, or disease occurring at the use of a pharmaceutical product, whether or not 
considered related to the pharmaceutical product. 
Following cases should also be handled as adverse events. 
 
Symptoms developed in an infant breastfed by a mother receiving the pharmaceutical product 
 
Unfavorable symptoms, etc. developed in a child after administration of the pharmaceutical product 
 
Symptoms developed after occupational exposure to the pharmaceutical product 
 
Symptoms developed due to the use of a counterfeit of a pharmaceutical product 
manufactured/marketed by Takeda Pharmaceutical Company Limited 
 
Unfavorable symptoms developed in a user of the pharmaceutical product which information was 
obtained through litigation or other legal actions 
 

8 
Table 2 
Seriousness assessment criteria 
An event meeting any of the following criteria is assessed as “serious”: 
1. Fatal (death) 
2. Life-threatening (life-threatening) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolongation of hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Congenital anomaly/birth defect (congenital anomaly) 
6. Other medically important condition than 1-5. Events listed in “Takeda Medically Significant AE 
List” are included in this criterion. 
 
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/hyperthermia malignant 
 
Aplastic anaemia 
 
Abortion spontaneous/stillbirth and dead foetus 
 
Toxic epidermal necrolysis/oculomucocutaneous syndrome (Stevens-Johnson syndrome) 
 
Transmission or suspected transmission of infection via a medicinal product 
 
Hepatic necrosis 
 
Endotoxic shock or suspected endotoxic shock 
 
Acute hepatic failure 
 
Table 3 
Causality assessment criteria for adverse events and triple therapy 
Assessment 
Assessment criteria 
Related 
There is temporal relationship (including the clinical course after the 
discontinuation of the triple therapy). Or, while other factors such as 
underlying disease, complication, concomitant drug or concomitant 
procedure could be presumed, the AE is possibly related to triple 
therapy. 
Not related 
There is no temporal relationship with the triple therapy. Or, other 
factors such as underlying disease, complication, concomitant drug or 
concomitant procedure are quite considerable as the cause. 
Unassessable 
Information required for causality assessment, such as temporal 
relationship (including the clinical course after the discontinuation of 
the triple therapy), underlying disease, complication, concomitant 
drug, and concomitant procedure is insufficient. 
 

9 
10.0 
Analysis items and method 
10.1 Items related to patient disposition 
Following data will be accumulated: number of patients enrolled; number of patients whose 
survey form (electronic) have been collected; number of patients in the safety analysis set and 
the efficacy analysis set; number of patients excluded from analysis and reasons for exclusion 
 
10.2 Patient demographics 
Patient demographic data including sex, age, hypersensitivity predisposition and complication 
will be accumulated. 
 
10.3 Details of treatment 
Treatment compliance to Takecab Tablets and antimicrobials used for the triple therapy and 
concomitant drugs (other than antimicrobials used for the triple therapy) will be accumulated. 
 
10.4 Items related to safety 
Following data will be accumulated for the safety analysis set. Adverse events are coded with 
MedDRA/J, and accumulated by Preferred Term (PT) and System Organ Class (SOC). 
The patients enrolled to this survey in both first-line and second-line eradication cases will be 
accumulated separately. 
10.4.1 Onset of adverse events 
Frequencies of adverse events which developed during the observational period will be 
accumulated by type, onset period, seriousness, and causality with the triple therapy. 
 
10.4.2 Factors which may affect safety 
Frequencies of adverse reactions which developed during the observational period will be 
accumulated by subgroups of patient demographic factors (e.g., sex; age; target disease of 
H. pylori eradication; presence/absence of renal disorder complication; and 
presence/absence of liver disorder complication) and details of treatment (first-line and 
second-line eradication). 
 
10.5 Items related to efficacy 
Following data will be accumulated for the efficacy analysis set. 
10.5.1 Eradication rate of H. pylori 
In patients who have the result of determination of eradication, proportion of patients with 
H. pylori negative (eradication rate) will be accumulated by first-line and second-line 
eradication. 
 
10.5.2 Factors which may affect efficacy 
The eradication rates of H. pylori will be accumulated by subgroup of patient demographic 
factors (e.g., sex; age; target disease of H. pylori eradication; complication). 

10 
 
11.0 
Registration of survey information 
Takeda Pharmaceutical Company Limited will register information of this survey on the 
public websites before starting this survey. 
 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization of this survey 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
Post-marketing surveillance manager 
 
13.0 
Clinical research organizations 
 
14.0 
Other required items 
14.1 Revision of the protocol 
During the period of conducting this survey, following information will be captured: 
development of ADRs not expectable from Precautions for Use and onset of serious ADRs; 
whether there is increased frequency of specific ADRs or not; validity of the survey items. The 
protocol will be reviewed and revised if it is considered necessary. In addition, if a 
supplemental approval of a new dosage and administration or a new indication is granted 
during the period of conducting this survey, necessity of revision of the protocol will be 
examined if needed, and the protocol will be revised if needed. 
 
14.2 Procedure when there is any issue or doubt 
If there is any safety or efficacy issue, data will be closely examined, and action will be 
considered. 
PPD

11 
Appendix: Observation schedule 
Period of survey/data entry 
 
 
 
 
Data to be collected 
Observational period 
At the time of patient 
enrollment 
At the start of triple 
therapy 
At the completion of 
triple therapy 
At the time of 
determination of H. 
pylori eradication Note 1) 
At the time of 
discontinuation of 
triple therapy 
Patient 
enrollment 
Prescription date of 3 drugs 
including Takecab Tablets in triple 
therapy 
○ 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
Patient initials 
○ 
 
 
 
 
Sex 
○ 
 
 
 
 
Date of birth 
○ 
 
 
 
 
Target disease of H. pylori eradication 
○ 
 
 
 
 
Assessment of inclusion criteria 
○ 
 
 
 
 
Assessment of exclusion criteria 
○ 
 
 
 
 
Patient 
demographic 
information 
Inpatient/outpatient classification 
 
○ 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
Complication 
 
○ 
 
 
 
Previous H. pylori eradication Note 2) 
 
○ 
 
 
 
Height, weight 
 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
Drinking history 
 
○ 
 
 
 
Diagnosis of H. pylori infection 
 
○ 
 
 
 
Information 
of treatment 
Treatment compliance to Takecab 
Tablets and antimicrobials 
 
○ 
 
○ 
Treatment compliance to 
concomitant drugs (excluding 
antimicrobials) 
 
 
○ 
 
○ 
Test/ 
examination 
items 
Determination of H. pylori 
eradication 
 
 
 
○ 
 
Liver function test 
 
   ○Note 3) 
○ 
Presence/absence of pregnancy 
(only female patients) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○ 
: To be conducted 
○ 
: To be conducted throughout the period 
Note 1) Approximately from 4 weeks to 2 months after the triple therapy is completed 
Note 2) In patients with a history of unsuccessful H. pylori eradication with Takecab Tablets or a proton 
pump inhibitor in combination with amoxicillin and clarithromycin 
Note 3) From within one month before the start of triple therapy to determination of H. pylori 
eradication 

