The Special Drug Use-results Survey on Long-term Use of Telmisartan 80 mg/Amlodipine 5 mg/Hydrochlorothiazide 12.5 mg Fixed Dose Combination Tablets in Patients With Hypertension
Conditions: Hypertension
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Non-interventional Study Protocol
Document Number:
c04592560-02
BI Study Number:
1348.6
BI Investigational
Product(s):
Telmisartan / amlodipine / hydrochlorothiazide combination 
tablets
Title:
The special drug use-results survey on long-term use of
telmisartan 80 mg/amlodipine 5 mg/hydrochlorothiazide 12.5 mg
fixed dose combination tablets in Patients with Hypertension
Protocol version 
identifier:
2.0
Date of last version of 
protocol:
16 October 2015
PASS:
Yes
EU PAS register 
number:
Not applicable
Active substance:
Telmisartan (C09CA07) / amlodipine (C08CA01) / 
hydrochlorothiazide (C03AA03)
Medicinal product:
Micatrio® Combination Tablets
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Nippon Boehringer Ingelheim Co., Ltd.
Joint PASS:
No
Research question and 
objectives:
To evaluate real-world safety, effectiveness and appropriate use
of Micatrio® Combination Tablets treatment in patients with 
hypertension
Country(-ies) of study:
Japan
Author:
Phone: 
Fax: 
Marketing authorisation 
holder(s):
Nippon Boehringer Ingelheim Co., Ltd.

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Non-interventional Study Protocol
BI Study Number 1348.6
c04592560-02
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Date:
12 December 2016
Page 1 of 32
Proprietary confidential information
© 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 11
6.
MILESTONES..................................................................................................... 12
7.
RATIONALE AND BACKGROUND................................................................ 13
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 15
9.
RESEARCH METHODS .................................................................................... 16
9.1
STUDY DESIGN............................................................................................ 16
9.2
SETTING........................................................................................................ 16
9.2.1
Site selection ........................................................................................... 16
9.2.2
Selection of population............................................................................ 17
9.2.2.1
Inclusion / exclusion criteria ................................................................ 17
9.2.2.2
Registration period ............................................................................... 17
9.2.2.3
Patient registration method................................................................... 17
9.2.3
Discontinuation of the study by the sponsor ........................................... 17
9.3
VARIABLES .................................................................................................. 18
9.3.1
Exposures ................................................................................................ 18
9.3.2
Outcomes................................................................................................. 18
9.3.3
Other........................................................................................................ 19
9.4
DATA SOURCES........................................................................................... 20
9.5
STUDY SIZE.................................................................................................. 20
9.6
DATA MANAGEMENT................................................................................ 21
9.7
DATA ANALYSIS......................................................................................... 21
9.7.1
Analyses of outcome events.................................................................... 22
9.7.2
Safety analyses ........................................................................................ 22
9.7.3
Effectiveness analyses............................................................................. 22
9.7.4
Interim analyses....................................................................................... 22
9.8
QUALITY CONTROL................................................................................... 23
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 23
9.10
OTHER ASPECTS ......................................................................................... 23
9.10.1
Informed consent, data protection, study records ................................... 23

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9.10.1.1 Study approval, patient information and informed consent ................. 23
9.10.1.2 Data quality assurance.......................................................................... 23
9.10.1.3 Records................................................................................................. 23
9.10.1.3.1 Source documents.............................................................................. 23
9.10.1.3.2 Direct access to source data and documents...................................... 24
9.10.1.4 Statement of confidentiality ................................................................. 24
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 25
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 26
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 26
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING.... 27
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30
13.2
UNPUBLISHED REFERENCES................................................................... 30
ANNEX 1. SUMMARY OF SAFETY SPECIFICATION in Local RMP .................. 31
ANNEX 2. GRADE FOR RENAL AND HEPATIC DYSFUNCTION...................... 32

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ARB
Angiotensin II receptor blocker
CCB
Calcium channel blocker
CRF
Case Report Form
CTP
Clinical Trial Protocol
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EU-QPPV
European Union-Qualified Person for Pharmacovigilance
FDC
Fixed-dose combination
GPSP
Good Post-marketing Study Practice
HCTZ
Hydrochlorothiazide
J-RMP
Japanese Risk Management Plan
MedDRA
Medical Dictionary for Regulatory Activities
NBI
Nippon Boehringer Ingelheim Co., Ltd.
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
PSUR
Periodic Safety Update Report
SAE
Serious Adverse Event
TSAP
Trial Statistical Analysis Plan

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3.
RESPONSIBLE PARTIES
Nippon Boehringer Ingelheim Co., Ltd.
Contact details and the list of all investigators will be kept in a stand-alone document. This 
document will be managed in the special drug use-results survey tracking system which 
manages the contracts with site and investigators name.

