Special Drug Use Surveillance of Takecab Tablets for "Prevention of Recurrence of Gastric/Duodenal Ulcer in Patients Receiving Low-dose Aspirin: Long-term Use"
Conditions: Gastric or Duodenal Ulcers
Sponsor: Takeda

 
 
Title: Special drug use surveillance of Takecab tablets for "prevention of recurrence of 
gastric/duodenal ulcer in patients receiving low-dose aspirin:long-term use" 
 
NCT Number: NCT03214094 
Protocol  Approve Date: 02-JUN-2017 
 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
 
 
 
Special Drug Use Surveillance Protocol 
Takecab Tablets Special Drug Use Surveillance 
“Suppression of gastric or duodenal ulcer recurrence 
on low-dose aspirin: Long-term use” 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol Number 
Vonoprazan-5004 
Version Number 
Version 2 
Date of 
preparation 
 
June 2, 2017 
 

Table of Contents 
1.0 
Background .............................................................................................................................................. 1 
2.0 
Objectives................................................................................................................................................. 1 
3.0 
Planned sample size and rationale ............................................................................................................ 1 
3.1 
Planned sample size ................................................................................................................................. 1 
3.2 
Rationale .................................................................................................................................................. 1 
4.0 
Surveillance population ............................................................................................................................ 1 
4.1 
Inclusion criterion .................................................................................................................................... 2 
4.2 
Exclusion criteria...................................................................................................................................... 2 
5.0 
Dosage and administration ....................................................................................................................... 2 
6.0 
Planned number of surveillance sites by specialty department ................................................................ 2 
7.0 
Methods .................................................................................................................................................... 2 
7.1 
Duration of observation ............................................................................................................................ 2 
7.2 
Request to and contract with medical institutions .................................................................................... 2 
7.3 
Patient enrollment method........................................................................................................................ 3 
7.4 
Data entry to the survey form (electronic) and electronic signature......................................................... 3 
7.5 
Actions taken for serious adverse events.................................................................................................. 3 
8.0 
Planned surveillance period ..................................................................................................................... 3 
9.0 
Surveillance items .................................................................................................................................... 4 
9.1 
Patient enrollment .................................................................................................................................... 4 
9.2 
Patient demographics information ............................................................................................................ 4 
9.3 
Treatment information .............................................................................................................................. 4 
9.4 
Tests and observations .............................................................................................................................. 4 
9.4.1 
Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of Takecab therapy 
 
 .......................................................................................................................................................... 4 
9.4.2 
Liver function tests ........................................................................................................................... 5 
9.4.3 
Serum gastrin.................................................................................................................................... 5 
9.4.4 
Other items of observations .............................................................................................................. 5 
9.5 
Adverse events ......................................................................................................................................... 5 
10.0 
Analysis items and methods ..................................................................................................................... 8 
10.1 
Disposition of patients .............................................................................................................................. 8 
10.2 
Patient demographics ............................................................................................................................... 8 
10.3 
Treatment details ...................................................................................................................................... 8 
10.4 
Safety data ................................................................................................................................................ 8 
10.4.1 
Incidence of adverse events .............................................................................................................. 8 
10.4.2 
Factors which may affect safety ....................................................................................................... 9 
10.5 
Efficacy data ............................................................................................................................................. 9 
10.5.1 
Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of Takecab therapy 
 
 .......................................................................................................................................................... 9 
10.5.2 
Factors which may affect efficacy .................................................................................................... 9 

11.0 
Registration of surveillance information .................................................................................................. 9 
12.0 
Administrative structure ........................................................................................................................... 9 
13.0 
.................................................................................................................................................................. 9 
14.0 
Other necessary items ............................................................................................................................ 10 
14.1 
Protocol amendments ............................................................................................................................. 10 
14.2 
Actions to be taken in response to detection of any issues or concerns ................................................. 10 
 
Appendix Observation Schedule..............................................................................................................................11 
 

1 
1.0 
Background 
Administration of Takecab Tablets for suppression of gastric or duodenal ulcer recurrence on 
low-dose aspirin is anticipated to be continued long-term in routine clinical settings. 
Administration of Takecab Tablets 10 mg for suppression of gastric or duodenal ulcer 
recurrence on low-dose aspirin was evaluated for 24 weeks (168 days) or more in 165 patients 
and 48 weeks (336 days) or more in 145 patients in a Japanese phase III double-blind 
comparative study and long-term extension, and raised no particular safety issues. To verify 
the safety of Takecab Tablets used in routine clinical practice and the consistency of the 
long-term safety profile with the known safety profile of the drug, the present special drug use 
surveillance has been planned. 
This surveillance will be conducted in compliance with the Ministerial Ordinance on Good 
Post-Marketing Study Practice (GPSP) and relevant regulatory requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of Takecab Tablets for up to 12 months in patients on 
low-dose aspirin in routine clinical practice 
 
3.0 
Planned sample size and rationale 
3.1 Planned sample size 
1,000 patients 
 
3.2 Rationale 
The target sample size is set to 1000 for collection of 12-month therapy data from 300 
patients. 
Based on the results from Takepron (lansoprazole) post-marketing surveillance*, the 
percentage of patients given 12-month therapy is conservatively assumed to be 30%. Thus, a 
target sample size of 1000 would allow collection of 12-month therapy data from 300 patients. 
With the data collection from 300 patients, an adverse drug reaction (ADR) occurring with an 
incidence of 1% or more can be detected with a probability of at least 95%, which should 
allow determination of ADRs characteristic of long-term use of the drug. 
 