 
 
 
 
Protocol of drug use surveillance 
Drug use surveillance of Takecab tablets 
“Supplement to Helicobacter pylori eradication” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5002 
Version 
Version 2 
Date 
June 22, 2015 
 

Table of contents 
1.0 
Background of conduct ................................................................................................................................ 1 
2.0 
Objectives ..................................................................................................................................................... 1 
3.0 
Planned sample size and its rationale ........................................................................................................... 1 
3.1 
Sample size ............................................................................................................................................... 1 
3.2 
Rationale................................................................................................................................................... 1 
4.0 
Study population .......................................................................................................................................... 2 
4.1 
Inclusion criteria ....................................................................................................................................... 3 
4.2 
Exclusion criteria ...................................................................................................................................... 3 
5.0 
Dosage and administration ........................................................................................................................... 3 
6.0 
Number of medical institutions by departments where the survey is planned ............................................. 3 
7.0 
Method ......................................................................................................................................................... 3 
7.1 
Observational period ................................................................................................................................ 3 
7.2 
Request to and contract with the medical institutions .............................................................................. 4 
7.3 
Method of patient enrollment ................................................................................................................... 4 
7.4 
Data entry and electronic signature in the survey form (electronic) ........................................................ 4 
7.5 
Actions to take at the time of development of a serious adverse event .................................................... 4 
8.0 
Scheduled period of the survey .................................................................................................................... 5 
9.0 
Data to be collected ...................................................................................................................................... 5 
9.1 
Patient enrollment .................................................................................................................................... 5 
9.2 
Patient demographic information ............................................................................................................. 5 
9.3 
Information of treatment .......................................................................................................................... 5 
9.4 
Test/examination items ............................................................................................................................. 6 
9.4.1 
Determination of H. pylori eradication ............................................................................................ 6 
9.4.2 
Liver function test ............................................................................................................................ 6 
9.4.3 
Other examination items .................................................................................................................. 6 
9.5 
Adverse event ........................................................................................................................................... 6 
10.0 
Analysis items and method........................................................................................................................... 9 
10.1 
Items related to patient disposition ........................................................................................................... 9 
10.2 
Patient demographics ............................................................................................................................... 9 
10.3 
Details of treatment .................................................................................................................................. 9 
10.4 
Items related to safety............................................................................................................................... 9 
10.4.1 
Onset of adverse events .................................................................................................................... 9 
10.4.2 
Factors which may affect safety ....................................................................................................... 9 
10.5 
Items related to efficacy ........................................................................................................................... 9 
10.5.1 
Eradication rate of H. pylori............................................................................................................. 9 
10.5.2 
Factors which may affect efficacy ................................................................................................... 9 
11.0 
Registration of survey information ............................................................................................................. 10 
12.0 
Organization of this survey ........................................................................................................................ 10 
12.1 
Manager .................................................................................................................................................. 10 

13.0 
Clinical research organizations................................................................................................................... 10 
14.0 
Other required items ................................................................................................................................... 10 
14.1 
Revision of the protocol ......................................................................................................................... 10 
14.2 
Procedure when there is any issue or doubt ........................................................................................... 10 
 
Appendix: Observation schedule............................................................................................................................11 
 

1 
1.0 
Background of conduct 
In the domestic clinical studies of Helicobacter Pylori (H. pylori) eradication with Takecab 
Tablets in combination with antimicrobials, safety of triple therapy was evaluated: Takecab 
Tablets, amoxicillin and clarithromycin (first-line eradication) in 329 patients, and Takecab 
Tablets, amoxicillin and metronidazole (second-line eradication) in 50 patients, and the results 
showed no specific issue. 
The safety profile of the first-line eradication could be expected in view of the results of 
Takecab Tablets clinical studies in patients with acid-related diseases (gastric ulcer, duodenal 
ulcer and reflux oesophagitis) and information provided in the package inserts of 
antimicrobials. Most of the adverse reactions (ADRs) developed during the second-line 
eradication were also observed in the first-line eradication, and there was no substantial 
difference between them. Accordingly, the safety profile of the use of Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
The Drug use surveillance of Takecab Tablets (this survey) for the supplement to H. pylori 
eradication in first-line and second-line eradication in the routine clinical setting is planned to 
confirm validity of this estimation (whether there is a new safety concern or not). 
This survey is conducted in compliance with relevant regulatory requirements such as GPSP 
ministerial ordinance. 
 
2.0 
Objectives 
The objective of this survey is to evaluate the safety and efficacy of first-line and second-line 
eradication including Takecab Tablets (triple therapy) in the routine clinical setting. 
 
3.0 
Planned sample size and its rationale 
3.1 Sample size 
500 patients 
 
3.2 Rationale 
The safety profile of H. pylori eradication with a proton pump inhibitor (lansoprazole) in 
combination with antimicrobials (amoxicillin and clarithromycin) observed in the domestic 
clinical studies and the drug use surveillance could be expected from the results of the 
domestic clinical studies and the drug use surveillance of lansoprazole in patients with 
acid-related diseases (gastric ulcer, duodenal ulcer and reflux oesophagitis), and from the 
information provided in the package inserts of antimicrobials. 
The safety profile of the first-line eradication observed in the clinical studies for H. pylori 
eradication with Takecab Tablets in combination with antimicrobials could be expected from 

2 
the results of the clinical studies of Takecab Tablets in patients with acid-related diseases and 
information provided in the package inserts of antimicrobials. 
Based on the above, the safety profile of the first-line eradication with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
In addition, it has been confirmed that ADRs of H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and metronidazole) in the specific 
drug use surveillance of proton pump inhibitors (lansoprazole, omeprazole and rabeprazole) 
were mostly similar to the ADRs reported in H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and clarithromycin). Most of the 
ADRs developed during the second-line H. pylori eradication in the clinical study of Takecab 
Tablets in combination with antimicrobials were also observed in the first-line eradication. 
Therefore, it is estimated that ADRs developed in association with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication are not substantially different 
between first-line eradication and second-line eradication. In view of the above, the drug use 
surveillance of Takecab Tablets for supplement of H. pylori eradication is to be conducted for 
both first-line and second-line eradication. 
Accordingly, in this survey, data will be collected from 500 patients to whom Takecab Tablets 
is administered for supplement of H. pylori eradication, and will be compared with the safety 
information of Takecab Tablets collected in the drug use surveillance in patients with 
acid-related diseases (total 3,000 patients) and with information provided in the package 
inserts of antimicrobials, and it will be confirmed whether there is a new safety concern or not 
(please note that the sample size of 500 patients is not statistically calculated). 
In this survey, patients excluded from the clinical studies such as with gastric 
mucosa-associated lymphoid tissue (MALT) lymphoma, idiopathic thrombocytopenic purpura, 
stomach following endoscopic treatment of early gastric cancer, or H. pylori gastritis will be 
enrolled. 
 