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4.
ABSTRACT
Name of company:
Nippon Boehringer Ingelheim Co., 
Ltd.
Name of finished medicinal 
product:
Micatrio® Combination Tablets
Name of active ingredient:
Telmisartan (C09CA07) / 
amlodipine (C08CA01) / 
hydrochlorothiazide (C03AA03)
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
12 December 2016
1348.6
2.0
16 October 2015
Title of study:
The special drug use-results survey on long-term use of telmisartan 80 
mg/amlodipine 5 mg/hydrochlorothiazide 12.5 mg fixed dose 
combination tablets in Patients with Hypertension
Trial Clinical Monitor : 
Rationale and 
background:
The Japanese Law for Ensuring the Quality, Efficacy, and Safety of 
Drugs and Medical requires accumulating safety and effectiveness data 
of launched products in Japan for re-examination. The PMS plan is a 
part of the J-RMP. The J-RMP was submitted to the PMDA as a part 
of J-CTD and need to be approved by PMDA as approval condition. 
After 4 or 6 years from approval, the results of the PMS are needed to 
be submitted to the Japanese regulatory authority, the PMDA, as a part 
of the re-examination dossier.
Research question 
and objectives:
This PMS is designed to investigate the safety, effectiveness and 
appropriate use of Micatrio® Combination Tablets in patients with 
hypertension under real-world use according to the Japanese package 
insert.
Study design:
Non-interventional study based on newly collected data.
The study will consist of a baseline visit and follow-up visits at Week 
4, 8, 12, 24, 36 and 52 for patients who have newly initiated Micatrio®
Combination Tablets. The patients will be followed up until 
discontinuation of Micatrio® Combination Tablets treatment or the end 
of study.
All patients administrated Micatrio® Combination Tablets after the 
launch at the sites contracted with the sponsor will be registered.

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Name of company:
Nippon Boehringer Ingelheim Co., 
Ltd.
Name of finished medicinal 
product:
Micatrio® Combination Tablets
Name of active ingredient:
Telmisartan (C09CA07) / 
amlodipine (C08CA01) / 
hydrochlorothiazide (C03AA03)
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
12 December 2016
1348.6
2.0
16 October 2015
Population:
Patients who diagnosed with hypertension based upon the most recent 
JSH guideline, and who comply with inclusion and exclusion criteria 
may qualify for participation in this study. (if applicable)
Inclusion criteria
-
Patients who are prescribed with Micatrio® Combination Tablets
by the discretion of investigators based on the Japanese package 
insert
-
Patients who have never been treated with Micatrio®
Combination Tablets before enrolment
Exclusion criteria
-
Patients who are participating/ planned to participate in a clinical 
trial.
*Contraindication as per Japanese Package Insert should be respected.
Variables:
Exposure to Micatrio® Combination Tablets is estimated as time from 
the day Micatrio® Combination Tablets is initiated until the day the 
drug is last administrated on a patient-level (or the final contact with  
last regular observation) and considering dosage.
Outcomes: 
Safety
Any suspected ADRs (primary outcome), Serious AEs, AEs for 
important identified risks and AEs for important potential risks
Effectiveness
Effectiveness will be assessed with a focus on the following variable as 
secondary outcome.
-
Change from the baseline in clinic diastolic blood pressure 
(DBP)[mmHg] at Week 52
-
Change from the baseline in clinic systolic blood pressure 
(SBP)[mmHg] at Week 52
Others
Demographics, Administration of Micatrio® Combination Tablets,
adherence, Previous/Concomitant medications, Blood pressure, 
controlled hypertension, pulse rate and Laboratory tests