*“Reflux esophagitis/maintenance therapy 3 to 6 months”: 6-month therapy in 57% 
  “Suppression of ulcer recurrence on low-dose aspirin: Long-term use”: 12-month therapy in 79.1% 
“Suppression of ulcer recurrence on non-steroidal anti-inflammatory drugs: Long-term use”: 12-month 
therapy in 46.1% 
 
4.0 
 Surveillance population 
This surveillance will enroll patients who are on low-dose aspirin for suppression of 
thrombosis and embolism (including those who start Takecab therapy on the same day as the 
day of initiation of low-dose aspirin) and who meet the additional inclusion criterion and do 

2 
not meet the exclusion criteria specified below. The PRECAUTIONS section of the Takecab 
package insert should also be referenced in the enrollment judgment. 
4.1 Inclusion criterion 
Patients who are on low-dose aspirin for suppression of thrombosis and embolism (including 
those who start Takecab therapy on the same day as the day of initiation of low-dose aspirin) 
and also meet the following criterion will be included: 
Patients with a history of gastric or duodenal ulcer 
4.2 Exclusion criteria 
Patients who meet any of the following criteria will be excluded: 
(1) Patients with gastric or duodenal ulcer at initiation of Takecab therapy 
(2) Patients with active upper gastrointestinal haemorrhage at initiation of Takecab therapy 
(3) Patients with a history of hypersensitivity to any ingredients of Takecab Tablets 
(4) Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual adult dosage is 10 mg of vonoprazan administered orally once daily. The 
PRECAUTIONS section of the Takecab package insert should also be referenced. 
 
6.0 
Planned number of surveillance sites by specialty department  
Approximately 300 sites, including the internal medicine and neurosurgery departments 
 
7.0 
Methods 
7.1 Duration of observation 
12 months 
This surveillance will be ended when either criterion (1) or (2) specified below is found to be 
met. 
(1) If Takecab therapy is discontinued 
(2) If low-dose aspirin is discontinued 
If either a gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion develops during 
combination therapy with Takecab Tablets and low-dose aspirin, observation will be continued 
up to assessment of the post-treatment outcome of the ulcer/lesion and the surveillance will 
then be ended. 
 
7.2 Request to and contract with medical institutions 
The surveillance implementation will use a Web-based electronic data capture system 
(
). Upon request, a medical representative of 
 
(hereinafter referred to as “
”) will explain to the potential surveillance investigator 
about the surveillance objectives and contents, as well as how to use 
 and enter the 
electronic signature and handling of the user ID and the password according to the 
“Surveillance Implementation Outline,” “
 Data Entry screen images” and 
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“
 User Manual.” If the request is accepted, a written contract for the surveillance 
within the specified period will be made with the medical institution. 
 
 
7.3 Patient enrollment method 
Patients will be enrolled using a centralized enrollment method via 
. For patients 
prescribed Takecab Tablets on or after the first day of the contract period for the medical 
institution, the surveillance investigators will enter the patient information required for 
enrollment (see Section 9.1) and the electronic signature in 
 within 14 days after 
the prescription of Takecab Tablets (with the day of prescription counted as zero and the day 
following prescription counted as “1 day after prescription”). 
 
7.4 Data entry to the survey form (electronic) and electronic signature 
The surveillance investigator will enter data on patient demographics, treatment details, etc. 
and the electronic signature in 
, roughly within 1 month after the end of required 
observations at Month 12 of Takecab therapy. If administration of this drug could not be 
confirmed, this fact should be entered (no other data are required). 
 
For patients who discontinued treatment with Takecab Tablets for certain reasons during the 
observation period, the surveillance investigator will enter data on patient demographics, 
treatment details, etc. and the electronic signature in 
 roughly within 1 month after 
the end of required observations. However, for patients who discontinued Takecab therapy 
because of onset of an adverse event (AE), even after the discontinuation of this drug, the 
surveillance investigator will continue observation as far as possible up to resolution or 
improvement of the adverse event. The surveillance investigator will then enter the 
observation result and the electronic signature in 
. 
 
7.5 Actions taken for serious adverse events 
If any serious AE occurs during the observation period, the surveillance investigator will 
immediately report it to an 
. If requested by the 
, the surveillance 
investigator will provide detailed information separately. 
 
8.0 
Planned surveillance period 
Surveillance period: September 2016 to August 31, 2019 
Patient enrollment period: September 2016 to August 31, 2018 Note) 
Note) No patient enrollment (via 
) will be acceptable on or after September 1, 2018, 
even if Takecab is prescribed by August 31, 2018. 
If the total number of the enrolled patients in the entire surveillance reach the planned 
sample size before August 31, 2018, patient enrollment will be closed before the end of the 
patient enrollment period. If the patient enrollment period is shortened, the surveillance 
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period will also be changed according to the shortened enrollment period. 
 
9.0 
Surveillance items 
The surveillance investigator will enter data of the following items into 
. The 
surveillance schedule is shown in the Appendix. 
9.1 Patient enrollment 
1) Surveillance items 
Date of prescription of Takecab Tablets, patient identification number, patient initials, sex, 
date of birth, assessment against the inclusion criteria (details of the history of gastric or 
duodenal ulcer (time and site of onset)), assessment against the exclusion criteria 
2) Time of data collection 
At enrollment of the patient 
 