4.0 
Study population 
Patients with the diseases described below* will receive triple therapy for H. pylori eradication. 
However, patients should meet the inclusion criterion and should not meet the exclusion 
criterion described below. Refer to the Precautions section of the package insert. 
* If a patient’s first-line eradication is unsuccessful in this survey, the patient can be enrolled in the 
second-line eradication in this survey. 
Gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) 
lymphoma, idiopathic thrombocytopenic purpura, stomach following endoscopic 
treatment of early gastric cancer, or H. pylori gastritis 

3 
4.1 Inclusion criteria 
Patients who meet either of the following criteria will be included in the survey: 
[1] Patients receiving H. pylori eradication for the first time 
[2] Patients for whom H. pylori eradication with Takecab Tablets or proton pump inhibitor + 
amoxicillin + clarithromycin was found unsuccessful and who are to receive eradication 
treatment with amoxicillin and metronidazole 
 
4.2 Exclusion criteria 
Patients who meet either of the following criteria will not be included in the survey. Refer to 
the Contraindications and Precautions section of the package insert of antimicrobials used in 
the triple therapy. 
[1] Patients with previous history of hypersensitivity to ingredients in Takecab Tablets 
[2] Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual dose for adults is 20 mg of vonoprazan, 750 mg (potency) of amoxicillin hydrate, 
and 200 mg (potency) of clarithromycin. These three drugs will be orally administered at the 
same time, twice daily for 7 days. The dose of clarithromycin can be increased as clinically 
warranted. However, the dosage of clarithromycin should not exceed 400 mg (potency)/dose 
twice daily. 
If H. pylori eradication with a three-drug regimen comprising vonoprazan or proton pump 
inhibitor + amoxicillin hydrate + clarithromycin is unsuccessful, as an alternative treatment, 
the following three drugs will be orally administered to adults at the same time, twice daily for 
7 days: vonoprazan at a dose of 20 mg, amoxicillin hydrate at a dose of 750 mg (potency), and 
metronidazole at a dose of 250 mg. Refer to the Precautions section of the package insert of 
antimicrobials used in triple therapy. 
 
6.0 
Number of medical institutions by departments where the survey is planned 
Internal medicine department (such as gastrointestinal medicine department)
 
Approximately 150 medical institutions 
Hematology department 
Approximately 10 medical institutions 
 
7.0 
Method 
7.1 Observational period 
Triple therapy period (7 days) and the period from the completion of the triple therapy to the 
determination of H. pylori eradication 
Time frame of the H. pylori determination is approximately from 4 weeks* to 2 months after 
the triple therapy. 
*  According to the “Guidelines for diagnosis and treatment of H. pylori infection” of the Japanese Society 
for Helicobacter Research, determination of H. pylori eradication should be conducted after 4 weeks 

4 
from discontinuation of eradication therapy. 
 
7.2 Request to and contract with the medical institutions 
Request to and contract with the medical institutions will be conducted using web-based 
electronic data collection system (
). The Medical Representative of 
 
 will explain objectives and details of this survey, 
procedure, electronic signature, and handling of user ID and password of 
 to the 
surveillance investigator based on “Implementation guidance”, “Data entry screens of 
” and “
 operational manual” when this survey is requested. Thereafter, 
written contract is made with the medical institution and conduct of the survey will be 
requested within the prespecified duration of the survey. 
 
7.3 Method of patient enrollment 
Patients will be enrolled with “central enrollment method” using 
. The surveillance 
investigator will enter the information required for patient enrollment (see Section 9.1) and 
will provide his/her electronic signature in 
 concerning patients to whom drugs of 
triple therapy (three drugs including Takecab Tablets) are prescribed within 5 days after 
prescription day of the three drugs including Takecab Tablets (the prescription day is defined 
as “Day 0”, and the day after prescription as “Day 1”) after term of contract with the medical 
institution is started. 
 
7.4 Data entry and electronic signature in the survey form (electronic) 
The surveillance investigator will enter the information of patient demographics and treatment 
and will provide electronic signature in 
 for all patients enrolled in this survey by 
one month after completion of the observational period of each patient. If receipt of Takecab 
Tablets was not confirmed, it will be entered so in 
 (it is not required to enter other 
data). 
For the patients who discontinued triple therapy including Takecab Tablets for any reason 
during the observational period, the surveillance investigator will enter the information of 
patient demographics and treatment and will provide his/her electronic signature in 
 
by one month after completion of required observation. However, for patients who 
discontinued triple therapy including Takecab Tablets due to development of an AE, 
observation will be continued as much as possible until resolve or resolving from the AE even 
after the treatment is discontinued, and the observation results will be entered in 
 
with his/her electronic signature. 
 
7.5 Actions to take at the time of development of a serious adverse event 
The surveillance investigator will immediately communicate 
 on development of a 
serious adverse event during the observational period. In addition, the surveillance investigator 
will provide detailed information separately if requested by 
. 
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8.0 
Scheduled period of the survey 
Duration of the survey: September 2015 to April 30, 2017 
Patient enrollment period: September 2015 to February 28, 2017 Note) 
Note) Patients will not be enrolled in this survey (or entered in 
) on or after March 1, 
2017 even if Takecab Tablets is prescribed on or before February 28, 2017. 
If enrollment of the planned number of patients of this survey is completed prior to 
February 28, 2017, the patient enrollment will be discontinued prior to the end of the 
patient enrollment period. When the patient enrollment period is shortened, the duration of 
the survey is to be changed according to the shortened period. 
 
9.0 
Data to be collected 
The surveillance investigator will enter the information of the following items in 
. 
The schedule of this survey is presented in the Appendix. 
9.1 Patient enrollment 
1) Data to be collected 
Prescription date of the three drugs including Takecab Tablets used in the triple therapy; 
patient identification number; patient initials; sex; date of birth; target disease of H. pylori 
eradication; assessment of inclusion and exclusion criteria 
2) Data collection period 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Data to be collected 
Inpatient/outpatient classification (at the time when triple therapy is started); predisposition 
of hypersensitivity (presence/absence and details); complication (presence/absence and 
details); details of previous H. pylori eradication (in patients with a history of unsuccessful 
H. pylori eradication with Takecab Tablets or a proton pump inhibitor with amoxicillin and 
clarithromycin); height; weight; smoking history; drinking history; diagnosis of H. pylori 
infection (time of diagnosis and testing method) 
2) Data collection period 
At the start of triple therapy 
 
9.3 Information of treatment 
1) Data to be collected 
Treatment compliance to Takecab Tablets and antimicrobials used for triple therapy (name 
of drugs; daily dose; duration of triple therapy and reason for discontinuation of the triple 
therapy); treatment compliance to concomitant drugs (excluding antimicrobials used for the 
triple therapy) (presence/absence; drug name(s), and indication(s)) 
2) Data collection period 
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Duration from the start to the completion (or the discontinuation) of triple therapy 
 
9.4 Test/examination items 
9.4.1 Determination of H. pylori eradication 
1) Test items 
Conduct of tests (presence/absence; reason if test is not conducted; testing method; date 
and result of determination) 
2) Testing period 
At the time of determination of H. pylori eradication* 
*  Time frame of the H. pylori determination is approximately from 4 weeks to 2 months after the triple 
therapy. 
 