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Name of company:
Nippon Boehringer Ingelheim Co., 
Ltd.
Name of finished medicinal 
product:
Micatrio® Combination Tablets
Name of active ingredient:
Telmisartan (C09CA07) / 
amlodipine (C08CA01) / 
hydrochlorothiazide (C03AA03)
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
12 December 2016
1348.6
2.0
16 October 2015
Data sources:
CRFs for individual patients will be gathered by the EDC system.
After the medical examination and observation at the specified points
(Baseline, Week 4, 8, 12, 24, 36 and 52 or discontinuation) are 
completed, the investigator needs to immediately enter data of the 
registered patients (including withdrawals and dropouts) in the EDC.
Two case books will be used, data are to be transmitted immediately
after being entered into EDC at Week 8 (Book 1) and Week 52 (Book 
2) after the start of treatment or at discontinuation. 
In case that any adverse events occur, the data should be immediately 
entered into EDC and transmitted.
Study size:
500
Data analysis:
Due to the nature of the observational study, no confirmatory statistical 
testing is foreseen in this study. Analyses are descriptive in nature 
including means, standard deviation, min, Q1, medians, Q3, max, 
frequency and percentages.
Milestones:
Start of data collection: 20 January 2017
End of data collection: 30 April 2019 (in plan)
Interim report: After Week 8 data will be collected
Final report of study results: 1Q 2020(in plan)

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Figure 1
Flow chart
Time
Item
Observation period
Baseline
(before 
treatment
of 
Micatrio®
Combinati
on 
Tablets)
4W
8W
(or at 
disco
ntinua
tion)
12W
24W
36W
52W
(or at 
disco
ntinua
tion)
Patient registration*1
X
Patient demographics
X
Administration of 
Micatrio® Combination 
Tablets
X (to be reported throughout the observation period)
Previous/concomitant 
medications
X (to be reported throughout the observation period)
Administration/adherence of 
previous anti-
hypertensivemedications*2
X
Adherence of Micatrio®
Combination Tablets
X
X
X
X
X
X
Blood pressure, pulse rate
X*4
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
Adverse events
X (to be reported throughout the observation period)
EDC transmitted time*3
-----------------X (Book1)
----------------------X (Book2)
Observation / Evaluation time points are approximate. Collected data should be reported as 
those to the closest available visit.
*1: Patients administered Micatrio® Combination Tablets will be registered within 14 days 
whenever the day of first administration is possible.
*2: Previous anti-hypertensive medications*3: eCRF (electric case report form): Data are to 
be transmitted immediately after being entered into the eCRF at 8 weeks and 52 weeks after 
the start of treatment or at discontinuation. In case of occurrence of any adverse events, the 
data should be immediately entered into the eCRF and transmitted.
*4: Two points (baseline and before a certain period from treatment of Micatrio® 
Combination Tablets)

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
2.0
12 December 
2016
Study size
Change the size
Decreased
estimate
number of 
patient due to 
changed 
“Precautions 
with related to 
dosage and 
administration
”
Milestones
Change the study 
period
Approved 
behind 
schedule
Planned 
number of 
sites
Change the size
Decreased
estimate
number of 
patient due to 
changed 
“Precautions 
with related to 
dosage and 
administration
”
Data 
management
Change name of 
CRO
CRO changed 
their name
ANNEX 1. 
Summary of 
safety 
specification 
in local 
RMP
Add events
Direction from
PMDA

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
20 January 2017
End of data collection
30 April 2019 (in plan)
Registration in the EU 
PASS register
Final report of study results
1Q 2020 (in plan)