9.2 Patient demographics information 
1) Surveillance items 
Reason for use of low-dose aspirin, time of initiation of low-dose aspirin, coronary artery 
stent (presence or absence, and time), inpatient/outpatient classification (at initiation of 
Takecab therapy), hypersensitive diathesis (presence or absence, and details), complication 
(excluding the reason for use of low-dose aspirin: presence or absence, and details), height, 
weight, presence or absence of Helicobacter pylori infection (at initiation of Takecab 
therapy), smoking history, drinking history, presence or absence of stress as a risk factor of 
onset of gastric or duodenal ulcer, detailed use of acid secretion inhibitors for suppression 
of gastric or duodenal ulcer recurrence within 1 month before initiation of Takecab therapy 
(presence or absence, and name of drug) 
2) Time of data collection 
At initiation of Takecab therapy 
 
9.3 Treatment information 
1) Surveillance items 
Takecab therapy details (daily dose, therapy dates, and reason for discontinuation), 
low-dose aspirin therapy details (name of drug, daily dose, and therapy dates), reason for 
use of Takecab after the end of low-dose aspirin therapy, concomitant drug (other than 
low-dose aspirin) details (presence or absence, name of drug, and reason for use) 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy) 
 
9.4 Tests and observations 
9.4.1 Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of 
Takecab therapy 
1) Data items 
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Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion (presence or absence of 
onset, details, basis for the diagnosis, and date of endoscopy or diagnosis) 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy) 
 
9.4.2 Liver function tests 
1) Test parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Time of data collection 
At the testing from initiation of Takecab therapy* to Month 12 (or discontinuation of the 
therapy) 
*Within 1 month before initiation of Takecab therapy 
 
9.4.3 Serum gastrin 
1) Test parameter 
Serum gastrin level 
2) Time of data collection 
At the testing from initiation of Takecab therapy* to Month 12 (or discontinuation of the 
therapy) 
*Within 1 month before initiation of Takecab therapy 
 
9.4.4 Other items of observations 
1) Observation items 
Presence or absence of pregnancy during the observation period (only in women) 
Any pregnancy found during the observation period should be immediately notified to an 
. In response to a request by an 
, the surveillance investigator will 
provide detailed information (wherever possible up to the outcome of pregnancy, such as 
premature delivery) separately using a pregnancy report form. 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy) 
 
9.5 Adverse events 
1) Surveillance items 
Presence or absence of AEs (see Table 1), AE term, date of onset, seriousness and reason 
for the assessment as serious (see Table 2), reason for discontinuation of Takecab, 
outcome assessment date, outcome, causal relationship to Takecab* (see Table 3) 
If the outcome is “not resolved” or “unknown,” or if the causal relationship is 
“unassessable,” the event should be followed as far as possible. 
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Detailed event information (clinical course, results of diagnostic tests, etc.) should be 
collected as much as possible in the event of hepatic function disorder, fracture, 
gastrointestinal infection with Clostridium difficile, neuroendocrine tumor, or 
cardiovascular/cerebrovascular event. 
*If the causal relationship to Takecab is “Not related,” the basis for the assessment should be recorded. If 
the causal relationship to Takecab is “Unassessable,” the reason should be recorded. 
Note) Special guidance about reporting of AEs: 
Onset of a gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion, which is an efficacy 
endpoint, is not regarded as an AE. 
Serum gastrin can increase due to the pharmacological action of Takecab. However, if Takecab 
therapy is discontinued because of increased serum gastrin, this event should be handled as an AE. 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy)  
 

7 
Table 1 Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product. 
Note that the following events will also be handled as adverse events:  
• 
Any manifestation in an infant breastfed by a mother taking this drug 
• 
Any untoward manifestation in a child given this drug 
• 
Any manifestation due to occupational exposure to this drug 
• 
Any manifestation due to a counterfeit product of a prescription drug marketed by Takeda 
• 
Any untoward manifestation in a patient given this drug revealed by a lawsuit or any other legal 
action 
 
Table 2 Criteria for Serious Adverse Events 
An adverse event is assessed as “serious” if it results in any of the following outcomes: 
1. results in death (Death), 
2. is life-threatening (Life-threatening), 
3. requires hospitalization or prolongation of existing hospitalization (Hospitalization/Prolongation of 
hospitalization), 
4. results in persistent or significant disability/incapacity (Disability), 
5. leads to a congenital anomaly or birth defect (Congenital anomaly), or 
6. is any other important medical event that does not fulfil 1 to 5 above. 
Serious adverse events include events described in the “Takeda Medically Significant AE List.”  
 
Takeda Medically Significant AE List 
- Acute respiratory failure / Acute respiratory 
distress syndrome (ARDS) 
- Torsade de pointes / Ventricular fibrillation / 
Ventricular tachycardia 
- Malignant hypertension 
- Convulsive seizure (including convulsion and 
epilepsy) 
- Agranulocytosis 
- Aplastic anaemia 
- Toxic epidermal necrolysis / Oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
- Hepatic necrosis 
- Anaphylactic shock 
- Acute renal failure 
- Pulmonary hypertension 
- Pulmonary fibrosis (including interstitial 
pneumonia) 
- Neuroleptic malignant syndrome/ Malignant 
hyperthermia 
- Spontaneous abortion / Stillbirth and fetal death 
- Confirmed or suspected transmission of infectious 
agent by a medicinal product 
- Confirmed or suspected endotoxin shock 
- Acute hepatic failure 
 

8 
Table 3 Assessment of the causal relationship between an adverse event and Takecab 
Causality classification 
Definition 
Related 
An adverse event that follows a temporal sequence from 
administration of this drug (including the course after withdrawal of 
the drug), or for which possible involvement of this drug can be 
considered, although factors other than this drug, such as the primary 
disease, complication, concomitant drugs or concurrent treatments, 
may also be responsible. 
Not related 
An adverse event that does not follow a temporal sequence from 
administration of this drug or that can reasonably be explained by other 
factors, such as the primary disease, complication, concomitant drugs 
or concurrent treatments. 
Unassessable 
The causality cannot be assessed because of insufficiency of required 
information, such as temporal sequence of the event onset relative to 
administration of this drug (including the course after withdrawal of 
the drug), primary disease, complication, concomitant drugs, and 
concurrent treatments. 
 