9.4.2 Liver function test 
1) Test items 
Aspartate aminotransferase (AST); alanine aminotransferase (ALT); γ-glutamyl 
transpeptidase (γ-GTP); alkaline phosphatase (ALP); total bilirubin; lactate 
dehydrogenase (LDH) 
2) Testing period 
Duration from the start of triple therapy* to the determination of H. pylori eradication (or the 
discontinuation of triple therapy) 
* Within 1 month before starting triple therapy 
 
9.4.3 Other examination items 
1) Examination items 
Presence/absence of pregnancy during the observational period (only female patients) 
If pregnancy is confirmed during the observational period, the information is immediately 
communicated to 
 The surveillance investigator provides detailed information 
(including information until delivery, e.g., pregnancy outcome such as premature delivery, 
as much as possible) separately when 
 requests it. 
2) Examination period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
9.5 Adverse event 
1) Data to be collected 
Presence/absence of adverse event (AE) (See Table 1); AE term; onset date; seriousness 
and reason for seriousness (See Table 2); cause of discontinuation of triple therapy; 
outcome date; outcome; causality* with triple therapy (See Table 3) 
Follow-up survey will be conducted as much as possible when outcome is not resolved or 
unknown and causality is determined as unassessable. 
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Detailed information (e.g., clinical course and results of tests conducted for diagnosis) 
will be collected as much as possible when onset of hepatic function disorder or 
gastrointestinal infection of clostridium difficile is observed. 
* Following information will be collected: rationale of assessment when causality is assessed as not 
related, and reason when causality is determined as unassessable. 
Note) A point to consider concerning adverse events 
Abnormal exacerbation of the target disease, i.e., exacerbation worse than the expected natural 
course of the disease will be handled as an adverse event, but expected exacerbation of the target 
disease will not be handled as an adverse event. 
2) Data collection period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
Table 1 
Definition of adverse event 
Adverse event (AE) is any unfavorable medical occurrence in a patient administered a pharmaceutical 
product. It does not necessarily need to have a causal relationship with the pharmaceutical product. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including abnormal 
laboratory values), symptom, or disease occurring at the use of a pharmaceutical product, whether or not 
considered related to the pharmaceutical product. 
Following cases should also be handled as adverse events. 
 Symptoms developed in an infant breastfed by a mother receiving the pharmaceutical product 
 Unfavorable symptoms, etc. developed in a child after administration of the pharmaceutical 
product 
 Symptoms developed after occupational exposure to the pharmaceutical product 
 Symptoms developed due to the use of a counterfeit of a pharmaceutical product 
manufactured/marketed by Takeda Pharmaceutical Company Limited 
 Unfavorable symptoms developed in a user of the pharmaceutical product which information was 
obtained through litigation or other legal actions 
 

8 
Table 2 
Seriousness assessment criteria 
An event meeting any of the following criteria is assessed as “serious”: 
1. Fatal (death) 
2. Life-threatening (life-threatening) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolongation of hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Congenital anomaly/birth defect (congenital anomaly) 
6. Other medically important condition than 1-5. Events listed in “Takeda Medically Significant AE 
List” are included in this criterion. 
 
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/hyperthermia malignant 
 
Aplastic anaemia 
 
Abortion spontaneous/stillbirth and dead foetus 
 
Toxic epidermal necrolysis/oculomucocutaneous syndrome (Stevens-Johnson syndrome) 
 
Transmission or suspected transmission of infection via a medicinal product 
 
Hepatic necrosis 
 
Endotoxic shock or suspected endotoxic shock 
 
Acute hepatic failure 
 
Table 3 
Causality assessment criteria for adverse events and triple therapy 
Assessment 
Assessment criteria 
Related 
There is temporal relationship (including the clinical course after the 
discontinuation of the triple therapy). Or, while other factors such as 
underlying disease, complication, concomitant drug or concomitant 
procedure could be presumed, the AE is possibly related to triple 
therapy. 
Not related 
There is no temporal relationship with the triple therapy. Or, other 
factors such as underlying disease, complication, concomitant drug or 
concomitant procedure are quite considerable as the cause. 
Unassessable 
Information required for causality assessment, such as temporal 
relationship (including the clinical course after the discontinuation of 
the triple therapy), underlying disease, complication, concomitant 
drug, and concomitant procedure is insufficient. 
 

9 
10.0 
Analysis items and method 
10.1 Items related to patient disposition 
Following data will be accumulated: number of patients enrolled; number of patients whose 
survey form (electronic) have been collected; number of patients in the safety analysis set and 
the efficacy analysis set; number of patients excluded from analysis and reasons for exclusion 
 
10.2 Patient demographics 
Patient demographic data including sex, age, hypersensitivity predisposition and complication 
will be accumulated. 
 
10.3 Details of treatment 
Treatment compliance to Takecab Tablets and antimicrobials used for the triple therapy and 
concomitant drugs (other than antimicrobials used for the triple therapy) will be accumulated. 
 
10.4 Items related to safety 
Following data will be accumulated for the safety analysis set. Adverse events are coded with 
MedDRA/J, and accumulated by Preferred Term (PT) and System Organ Class (SOC). 
The patients enrolled to this survey in both first-line and second-line eradication cases will be 
accumulated separately. 
10.4.1 Onset of adverse events 
Frequencies of adverse events which developed during the observational period will be 
accumulated by type, onset period, seriousness, and causality with the triple therapy. 
 
10.4.2 Factors which may affect safety 
Frequencies of adverse reactions which developed during the observational period will be 
accumulated by subgroups of patient demographic factors (e.g., sex; age; target disease of 
H. pylori eradication; presence/absence of renal disorder complication; and 
presence/absence of liver disorder complication) and details of treatment (first-line and 
second-line eradication). 
 
10.5 Items related to efficacy 
Following data will be accumulated for the efficacy analysis set. 
10.5.1 Eradication rate of H. pylori 
In patients who have the result of determination of eradication, proportion of patients with 
H. pylori negative (eradication rate) will be accumulated by first-line and second-line 
eradication. 
 
