Special Drug Use Surveillance of Takecab Tablets for "Prevention of Recurrence of Gastric/Duodenal Ulcer in Patients Receiving Non-steroidal Anti-inflammatory Drugs: Long-term Use"
Conditions: A History of Gastric or Duodenal Ulcers
Sponsor: Takeda

 
 
Title: Takecab Tablets Special Drug Use Surveillance “ Suppression of gastric or 
duodenal ulcer recurrence on non-steroidal anti-inflammatory drugs: Long-term use” 
 
NCT Number: NCT03214198   
Protocol Approve Date: 12-JUN-2020 
 
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 non-steroidal anti-inflammatory drugs: Long-term 
use” 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol Number Vonoprazan-5005 
Version Number 
Version 5 
Date of 
preparation 
June 12, 2020 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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 .................................................................................................. 4 
8.0 
Planned surveillance period ..................................................................................................................... 4 
9.0 
Surveillance items .................................................................................................................................... 4 
9.1 
Patient enrollment .................................................................................................................................... 4 
9.2 
Patient demographics information ............................................................................................................ 4 
9.3 
Treatment information .............................................................................................................................. 5 
9.4 
Tests and observations .............................................................................................................................. 5 
9.4.1 
Gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion after initiation of Takecab therapy 
 
 .......................................................................................................................................................... 5 
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 ......................................................................................................................................... 6 
10.0 
Analysis items and methods ..................................................................................................................... 8 
10.1 
Disposition of patients .............................................................................................................................. 8 
10.2 
Patient demographics ............................................................................................................................... 8 
10.3 
Treatment details ...................................................................................................................................... 8 
10.4 
Safety data ................................................................................................................................................ 8 
10.4.1 
Incidence of adverse events .............................................................................................................. 8 
10.4.2 
Factors which may affect safety ....................................................................................................... 8 
10.5 
Efficacy data ............................................................................................................................................. 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 
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11.0 
Registration of surveillance information .................................................................................................. 9 
12.0 
Administrative structure ........................................................................................................................... 9 
13.0 
Contract Research Organizations ............................................................................................................. 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 
 
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1.0 
Background 
Administration of Takecab Tablets for suppression of gastric or duodenal ulcer recurrence on 
non-steroidal anti-inflammatory drugs (NSAIDs) 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 NSAIDs was evaluated for 24 weeks (168 days) or more in 166 
patients and 48 weeks (336 days) or more in 137 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 
NSAIDs 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 NSAIDs: Long-term use”: 12-month therapy in 46.1% 
 
4.0 
 Surveillance population 
This surveillance will enroll patients who are on NSAIDs (except low-dose aspirin) for control 
of pain of rheumatoid arthritis, osteoarthritis, and other diseases (including those who start 
Takecab therapy on the same day as the day of initiation of NSAIDs) and who meet the 
additional inclusion criterion and do not meet the exclusion criteria specified below. The 
PRECAUTIONS section of the Takecab package insert should also be referenced in the 
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enrollment judgment. 
4.1 Inclusion criterion 
Patients who are receiving NSAIDs (excluding low-dose aspirin) for pain control for rheumatoid 
arthritis, osteoarthritis, etc. (including patients who start Takecab therapy on the same day of 
initiation of NSAID) and also meet the following criteria will be included: 
Patients with a history of gastric or duodenal ulcer  
Refer to Precautions in the package insert. 
 
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 rheumatology and orthopedic surgery 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 NSAIDS are discontinued 
If either a gastric/duodenal ulcer or gastric/duodenal haemorrhagic lesion develops during 
combination therapy with Takecab Tablets and NSAIDs, 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 representative of Takeda Pharmaceutical Company Limited. 
(hereinafter referred to as “Takeda representative”) 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 
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“Request for Cooperation with Special Drug Use Surveillance,” “Surveillance Implementation 
Outline,” “
 Data Entry screen images” and “
 User Manual (brief version).” 
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 or the persons designated by the surveillance investigator* will 
enter data on patient demographics, treatment details, etc. for all the enrolled patients in 
, and the surveillance investigator will provide the electronic signature, 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 or the persons designated by the surveillance 
investigator will enter data on patient demographics, treatment details, etc. in 
, and 
the surveillance investigator will provide the electronic signature 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 or the persons designated by 
the surveillance investigator will then enter the observation result in 
, and the 
surveillance investigator will provide the electronic signature. 
 
*The persons designated by the surveillance investigator should be persons who belong to the 
surveillance site (including persons with a service contract with the surveillance site such as a 
dispatched clinical research coordinator). The physician responsible for implementation of the 
surveillance (1 each from the surveillance sites or treating departments, determined at the time 
of diagnosis) will prepare the records of designation and the date of designation (any format 
allowed) and submit them with his/her signature or printed name and seal to the Takeda 
representative before the persons designated by the surveillance investigator enter data in 
. 
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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 a Takeda representative. If requested by the Takeda representative, the 
surveillance investigator will provide detailed information separately. 
 
8.0 
Planned surveillance period 
Surveillance period: September 2016 to April 30, 2020 
Patient enrollment period: September 2016 to April 30, 2019 Note) 
Note) No patient enrollment (via 
) will be acceptable on or after May 1, 2019, even if 
Takecab is prescribed by April 30, 2019. 
If the total number of the enrolled patients in the entire surveillance reach the planned sample 
size before April 30, 2019, patient enrollment will be closed before the end of the patient 
enrollment period. If the patient enrollment period is shortened, the surveillance period will 
also be changed according to the shortened enrollment period. 
 
9.0 
Surveillance items 
The surveillance investigator or the persons designated by 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 NSAIDs, time of initiation of NSAIDs, inpatient/outpatient classification 
(at initiation of Takecab therapy), hypersensitive diathesis (presence or absence, and 
details), complication (excluding the reason for use of NSAIDs: 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 
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9.3 Treatment information 
1) Surveillance items 
Takecab therapy details (daily dose, therapy dates, and reason for discontinuation), NSAID 
therapy details (name of drug, daily dose, and therapy dates), reason for use of Takecab 
after the end of NSAID therapy, concomitant drug (other than NSAIDs) 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 
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 a 
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Takeda representative. Based on a request by a Takeda representative, 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. 
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, or neuroendocrine tumor. 
*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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with stratification of patients according to patient demographic factors (e.g., sex, age, 
reason for use of NSAIDs, any renal impairment, any hepatic impairment) and treatment 
details (e.g., detailed use of Takecab, detailed use of NSAIDs). 
 
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 NSAIDs). 
 
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 
- National Institute of Health Clinical Trial Registration System: Clinical Trials.gov 
 
12.0 
Administrative structure 
Responsible Manager 
Post-marketing surveillance manager, Takeda Pharmaceutical Company Limited 
 
13.0 
Contract Research Organizations 
(1) A2 Healthcare Corporation 
Address: 1-4-1, Koishikawa, Bunkyo-ku, Tokyo 
Duties: Data management and statistical analysis 
 
(2) PRA Health Sciences K.K. 
Address: 4-1-3, Kyutaromachi, Chuo-ku, Osaka-shi, Osaka 
Duties: Data management, storage of records, PDF conversion of AE reports and 
supportive activities related to dissemination of information 
 
(3) Fujitsu FIP Corporation 
Address: 2-2-2, Nakanoshima, Kita-ku, Osaka-shi, Osaka 
Duties: 
 construction and operation 
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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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