10.0 
Analysis items and methods 
10.1 Disposition of patients 
Number of patients enrolled, number of patients with collected survey forms (electronic), 
numbers of patients for safety and efficacy analyses, number of patients excluded from 
analysis, reasons for exclusion, etc. will be summarized. 
 
10.2 Patient demographics 
Patient demographic data such as sex, age, hypersensitive diathesis, and complication will be 
summarized. 
 
10.3 Treatment details 
Detailed use of Takecab, low-dose aspirin, and concomitant drugs (other than low-dose 
aspirin) will be summarized. 
 
10.4 Safety data 
The following data will be summarized using the safety analysis set. AEs will be coded using 
the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Incidence of adverse events 
AEs occurring during the observation period will be summarized using frequency count by 
event type, time of onset, seriousness, causal relationship to Takecab, etc. 
 

9 
10.4.2 Factors which may affect safety 
ADRs occurring during the observation period will be summarized using frequency count, 
with stratification of patients according to patient demographic factors (e.g., sex, age, 
reason for use of low-dose aspirin, any renal impairment, any hepatic impairment) and 
treatment details (e.g., detailed use of Takecab, detailed use of low-dose aspirin). 
 
10.5 Efficacy data 
The following data will be summarized using the efficacy analysis set. 
10.5.1 Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of 
Takecab therapy 
The presence or absence of onset of a gastric/duodenal ulcer or gastric/duodenal 
haemorrhagic lesion will be summarized. 
 
10.5.2 Factors which may affect efficacy 
The presence or absence of onset of a gastric/duodenal ulcer or gastric/duodenal 
haemorrhagic lesion will be summarized with stratification of patients according to patient 
demographic factors (e.g., sex, age, presence or absence of Helicobacter pylori infection) 
and treatment details (e.g., detailed use of Takecab, detailed use of low-dose aspirin). 
 
11.0 
Registration of surveillance information 
Before initiation of the surveillance, Takeda Pharmaceutical Company Limited will register 
the surveillance information with an online public clinical trials registry: 
- Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
 
12.0 
Administrative structure 
 
Takeda Pharmaceutical Company Limited 
 
13.0 
 
(1) 
 
 
 
 
(2) 
 
 
 
 
(3) 
 
 
 
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(4) 
 
 
 
 
 
(5) 
 
 
 
 
14.0 
Other necessary items 
14.1 Protocol amendments 
During the surveillance period, monitoring will be performed regarding the progress of the 
surveillance, occurrence of ADRs unexpected from the PRECAUTIONS and serious ADRs, 
any increase in the incidence of particular ADRs, validity of the surveillance items, etc., and 
the protocol will be reviewed and amended as necessary. If any partial change to the DOSAGE 
AND ADMINISTRATION, INDICATIONS, etc. is approved during the surveillance period, 
whether or not the protocol should be amended will be examined, and the protocol will be 
amended as necessary. 
 
14.2 Actions to be taken in response to detection of any issues or concerns 
Whenever an issue is found regarding the safety or efficacy, the data will be investigated in 
detail, and necessary actions will be determined. 
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Appendix Observation schedule 
○     : Performed 
○     : Performed throughout the period 
         Time of data collection/entry 
 
 
Surveillance items 
Observation period 
At 
enrollment 
Start of 
Takecab 
therapy 
Month 
12 
Discontinuation 
of Takecab 
therapy 
Patient enrollment 
Date of prescription of Takecab Tablets 
○ 
 
 
 
Patient identification number 
○ 
 
 
 
Patient initials 
○ 
 
 
 
Sex 
○ 
 
 
 
Date of birth 
○ 
 
 
 
Assessment against inclusion criterion (details 
of history of gastric or duodenal ulcer) 
○ 
 
 
 
Assessment against exclusion criteria 
○ 
 
 
 
Patient demographics 
Reason for use of low-dose aspirin 
 
○ 
 
 
Time of initiation of low-dose aspirin 
 
○ 
 
 
Coronary artery stent 
 
○ 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
Hypersensitive diathesis 
 
○ 
 
 
Complication (excluding the reason for use of 
low-dose aspirin) 
 
○ 
 
 
Height, weight 
 
○ 
 
 
H. pylori infection 
 
○ 
 
 
Smoking history 
 
○ 
 
 
Drinking history 
 
○ 
 
 
Presence or absence of stress as a risk factor of 
onset of gastric or duodenal ulcer 
 
○ 
 
 
Detailed use of acid secretion inhibitors for 
suppression of gastric or duodenal ulcer 
recurrence before initiation of Takecab therapy 
(within 1 month) 
 
○ 
 
 
Treatment details 
Detailed use of Takecab 
 
○ 
○ 
Detailed use of low-dose aspirin 
 
○ 
○ 
Reason for use of Takecab after the end of 
low-dose aspirin therapy 
 
○ 
 
Detailed use of concomitant drugs (other than 
low-dose aspirin) 
 
○ 
○ 
Assessments 
Gastric/duodenal ulcer or gastric/duodenal 
haemorrhagic lesion after initiation of Takecab 
therapy 
 
○ 
○ 
Liver function tests 
 
○Note) 
○ 
Serum gastrin 
 
○Note) 
○ 
Pregnancy (women only) 
 