10.5.2 Factors which may affect efficacy 
The eradication rates of H. pylori will be accumulated by subgroup of patient demographic 
factors (e.g., sex; age; target disease of H. pylori eradication; complication). 

10 
 
11.0 
Registration of survey information 
Takeda Pharmaceutical Company Limited will register information of this survey on the 
public websites before starting this survey. 
 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organization of this survey 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
Post-marketing surveillance manager 
 
13.0 
Clinical research organizations 
 
14.0 
Other required items 
14.1 Revision of the protocol 
During the period of conducting this survey, following information will be captured: 
development of ADRs not expectable from Precautions for Use and onset of serious ADRs; 
whether there is increased frequency of specific ADRs or not; validity of the survey items. The 
protocol will be reviewed and revised if it is considered necessary. In addition, if a 
supplemental approval of a new dosage and administration or a new indication is granted 
during the period of conducting this survey, necessity of revision of the protocol will be 
examined if needed, and the protocol will be revised if needed. 
 
14.2 Procedure when there is any issue or doubt 
If there is any safety or efficacy issue, data will be closely examined, and action will be 
considered. 
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Appendix: Observation schedule 
Period of survey/data entry 
 
 
 
 
Data to be collected 
Observational period 
At the time of patient 
enrollment 
At the start of triple 
therapy 
At the completion of 
triple therapy 
At the time of 
determination of H. 
pylori eradication Note 1) 
At the time of 
discontinuation of 
triple therapy 
Patient 
enrollment 
Prescription date of 3 drugs 
including Takecab Tablets in triple 
therapy 
○ 
 
 
 
 
Patient identification number 
○ 
 
 
 
 
Patient initials 
○ 
 
 
 
 
Sex 
○ 
 
 
 
 
Date of birth 
○ 
 
 
 
 
Target disease of H. pylori eradication 
○ 
 
 
 
 
Assessment of inclusion criteria 
○ 
 
 
 
 
Assessment of exclusion criteria 
○ 
 
 
 
 
Patient 
demographic 
information 
Inpatient/outpatient classification 
 
○ 
 
 
 
Hypersensitivity predisposition 
 
○ 
 
 
 
Complication 
 
○ 
 
 
 
Previous H. pylori eradication Note 2) 
 
○ 
 
 
 
Height, weight 
 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
Drinking history 
 
○ 
 
 
 
Diagnosis of H. pylori infection 
 
○ 
 
 
 
Information 
of treatment 
Treatment compliance to Takecab 
Tablets and antimicrobials 
 
○ 
 
○ 
Treatment compliance to 
concomitant drugs (excluding 
antimicrobials) 
 
 
○ 
 
○ 
Test/ 
examination 
items 
Determination of H. pylori 
eradication 
 
 
 
○ 
 
Liver function test 
 
   ○Note 3) 
○ 
Presence/absence of pregnancy 
(only female patients) 
 
○ 
○ 
Adverse event 
 
○ 
○ 
○ 
: To be conducted 
○ 
: To be conducted throughout the period 
Note 1) Approximately from 4 weeks to 2 months after the triple therapy is completed 
Note 2) In patients with a history of unsuccessful H. pylori eradication with Takecab Tablets or a proton 
pump inhibitor in combination with amoxicillin and clarithromycin 
Note 3) From within one month before the start of triple therapy to determination of H. pylori 
eradication 

 
 
 
 
Protocol of drug use surveillance 
Drug use surveillance of Takecab tablets 
“Supplement to Helicobacter pylori eradication” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
Vonoprazan-5002 
Version 
Version 1 
Date 
January 6, 2015 
 

Table of contents 
1.0 
Background of conduct ................................................................................................................................ 1 
2.0 
Objectives ..................................................................................................................................................... 1 
3.0 
Planned sample size and its rationale ........................................................................................................... 1 
3.1 
Sample size ............................................................................................................................................... 1 
3.2 
Rationale................................................................................................................................................... 1 
4.0 
Study population .......................................................................................................................................... 2 
4.1 
Inclusion criteria ....................................................................................................................................... 3 
4.2 
Exclusion criteria ...................................................................................................................................... 3 
5.0 
Dosage and administration ........................................................................................................................... 3 
6.0 
Number of medical institutions by departments where the survey is planned ............................................. 3 
7.0 
Method ......................................................................................................................................................... 3 
7.1 
Observational period ................................................................................................................................ 3 
7.2 
Request to and contract with the medical institutions .............................................................................. 4 
7.3 
Method of patient enrollment ................................................................................................................... 4 
7.4 
Data entry and electronic signature in the survey form (electronic) ........................................................ 4 
7.5 
Actions to take at the time of development of a serious adverse event .................................................... 4 
8.0 
Scheduled period of the survey .................................................................................................................... 5 
9.0 
Data to be collected ...................................................................................................................................... 5 
9.1 
Patient enrollment .................................................................................................................................... 5 
9.2 
Patient demographic information ............................................................................................................. 5 
9.3 
Information of treatment .......................................................................................................................... 5 
9.4 
Test/examination items ............................................................................................................................. 6 
9.4.1 
Determination of H. pylori eradication ............................................................................................ 6 
9.4.2 
Liver function test ............................................................................................................................ 6 
9.4.3 
Other examination items .................................................................................................................. 6 
9.5 
Adverse event ........................................................................................................................................... 6 
10.0 
Analysis items and method........................................................................................................................... 9 
10.1 
Items related to patient disposition ........................................................................................................... 9 
10.2 
Patient demographics ............................................................................................................................... 9 
10.3 
Details of treatment .................................................................................................................................. 9 
10.4 
Items related to safety............................................................................................................................... 9 
10.4.1 
Onset of adverse events .................................................................................................................... 9 
10.4.2 
Factors which may affect safety ....................................................................................................... 9 
10.5 
Items related to efficacy ........................................................................................................................... 9 
10.5.1 
Eradication rate of H. pylori............................................................................................................. 9 
10.5.2 
Factors which may affect efficacy ................................................................................................... 9 
11.0 
Registration of survey information ............................................................................................................. 10 
12.0 
Organization of this survey ........................................................................................................................ 10 
12.1 
Manager .................................................................................................................................................. 10 

13.0 
Clinical research organizations................................................................................................................... 10 
14.0 
Other required items ................................................................................................................................... 10 
14.1 
Revision of the protocol ......................................................................................................................... 10 
14.2 
Procedure when there is any issue or doubt ........................................................................................... 10 
 
Appendix: Observation schedule............................................................................................................................11 
 

1 
1.0 
Background of conduct 
In the domestic clinical studies of Helicobacter Pylori (H. pylori) eradication with Takecab 
Tablets in combination with antimicrobials, safety of triple therapy was evaluated: Takecab 
Tablets, amoxicillin and clarithromycin (first-line eradication) in 329 patients, and Takecab 
Tablets, amoxicillin and metronidazole (second-line eradication) in 50 patients, and the results 
showed no specific issue. 
The safety profile of the first-line eradication could be expected in view of the results of 
Takecab Tablets clinical studies in patients with acid-related diseases (gastric ulcer, duodenal 
ulcer and reflux oesophagitis) and information provided in the package inserts of 
antimicrobials. Most of the adverse reactions (ADRs) developed during the second-line 
eradication were also observed in the first-line eradication, and there was no substantial 
difference between them. Accordingly, the safety profile of the use of Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
The Drug use surveillance of Takecab Tablets (this survey) for the supplement to H. pylori 
eradication in first-line and second-line eradication in the routine clinical setting is planned to 
confirm validity of this estimation (whether there is a new safety concern or not). 
This survey is conducted in compliance with relevant regulatory requirements such as GPSP 
ministerial ordinance. 
 
2.0 
Objectives 
The objective of this survey is to evaluate the safety and efficacy of first-line and second-line 
eradication including Takecab Tablets (triple therapy) in the routine clinical setting. 
 
3.0 
Planned sample size and its rationale 
3.1 Sample size 
500 patients 
 
3.2 Rationale 
The safety profile of H. pylori eradication with a proton pump inhibitor (lansoprazole) in 
combination with antimicrobials (amoxicillin and clarithromycin) observed in the domestic 
clinical studies and the drug use surveillance could be expected from the results of the 
domestic clinical studies and the drug use surveillance of lansoprazole in patients with 
acid-related diseases (gastric ulcer, duodenal ulcer and reflux oesophagitis), and from the 
information provided in the package inserts of antimicrobials. 
The safety profile of the first-line eradication observed in the clinical studies for H. pylori 
eradication with Takecab Tablets in combination with antimicrobials could be expected from 

2 
the results of the clinical studies of Takecab Tablets in patients with acid-related diseases and 
information provided in the package inserts of antimicrobials. 
Based on the above, the safety profile of the first-line eradication with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication in the routine clinical setting can be 
estimated based on the safety profile to be confirmed in the drug use surveillance of Takecab 
Tablets in patients with acid-related diseases (3,000 patients) and information provided in the 
package inserts of antimicrobials. 
In addition, it has been confirmed that ADRs of H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and metronidazole) in the specific 
drug use surveillance of proton pump inhibitors (lansoprazole, omeprazole and rabeprazole) 
were mostly similar to the ADRs reported in H. pylori eradication with a proton pump 
inhibitor in combination with antimicrobials (amoxicillin and clarithromycin). Most of the 
ADRs developed during the second-line H. pylori eradication in the clinical study of Takecab 
Tablets in combination with antimicrobials were also observed in the first-line eradication. 
Therefore, it is estimated that ADRs developed in association with Takecab Tablets in 
combination with antimicrobials for H. pylori eradication are not substantially different 
between first-line eradication and second-line eradication. In view of the above, the drug use 
surveillance of Takecab Tablets for supplement of H. pylori eradication is to be conducted for 
both first-line and second-line eradication. 
Accordingly, in this survey, data will be collected from 500 patients to whom Takecab Tablets 
is administered for supplement of H. pylori eradication, and will be compared with the safety 
information of Takecab Tablets collected in the drug use surveillance in patients with 
acid-related diseases (total 3,000 patients) and with information provided in the package 
inserts of antimicrobials, and it will be confirmed whether there is a new safety concern or not 
(please note that the sample size of 500 patients is not statistically calculated). 
In this survey, patients excluded from the clinical studies such as with gastric 
mucosa-associated lymphoid tissue (MALT) lymphoma, idiopathic thrombocytopenic purpura, 
stomach following endoscopic treatment of early gastric cancer, or H. pylori gastritis will be 
enrolled. 
 
4.0 
Study population 
Patients with the diseases described below* will receive triple therapy for H. pylori eradication. 
However, patients should meet the inclusion criterion and should not meet the exclusion 
criterion described below. Refer to the Precautions section of the package insert. 
* If a patient’s first-line eradication is unsuccessful in this survey, the patient can be enrolled in the 
second-line eradication in this survey. 
Gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) 
lymphoma, idiopathic thrombocytopenic purpura, stomach following endoscopic 
treatment of early gastric cancer, or H. pylori gastritis 

3 
4.1 Inclusion criteria 
Patients who meet either of the following criteria will be included in the survey: 
[1] Patients receiving H. pylori eradication for the first time 
[2] Patients for whom H. pylori eradication with Takecab Tablets or proton pump inhibitor + 
amoxicillin + clarithromycin was found unsuccessful and who are to receive eradication 
treatment with amoxicillin and metronidazole 
 
4.2 Exclusion criteria 
Patients who meet either of the following criteria will not be included in the survey. Refer to 
the Contraindications and Precautions section of the package insert of antimicrobials used in 
the triple therapy. 
[1] Patients with previous history of hypersensitivity to ingredients in Takecab Tablets 
[2] Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual dose for adults is 20 mg of vonoprazan, 750 mg (potency) of amoxicillin hydrate, 
and 200 mg (potency) of clarithromycin. These three drugs will be orally administered at the 
same time, twice daily for 7 days. The dose of clarithromycin can be increased as clinically 
warranted. However, the dosage of clarithromycin should not exceed 400 mg (potency)/dose 
twice daily. 
If H. pylori eradication with a three-drug regimen comprising vonoprazan or proton pump 
inhibitor + amoxicillin hydrate + clarithromycin is unsuccessful, as an alternative treatment, 
the following three drugs will be orally administered to adults at the same time, twice daily for 
7 days: vonoprazan at a dose of 20 mg, amoxicillin hydrate at a dose of 750 mg (potency), and 
metronidazole at a dose of 250 mg. Refer to the Precautions section of the package insert of 
antimicrobials used in triple therapy. 
 
6.0 
Number of medical institutions by departments where the survey is planned 
Internal medicine department (such as gastrointestinal medicine department)
 
Approximately 150 medical institutions 
Hematology department 
Approximately 10 medical institutions 
 
7.0 
Method 
7.1 Observational period 
Triple therapy period (7 days) and the period from the completion of the triple therapy to the 
determination of H. pylori eradication 
Time frame of the H. pylori determination is approximately from 4 weeks* to 2 months after 
the triple therapy. 
* According to the “Guidelines for diagnosis and treatment of H. pylori infection” of the Japanese Society 
for Helicobacter Research, determination of H. pylori eradication should be conducted after 4 weeks 

4 
from discontinuation of eradication therapy. 
 
7.2 Request to and contract with the medical institutions 
Request to and contract with the medical institutions will be conducted using web-based 
electronic data collection system (
). The Medical Representative of 
 
 will explain objectives and details of this survey, 
procedure, electronic signature, and handling of user ID and password of 
 to the 
surveillance investigator based on “Request of the Drug use surveillance”, “Implementation 
guidance”, “Data entry screens of 
” and “
 operational manual 
[abbreviated version]” when this survey is requested. Thereafter, written contract is made with 
the medical institution and conduct of the survey will be requested within the prespecified 
duration of the survey. 
 