○ 
○ 
AE monitoring 
 
○ 
○ 

12 
Note) From ≤1 month before initiation of Takecab therapy to Month 12 

 
 
 
 
Special Drug Use Surveillance Protocol 
Takecab Tablets Special Drug Use Surveillance 
“Suppression of gastric or duodenal ulcer recurrence 
on low-dose aspirin: Long-term use” 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol Number 
Vonoprazan-5004 
Version Number 
Version 1 
Date of 
preparation 
 
July 5, 2016 
 

Table of Contents 
1.0 
Background .............................................................................................................................................. 1 
2.0 
Objectives................................................................................................................................................. 1 
3.0 
Planned sample size and rationale ............................................................................................................ 1 
3.1 
Planned sample size ................................................................................................................................. 1 
3.2 
Rationale .................................................................................................................................................. 1 
4.0 
Surveillance population ............................................................................................................................ 1 
4.1 
Inclusion criterion .................................................................................................................................... 2 
4.2 
Exclusion criteria...................................................................................................................................... 2 
5.0 
Dosage and administration ....................................................................................................................... 2 
6.0 
Planned number of surveillance sites by specialty department ................................................................ 2 
7.0 
Methods .................................................................................................................................................... 2 
7.1 
Duration of observation ............................................................................................................................ 2 
7.2 
Request to and contract with medical institutions .................................................................................... 2 
7.3 
Patient enrollment method........................................................................................................................ 3 
7.4 
Data entry to the survey form (electronic) and electronic signature......................................................... 3 
7.5 
Actions taken for serious adverse events.................................................................................................. 3 
8.0 
Planned surveillance period ..................................................................................................................... 3 
9.0 
Surveillance items .................................................................................................................................... 4 
9.1 
Patient enrollment .................................................................................................................................... 4 
9.2 
Patient demographics information ............................................................................................................ 4 
9.3 
Treatment information .............................................................................................................................. 4 
9.4 
Tests and observations .............................................................................................................................. 4 
9.4.1 
Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of Takecab therapy 
 
 .......................................................................................................................................................... 4 
9.4.2 
Liver function tests ........................................................................................................................... 5 
9.4.3 
Serum gastrin.................................................................................................................................... 5 
9.4.4 
Other items of observations .............................................................................................................. 5 
9.5 
Adverse events ......................................................................................................................................... 5 
10.0 
Analysis items and methods ..................................................................................................................... 8 
10.1 
Disposition of patients .............................................................................................................................. 8 
10.2 
Patient demographics ............................................................................................................................... 8 
10.3 
Treatment details ...................................................................................................................................... 8 
10.4 
Safety data ................................................................................................................................................ 8 
10.4.1 
Incidence of adverse events .............................................................................................................. 8 
10.4.2 
Factors which may affect safety ....................................................................................................... 9 
10.5 
Efficacy data ............................................................................................................................................. 9 
10.5.1 
Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of Takecab therapy
 
9 
10.5.2 
Factors which may affect efficacy .................................................................................................... 9 

11.0 
Registration of surveillance information .................................................................................................. 9 
12.0 
Administrative structure ........................................................................................................................... 9 
13.0 
Trustees .................................................................................................................................................... 9 
14.0 
Other necessary items ............................................................................................................................ 10 
14.1 
Protocol amendments ............................................................................................................................. 10 
14.2 
Actions to be taken in response to detection of any issues or concerns ................................................. 10 
 
Appendix Observation Schedule..............................................................................................................................10 
 

1 
1.0 
Background 
Administration of Takecab Tablets for suppression of gastric or duodenal ulcer recurrence on 
low-dose aspirin is anticipated to be continued long-term in routine clinical settings. 
Administration of Takecab Tablets 10 mg for suppression of gastric or duodenal ulcer 
recurrence on low-dose aspirin was evaluated for 24 weeks (168 days) or more in 165 patients 
and 48 weeks (336 days) or more in 145 patients in a Japanese phase III double-blind 
comparative study and long-term extension, and raised no particular safety issues. To verify 
the safety of Takecab Tablets used in routine clinical practice and the consistency of the 
long-term safety profile with the known safety profile of the drug, the present special drug use 
surveillance has been planned. 
This surveillance will be conducted in compliance with the Ministerial Ordinance on Good 
Post-Marketing Study Practice (GPSP) and relevant regulatory requirements. 
 
2.0 
Objectives 
To evaluate the safety and efficacy of Takecab Tablets for up to 12 months in patients on 
low-dose aspirin in routine clinical practice 
 
3.0 
Planned sample size and rationale 
3.1 Planned sample size 
1,000 patients 
 
3.2 Rationale 
The target sample size is set to 1000 for collection of 12-month therapy data from 300 
patients. 
Based on the results from Takepron (lansoprazole) post-marketing surveillance*, the 
percentage of patients given 12-month therapy is conservatively assumed to be 30%. Thus, a 
target sample size of 1000 would allow collection of 12-month therapy data from 300 patients. 
With the data collection from 300 patients, an adverse drug reaction (ADR) occurring with an 
incidence of 1% or more can be detected with a probability of at least 95%, which should 
allow determination of ADRs characteristic of long-term use of the drug. 
 