7.3 Method of patient enrollment 
Patients will be enrolled with “central enrollment method” using 
. The surveillance 
investigator will enter the information required for patient enrollment (see Section 9.1) and 
will provide his/her electronic signature in 
 concerning patients to whom drugs of 
triple therapy (three drugs including Takecab Tablets) are prescribed within 5 days after 
prescription day of the three drugs including Takecab Tablets (the prescription day is defined 
as “Day 0”, and the day after prescription as “Day 1”) after term of contract with the medical 
institution is started. 
 
7.4 Data entry and electronic signature in the survey form (electronic) 
The surveillance investigator will enter the information of patient demographics and treatment 
and will provide electronic signature in 
 for all patients enrolled in this survey by 
one month after completion of the observational period of each patient. If receipt of Takecab 
Tablets was not confirmed, it will be entered so in 
 (it is not required to enter other 
data). 
For the patients who discontinued triple therapy including Takecab Tablets for any reason 
during the observational period, the surveillance investigator will enter the information of 
patient demographics and treatment and will provide his/her electronic signature in 
 
by one month after completion of required observation. However, for patients who 
discontinued triple therapy including Takecab Tablets due to development of an AE, 
observation will be continued as much as possible until resolve or resolving from the AE even 
after the treatment is discontinued, and the observation results will be entered in 
 
with his/her electronic signature. 
 
7.5 Actions to take at the time of development of a serious adverse event 
The surveillance investigator will immediately communicate 
 on development of a 
serious adverse event during the observational period. In addition, the surveillance investigator 
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will provide detailed information separately if requested by 
. 
 
8.0 
Scheduled period of the survey 
Duration of the survey: September 2015 to April 30, 2017 
Patient enrollment period: September 2015 to February 28, 2017 Note) 
Note) Patients will not be enrolled in this survey (or entered in 
) on or after March 1, 
2017 even if Takecab Tablets is prescribed on or before February 28, 2017. 
 
If enrollment of the planned number of patients of this survey is completed prior to 
February 28, 2017, the patient enrollment will be discontinued prior to the end of the 
patient enrollment period. When the patient enrollment period is shortened, the duration 
of the survey is to be changed according to the shortened period. 
 
9.0 
Data to be collected 
The surveillance investigator will enter the information of the following items in 
. 
The schedule of this survey is presented in the Appendix. 
9.1 Patient enrollment 
1) Data to be collected 
Prescription date of the three drugs including Takecab Tablets used in the triple therapy; 
patient identification number; patient initials; sex; date of birth; target disease of H. pylori 
eradication; assessment of inclusion and exclusion criteria 
2) Data collection period 
At the time of patient enrollment 
 
9.2 Patient demographic information 
1) Data to be collected 
Inpatient/outpatient classification (at the time when triple therapy is started); predisposition 
of hypersensitivity (presence/absence and details); complication (presence/absence and 
details); details of previous H. pylori eradication (in patients with a history of unsuccessful 
H. pylori eradication with Takecab Tablets or a proton pump inhibitor with amoxicillin and 
clarithromycin); height; weight; smoking history; drinking history; diagnosis of H. pylori 
infection (time of diagnosis and testing method) 
2) Data collection period 
At the start of triple therapy 
 
9.3 Information of treatment 
1) Data to be collected 
Treatment compliance to Takecab Tablets and antimicrobials used for triple therapy (name 
of drugs; daily dose; duration of triple therapy and reason for discontinuation of the triple 
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6 
therapy); treatment compliance to concomitant drugs (excluding antimicrobials used for the 
triple therapy) (presence/absence; drug name(s), and indication(s)) 
2) Data collection period 
Duration from the start to the completion (or the discontinuation) of triple therapy 
 
9.4 Test/examination items 
9.4.1 Determination of H. pylori eradication 
1) Test items 
Conduct of tests (presence/absence; reason if test is not conducted; testing method; date 
and result of determination) 
2) Testing period 
At the time of determination of H. pylori eradication* 
*  Time frame of the H. pylori determination is approximately from 4 weeks to 2 months after the triple 
therapy. 
 
9.4.2 Liver function test 
1) Test items 
Aspartate aminotransferase (AST); alanine aminotransferase (ALT); γ-glutamyl 
transpeptidase (γ-GTP); alkaline phosphatase (ALP); total bilirubin; lactate 
dehydrogenase (LDH) 
2) Testing period 
Duration from the start of triple therapy* to the determination of H. pylori eradication (or the 
discontinuation of triple therapy) 
* Within 1 month before starting triple therapy 
 
9.4.3 Other examination items 
1) Examination items 
Presence/absence of pregnancy during the observational period (only female patients) 
If pregnancy is confirmed during the observational period, the information is immediately 
communicated to 
. The surveillance investigator provides detailed information 
(including information until delivery, e.g., pregnancy outcome such as premature delivery, 
as much as possible) according to the request from 
. 
2) Examination period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
9.5 Adverse event 
1) Data to be collected 
Presence/absence of adverse event (AE) (See Table 1); AE term; onset date; seriousness; 
and reason for seriousness (See Table 2); cause of discontinuation of triple therapy; 
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outcome date; outcome; causality* with triple therapy (See Table 3) 
Follow-up survey will be conducted as much as possible when outcome is not resolved or 
unknown and causality is determined as unassessable. 
Detailed information (e.g., clinical course and results of tests conducted for diagnosis) 
will be collected as much as possible when onset of hepatic function disorder or 
gastrointestinal infection of clostridium difficile is observed. 
* Following information will be collected: rationale of assessment when causality is assessed as not 
related, and reason when causality is determined as unassessable. 
Note) A point to consider concerning adverse events 
Abnormal exacerbation of the target disease, i.e., exacerbation worse than the expected natural 
course of the disease will be handled as an adverse event, but expected exacerbation of the target 
disease will not be handled as an adverse event. 
2) Data collection period 
Duration from the start of triple therapy to the determination of H. pylori eradication (or 
the discontinuation of triple therapy) 
 
Table 1 
Definition of adverse event 
Adverse event (AE) is any unfavorable medical occurrence in a patient administered a pharmaceutical 
product. It does not necessarily need to have a causal relationship with the pharmaceutical product. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including abnormal 
laboratory values), symptom, or disease occurring at the use of a pharmaceutical product, whether or 
not considered related to the pharmaceutical product. 
Following cases should also be handled as adverse events. 
 