*“Reflux esophagitis/maintenance therapy 3 to 6 months”: 6-month therapy in 57% 
  “Suppression of ulcer recurrence on low-dose aspirin: Long-term use”: 12-month therapy in 79.1% 
“Suppression of ulcer recurrence on non-steroidal anti-inflammatory drugs: Long-term use”: 12-month 
therapy in 46.1% 
 
4.0 
Surveillance population 
This surveillance will enroll patients who are on low-dose aspirin for suppression of 
thrombosis and embolism (including those who start Takecab therapy on the same day as the 
day of initiation of low-dose aspirin) and who meet the additional inclusion criterion and do 

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not meet the exclusion criteria specified below. The PRECAUTIONS section of the Takecab 
package insert should also be referenced in the enrollment judgment. 
4.1 Inclusion criterion 
Patients who are on low-dose aspirin for suppression of thrombosis and embolism (including 
those who start Takecab therapy on the same day as the day of initiation of low-dose aspirin) 
and also meet the following criterion will be included: 
Patients with a history of gastric or duodenal ulcer 
4.2 Exclusion criteria 
Patients who meet any of the following criteria will be excluded: 
(1) Patients with gastric or duodenal ulcer at initiation of Takecab therapy 
(2) Patients with active upper gastrointestinal haemorrhage at initiation of Takecab therapy 
(3) Patients with a history of hypersensitivity to any ingredients of Takecab Tablets 
(4) Patients receiving atazanavir sulfate or rilpivirine hydrochloride 
 
5.0 
Dosage and administration 
The usual adult dosage is 10 mg of vonoprazan administered orally once daily. The 
PRECAUTIONS section of the Takecab package insert should also be referenced. 
 
6.0 
Planned number of surveillance sites by specialty department  
Approximately 300 sites, including the internal medicine and neurosurgery departments 
 
7.0 
Methods 
7.1 Duration of observation 
12 months 
This surveillance will be ended when either criterion (1) or (2) specified below is found to be 
met. 
(1) If Takecab therapy is discontinued 
(2) If low-dose aspirin is discontinued 
If either a gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion develops during 
combination therapy with Takecab Tablets and low-dose aspirin, observation will be continued 
up to assessment of the post-treatment outcome of the ulcer/lesion and the surveillance will 
then be ended. 
 
7.2 Request to and contract with medical institutions 
The surveillance implementation will use a Web-based electronic data capture system 
(
). Upon request, a medical representative of 
 
(hereinafter referred to as “
”) will explain to the potential surveillance investigator 
about the surveillance objectives and contents, as well as how to use 
 and enter the 
electronic signature and handling of the user ID and the password according to the 
“Surveillance Implementation Outline,” “
 Data Entry screen images” and 
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“
 User Manual.” If the request is accepted, a written contract for the surveillance 
within the specified period will be made with the medical institution. 
 
 
7.3 Patient enrollment method 
Patients will be enrolled using a centralized enrollment method via 
. For patients 
prescribed Takecab Tablets on or after the first day of the contract period for the medical 
institution, the surveillance investigators will enter the patient information required for 
enrollment (see Section 9.1) and the electronic signature in 
 within 14 days after 
the prescription of Takecab Tablets (with the day of prescription counted as zero and the day 
following prescription counted as “1 day after prescription”). 
 
7.4 Data entry to the survey form (electronic) and electronic signature 
The surveillance investigator will enter data on patient demographics, treatment details, etc. 
and the electronic signature in 
, roughly within 1 month after the end of required 
observations at Month 12 of Takecab therapy. If administration of this drug could not be 
confirmed, this fact should be entered (no other data are required). 
 
For patients who discontinued treatment with Takecab Tablets for certain reasons during the 
observation period, the surveillance investigator will enter data on patient demographics, 
treatment details, etc. and the electronic signature in 
 roughly within 1 month after 
the end of required observations. However, for patients who discontinued Takecab therapy 
because of onset of an adverse event (AE), even after the discontinuation of this drug, the 
surveillance investigator will continue observation as far as possible up to resolution or 
improvement of the adverse event. The surveillance investigator will then enter the 
observation result and the electronic signature in 
. 
 
7.5 Actions taken for serious adverse events 
If any serious AE occurs during the observation period, the surveillance investigator will 
immediately report it to an 
 If requested by the 
, the surveillance 
investigator will provide detailed information separately. 
 
8.0 
Planned surveillance period 
Surveillance period: September 2016 to August 31, 2019 
Patient enrollment period: September 2016 to August 31, 2018 Note) 
Note) No patient enrollment (via 
) will be acceptable on or after September 1, 2018, 
even if Takecab is prescribed by August 31, 2018. 
If the total number of the enrolled patients in the entire surveillance reach the planned 
sample size before August 31, 2018, patient enrollment will be closed before the end of the 
patient enrollment period. If the patient enrollment period is shortened, the surveillance 
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period will also be changed according to the shortened enrollment period. 
 
9.0 
Surveillance items 
The surveillance investigator will enter data of the following items into 
. The 
surveillance schedule is shown in the Appendix. 
9.1 Patient enrollment 
1) Surveillance items 
Date of prescription of Takecab Tablets, patient identification number, patient initials, sex, 
date of birth, assessment against the inclusion criteria (details of the history of gastric or 
duodenal ulcer (time and site of onset)), assessment against the exclusion criteria 
2) Time of data collection 
At enrollment of the patient 
 
9.2 Patient demographics information 
1) Surveillance items 
Reason for use of low-dose aspirin, time of initiation of low-dose aspirin, coronary artery 
stent (presence or absence, and time), inpatient/outpatient classification (at initiation of 
Takecab therapy), hypersensitive diathesis (presence or absence, and details), complication 
(excluding the reason for use of low-dose aspirin: presence or absence, and details), height, 
weight, presence or absence of Helicobacter pylori infection (at initiation of Takecab 
therapy), smoking history, drinking history, presence or absence of stress as a risk factor of 
onset of gastric or duodenal ulcer, detailed use of acid secretion inhibitors for suppression 
of gastric or duodenal ulcer recurrence within 1 month before initiation of Takecab therapy 
(presence or absence, and name of drug) 
2) Time of data collection 
At initiation of Takecab therapy 
 