Symptoms developed in an infant breastfed by a mother receiving the pharmaceutical product 
 
Symptoms developed in a child after administration of the pharmaceutical product 
 
Symptoms developed after occupational exposure to the pharmaceutical product 
 
Symptoms developed due to the use of a counterfeit of a pharmaceutical product 
manufactured/marketed by Takeda Pharmaceutical Company Limited 
 

8 
Table 2 
Seriousness assessment criteria 
An event meeting any of the following criteria is assessed as “serious”: 
1. Fatal (death) 
2. Life-threatening (life-threatening) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolongation of hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Congenital anomaly/birth defect (congenital anomaly) 
6. Other medically important condition than 1-5. Events listed in “Takeda Medically Significant AE 
List” are included in this criterion. 
 
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/hyperthermia malignant 
 
Aplastic anaemia 
 
Abortion spontaneous/stillbirth and dead foetus 
 
Toxic epidermal necrolysis/oculomucocutaneous syndrome  (Stevens-Johnson syndrome) 
 
Transmission or suspected transmission of infection via a medicinal product 
 
Hepatic necrosis 
 
Endotoxic shock or suspected endotoxic shock 
 
Acute hepatic failure 
 
Table 3 
Causality assessment criteria for adverse events and triple therapy 
Assessment 
Assessment criteria 
Related 
There is temporal relationship (including the clinical course after the 
discontinuation of the triple therapy). Or, while other factors such as 
underlying disease, complication, concomitant drug or concomitant 
procedure could be presumed, the AE is possibly related to triple 
therapy. 
Not related 
There is no temporal relationship with the triple therapy. Or, other 
factors such as underlying disease, complication, concomitant drug or 
concomitant procedure are quite considerable as the cause. 
Unassessable 
Information required for causality assessment, such as temporal 
relationship (including the clinical course after the discontinuation of 
the triple therapy), underlying disease, complication, concomitant 
drug, and concomitant procedure is insufficient. 
 

9 
10.0 
Analysis items and method 
10.1 Items related to patient disposition 
Following data will be accumulated: number of patients enrolled; number of patients whose 
survey form (electronic) have been collected; number of patients in the safety analysis set and 
the efficacy analysis set; number of patients excluded from analysis and reasons for exclusion 
 
10.2 Patient demographics 
Patient demographic data including sex, age, hypersensitivity predisposition and complication 
will be accumulated. 
 
10.3 Details of treatment 
Treatment compliance to Takecab Tablets and antimicrobials used for the triple therapy and 
concomitant drugs (other than antimicrobials used for the triple therapy) will be accumulated. 
 
10.4 Items related to safety 
Following data will be accumulated for the safety analysis set. Adverse events are coded with 
MedDRA/J, and accumulated by Preferred Term (PT) and System Organ Class (SOC). 
The patients enrolled to this survey in both first-line and second-line eradication cases will be 
accumulated separately. 
10.4.1 Onset of adverse events 
Frequencies of adverse events which developed during the observational period will be 
accumulated by type, onset period, seriousness, and causality with the triple therapy. 
 
10.4.2 Factors which may affect safety 
Frequencies of adverse reactions which developed during the observational period will be 
accumulated by subgroups of patient demographic factors (e.g., sex; age; target disease of 
H. pylori eradication; presence/absence of renal disorder complication; and 
presence/absence of liver disorder complication) and details of treatment (first-line and 
second-line eradication). 
 
10.5 Items related to efficacy 
Following data will be accumulated for the efficacy analysis set. 
10.5.1 Eradication rate of H. pylori 
In patients who have the result of determination of eradication, proportion of patients with 
H. pylori negative (eradication rate) will be accumulated by first-line and second-line 
eradication. 
 
10.5.2 Factors which may affect efficacy 
The eradication rates of H. pylori will be accumulated by subgroup of patient demographic 
factors (e.g., sex; age; target disease of H. pylori eradication; complication). 

10 
 
11.0 
Registration of survey information 
Takeda Pharmaceutical Company Limited will register information of this survey on the 
public websites before starting this survey. 
 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
Registration system of clinical trials of National Institutes of Health: ClinicalTrials.gov 
 
12.0 
Organization of this survey 
12.1 Manager 
Takeda Pharmaceutical Company Limited 
Post-marketing surveillance manager 
 
13.0 
Clinical research organizations 
 
14.0 
Other required items 
14.1 Revision of the protocol 
During the period of conducting this survey, following information will be captured: 
development of ADRs not expectable from Precautions for Use and onset of serious ADRs; 
whether there is increased frequency of specific ADRs or not; validity of the survey items. The 
protocol will be reviewed and revised if it is considered necessary. In addition, if a 
supplemental approval of a new dosage and administration or a new indication is granted 
during the period of conducting this survey, necessity of revision of the protocol will be 
examined if needed, and the protocol will be revised if needed. 
 
14.2 Procedure when there is any issue or doubt 
If there is any safety or efficacy issue, data will be closely examined, and action will be 
considered. 
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11 
Appendix: Observation schedule 
Period of survey/data entry 
 
 
 
 
Data to be collected 
Observational period 
At the time of patient 
enrollment 
At the start of triple 
therapy 
At the completion of 
triple therapy 
At the time of 
determination of H. 
pylori eradication Note 1) 
At the time of 
discontinuation of 
triple therapy 
Patient 
enrollment 
Prescription date of 3 drugs 
including Takecab Tablets in triple 
therapy 
○ 
 
 
 
 
Patient identification number 
○ 
Patient initials 
○ 
Sex 
○ 
Date of birth 
○ 
Target disease of H. pylori eradication 
○ 
 
 
Assessment of inclusion criteria 
○ 
 
 
 
 
Assessment of exclusion criteria 
○ 
 
 
 
 
Patient 
demographic 
information 
Inpatient/outpatient classification 
○ 
 
Hypersensitivity predisposition 
○ 
 
Complication 
○ 
 
Previous H. pylori eradication Note 2) 
 
○ 
 
Height, weight 
 
○ 
 
Smoking history 
 
○ 
 
Drinking history 
 
○ 
 
Diagnosis of H. pylori infection 
 
○ 
 
 
 
Information 
of treatment 
Treatment compliance to Takecab 
Tablets and antimicrobials 
 
○ 
 
○ 
Treatment compliance to 
concomitant drugs (excluding 
antimicrobials) 
 
 
○ 
 
○ 
Test/ 
examination 
items 
Determination of H. pylori 
eradication 
○ 
Liver function test 
 
   ○Note 3) 
○ 
Presence/absence of pregnancy 
(only female patients) 
○ 
○ 
Adverse event 
○ 
○ 
○ 
: To be conducted 
○ 
: To be conducted throughout the period 
Note 1) Approximately from 4 weeks to 2 months after the triple therapy is completed 
Note 2) In patients with a history of unsuccessful H. pylori eradication with Takecab Tablets or a proton 
pump inhibitor in combination with amoxicillin and clarithromycin 
Note 3) From within one month before the start of triple therapy to determination of H. pylori 
eradication