9.3 Treatment information 
1) Surveillance items 
Takecab therapy details (daily dose, therapy dates, and reason for discontinuation), 
low-dose aspirin therapy details (name of drug, daily dose, and therapy dates), reason for 
use of Takecab after the end of low-dose aspirin therapy, concomitant drug (other than 
low-dose aspirin) details (presence or absence, name of drug, and reason for use) 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy) 
 
9.4 Tests and observations 
9.4.1 Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of 
Takecab therapy 
1) Data items 
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Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion (presence or absence of 
onset, details, basis for the diagnosis, and date of endoscopy or diagnosis) 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy) 
 
9.4.2 Liver function tests 
1) Test parameters 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl 
transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH) 
2) Time of data collection 
At the testing from initiation of Takecab therapy* to Month 12 (or discontinuation of the 
therapy) 
*Within 1 month before initiation of Takecab therapy 
 
9.4.3 Serum gastrin 
1) Test parameter 
Serum gastrin level 
2) Time of data collection 
At the testing from initiation of Takecab therapy* to Month 12 (or discontinuation of the 
therapy) 
*Within 1 month before initiation of Takecab therapy 
 
9.4.4 Other items of observations 
1) Observation items 
Presence or absence of pregnancy during the observation period (only in women) 
Any pregnancy found during the observation period should be immediately notified to an 
. In response to a request by an 
, the surveillance investigator will 
provide detailed information (wherever possible up to the outcome of pregnancy, such as 
premature delivery) separately using a pregnancy report form. 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy) 
 
9.5 Adverse events 
1) Surveillance items 
Presence or absence of AEs (see Table 1), AE term, date of onset, seriousness and reason 
for the assessment as serious (see Table 2), reason for discontinuation of Takecab, 
outcome assessment date, outcome, causal relationship to Takecab* (see Table 3) 
If the outcome is “not resolved” or “unknown,” or if the causal relationship is 
“unassessable,” the event should be followed as far as possible. 
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Detailed event information (clinical course, results of diagnostic tests, etc.) should be 
collected as much as possible in the event of hepatic function disorder, fracture, 
gastrointestinal infection with Clostridium difficile, neuroendocrine tumor, or 
cardiovascular/cerebrovascular event. 
*If the causal relationship to Takecab is “Not related,” the basis for the assessment should be recorded. If 
the causal relationship to Takecab is “Unassessable,” the reason should be recorded. 
Note) Special guidance about reporting of AEs: 
Onset of a gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion, which is an efficacy 
endpoint, is not regarded as an AE. 
Serum gastrin can increase due to the pharmacological action of Takecab. However, if Takecab 
therapy is discontinued because of increased serum gastrin, this event should be handled as an AE. 
2) Time of data collection 
From initiation of Takecab therapy to Month 12 (or discontinuation of the therapy)  
 

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Table 1 Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product. 
Note that the following events will also be handled as adverse events:  
• 
Any manifestation in an infant breastfed by a mother taking this drug 
• 
Any untoward manifestation in a child given this drug 
• 
Any manifestation due to occupational exposure to this drug 
• 
Any manifestation due to a counterfeit product of a prescription drug marketed by Takeda 
• 
Any untoward manifestation in a patient given this drug revealed by a lawsuit or any other legal 
action 
 
Table 2 Criteria for Serious Adverse Events 
An adverse event is assessed as “serious” if it results in any of the following outcomes: 
1. results in death (Death), 
2. is life-threatening (Life-threatening), 
3. requires hospitalization or prolongation of existing hospitalization (Hospitalization/Prolongation of 
hospitalization), 
4. results in persistent or significant disability/incapacity (Disability), 
5. leads to a congenital anomaly or birth defect (Congenital anomaly), or 
6. is any other important medical event that does not fulfil 1 to 5 above. 
Serious adverse events include events described in the “Takeda Medically Significant AE List.”  
 
Takeda Medically Significant AE List 
- Acute respiratory failure / Acute respiratory 
distress syndrome (ARDS) 
- Torsade de pointes / Ventricular fibrillation / 
Ventricular tachycardia 
- Malignant hypertension 
- Convulsive seizure (including convulsion and 
epilepsy) 
- Agranulocytosis 
- Aplastic anaemia 
- Toxic epidermal necrolysis / Oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
- Hepatic necrosis 
- Anaphylactic shock 
- Acute renal failure 
- Pulmonary hypertension 
- Pulmonary fibrosis (including interstitial 
pneumonia) 
- Neuroleptic malignant syndrome/ Malignant 
hyperthermia 
- Spontaneous abortion / Stillbirth and fetal death 
- Confirmed or suspected transmission of infectious 
agent by a medicinal product 
- Confirmed or suspected endotoxin shock 
- Acute hepatic failure 
 

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Table 3 Assessment of the causal relationship between an adverse event and Takecab 
Causality classification 
Definition 
Related 
An adverse event that follows a temporal sequence from 
administration of this drug (including the course after withdrawal of 
the drug), or for which possible involvement of this drug can be 
considered, although factors other than this drug, such as the primary 
disease, complication, concomitant drugs or concurrent treatments, 
may also be responsible. 
Not related 
An adverse event that does not follow a temporal sequence from 
administration of this drug or that can reasonably be explained by other 
factors, such as the primary disease, complication, concomitant drugs 
or concurrent treatments. 
Unassessable 
The causality cannot be assessed because of insufficiency of required 
information, such as temporal sequence of the event onset relative to 
administration of this drug (including the course after withdrawal of 
the drug), primary disease, complication, concomitant drugs, and 
concurrent treatments. 
 
10.0 
Analysis items and methods 
10.1 Disposition of patients 
Number of patients enrolled, number of patients with collected survey forms (electronic), 
numbers of patients for safety and efficacy analyses, number of patients excluded from 
analysis, reasons for exclusion, etc. will be summarized. 
 
10.2 Patient demographics 
Patient demographic data such as sex, age, hypersensitive diathesis, and complication will be 
summarized. 
 
10.3 Treatment details 
Detailed use of Takecab, low-dose aspirin, and concomitant drugs (other than low-dose 
aspirin) will be summarized. 
 
10.4 Safety data 
The following data will be summarized using the safety analysis set. AEs will be coded using 
the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class (SOC). 
10.4.1 Incidence of adverse events 
AEs occurring during the observation period will be summarized using frequency count by 
event type, time of onset, seriousness, causal relationship to Takecab, etc. 
 

9 
10.4.2 Factors which may affect safety 
ADRs occurring during the observation period will be summarized using frequency count, 
with stratification of patients according to patient demographic factors (e.g., sex, age, 
reason for use of low-dose aspirin, any renal impairment, any hepatic impairment) and 
treatment details (e.g., detailed use of Takecab, detailed use of low-dose aspirin). 
 
10.5 Efficacy data 
The following data will be summarized using the efficacy analysis set. 
10.5.1 Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of 
Takecab therapy 
The presence or absence of onset of a gastric/duodenal ulcer or gastric/duodenal 
haemorrhagic lesion will be summarized. 
 
10.5.2 Factors which may affect efficacy 
The presence or absence of onset of a gastric/duodenal ulcer or gastric/duodenal 
haemorrhagic lesion will be summarized with stratification of patients according to patient 
demographic factors (e.g., sex, age, presence or absence of Helicobacter pylori infection) 
and treatment details (e.g., detailed use of Takecab, detailed use of low-dose aspirin). 
 
11.0 
Registration of surveillance information 
Before initiation of the surveillance, Takeda Pharmaceutical Company Limited will register 
the surveillance information with an online public clinical trials registry: 
- Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
 
12.0 
Administrative structure 
 
Takeda Pharmaceutical Company Limited 
 
13.0 
Trustees 
(1) 
 
 
 
(2) 
 
 
 
(3) 
 
 
 
 
(4) 
 
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14.0 
Other necessary items 
14.1 Protocol amendments 
During the surveillance period, monitoring will be performed regarding the progress of the 
surveillance, occurrence of ADRs unexpected from the PRECAUTIONS and serious ADRs, 
any increase in the incidence of particular ADRs, validity of the surveillance items, etc., and 
the protocol will be reviewed and amended as necessary. If any partial change to the DOSAGE 
AND ADMINISTRATION, INDICATIONS, etc. is approved during the surveillance period, 
whether or not the protocol should be amended will be examined, and the protocol will be 
amended as necessary. 
 
14.2 Actions to be taken in response to detection of any issues or concerns 
Whenever an issue is found regarding the safety or efficacy, the data will be investigated in 
detail, and necessary actions will be determined. 
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Appendix Observation schedule 
○     : Performed 
○     : Performed throughout the period 
         Time of data collection/entry 
 
 
Surveillance items 
Observation period 
At 
enrollment 
Start of 
Takecab 
therapy 
Month 
12 
Discontinuation 
of Takecab 
therapy 
Patient enrollment 
Date of prescription of Takecab Tablets 
○ 
 
 
 
Patient identification number 
○ 
 
 
 
Patient initials 
○ 
 
 
 
Sex 
○ 
 
 
 
Date of birth 
○ 
 
 
 
Assessment against inclusion criterion (details 
of history of gastric or duodenal ulcer) 
○ 
 
 
 
Assessment against exclusion criteria 
○ 
 
 
 
Patient demographics 
Reason for use of low-dose aspirin 
 
○ 
 
 
Time of initiation of low-dose aspirin 
 
○ 
 
 
Coronary artery stent 
 
○ 
 
 
Inpatient/outpatient classification 
 
○ 
 
 
Hypersensitive diathesis 
 
○ 
 
 
Complication (excluding the reason for use of 
low-dose aspirin) 
 
○ 
 
 
Height, weight 
 
○ 
 
 
H. pylori infection 
 
○ 
 
 
Smoking history 
 
○ 
 
 
Drinking history 
 
○ 
 
 
Presence or absence of stress as a risk factor of 
onset of gastric or duodenal ulcer 
 
○ 
 
 
Detailed use of acid secretion inhibitors for 
suppression of gastric or duodenal ulcer 
recurrence before initiation of Takecab therapy 
(within 1 month) 
 
○ 
 
 
Treatment details 
Detailed use of Takecab 
 
○ 
○ 
Detailed use of low-dose aspirin 
 
○ 
○ 
Reason for use of Takecab after the end of 
low-dose aspirin therapy 
 
○ 
 
Detailed use of concomitant drugs (other than 
low-dose aspirin) 
 
○ 
○ 
Assessments 
Gastric/duodenal ulcer or gastric/duodenal 
haemorrhagic lesion after initiation of Takecab 
therapy 
 
○ 
○ 
Liver function tests 
 
○Note) 
○ 
Serum gastrin 
 
○Note) 
○ 
Pregnancy (women only) 
 
○ 
○ 
AE monitoring 
 
○ 
○ 

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Note) From ≤1 month before initiation of Takecab therapy to Month 12