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7.
RATIONALE AND BACKGROUND
Blood pressure in hypertensive patients is rarely controlled to an optimal level by one 
drug alone, often combination of 2 or more drugs is essential to achieve a sufficient 
antihypertensive effect. Therefore JSH 2014 recommended to combine 3 agents in 
patients with inadequate control when treated with 2 antihypertensive agents. In addition, 
JSH 2014 mentions that as the use of small dose of a diuretic rarely causes adverse 
effects and synergistically increases the hypotensive effect when used with other 
antihypertensive drugs, it should be used positively in combination therapy.
Micatrio® Combination Tablets is a fixed-dose combination (FDC) tablet of telmisartan, 
amlodipine and hydrochlorothiazide (HCTZ). Each component of the triple FDC tablet 
of telmisartan, amlodipine and HCTZ is already approved and marketed in Japan as 
shown below.
Telmisartan is an Angiotensin II receptor blocker (ARB) synthesised by Boehringer 
Ingelheim GmbH. The efficacy and safety in a dose range of 20 to 80 mg once daily. 
Telmisartan was approved in October 2002 and marketed in December 2002. The tablet 
form was later developed to adjust dosage easily and to improve adherence. The 
telmisartan tablet was approved in August 2004 and marketed in January 2005 in Japan.
Amlodipine besylate is a long-acting Calcium channel blocker (CCB). The onset of 
action of amlodipine is slow and persistent. Once daily dosing of amlodipine provides 
antihypertensive and antianginal effects over 24 hours. In Japan, clinical trials in patients 
with hypertension or angina pectoris were started in 1986, and demonstrated that it has 
good antihypertensive effect with 2.5-5.0 mg once daily. Amlodipine was approved in 
October 1993. A dose increase of up to 10 mg was approved for hypertention in 
February 2009. The clinically recommended dose is 2.5-5.0 mg in Japan.
Hydrochlorothiazide is a diuretic of the benzothiadiazide class marketed in 1959 in 
Japan. It has been used in clinical practice for a long time. The action mechanism is 
thought to lower blood pressure through decreasing cardiac output, reducing plasma and 
extracellular fluid volume and reducing peripheral vascular resistance over the long term 
by inhibiting the reabsorption of sodium ions at the distal renal tubule and increasing the 
excretion of sodium and water. The approval dosage is 25-100 mg/day in Japan.
The FDC of telmisartan and HCTZ was approved as the combination of telmisartan 40 
mg and HCTZ 12.5 mg and the combination of telmisartan 80 mg and HCTZ 12.5 mg 
those names are Micombi® AP and Micombi® BP respectively in April 2009 in Japan. 
And the FDC of telmisartan and amlodipine was approved as the combination of 
telmisartan 40 mg and amlodipine 5 mg whose name is Micamlo® AP in July 2010 and 
as the combination of telmisartan 80 mg and amlodipine 5 mg whose name is Micamlo®
BP in December 2012 in Japan.
In clinical trials, safety of Micatrio® Combination Tablets has been evaluated in the 2 Phase 
III clinical trials, 1348.1 and 1348.2 conducted in Japan for the patients with essential 
hypertension. In the 1348.1 study, T80/A5+H12.5 mg or T80/A5 mg was administered to 
patients showing poor antihypertensive response to treatment with T80/A5 mg, and safety 

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was evaluated for 309 patients. In the 1348.2 study, T80/A5/H12.5 mg or T80/H12.5 mg was 
administered to patients showing poor antihypertensive response to treatment with T80/H12.5 
mg, and safety was evaluated for 132 patients. In addition, in the 1348.2 study, T80/H12.5 
mg combination product + A5 mg was administered for 52 weeks in the extension period 
after the double-blind period and long-term safety was investigated for 129 patients.
In the T80/H12.5/A5 mg group, common events were blood uric acid increased (9.2%), 
nasopharyngitis (6.9%) and hyperuricaemia (3.7%). Frequencies of blood uric acid increased 
and hyperuricaemia were higher than those in the T80/H12.5 mg group or the T80/A5 mg 
group. In the T80/H12.5/A5 mg group, common adverse events were all mild in severity, and 
causal relationship with the study drug was denied in all of these events except all the events 
of blood uric acid increased and hyperuricaemia. All adverse reactions in the T80/H12.5/A5 
mg group were already known to occur in Micamlo® Combination Tablets or Micombi®
Combination Tablets, and no event was newly found in combination with telmisartan, 
amlodipine and hydrochlorothiazide.
Japanese regulation related to Post Marketing Surveillance (PMS)
This PMS is planned according to the Japanese Law for Ensuring the Quality, Efficacy, 
and Safety of Drugs and Medical. The law requires in principle that data on the safety 
and effectiveness of all launched products to be accumulated under real-world clinical 
practice. The PMS is a part of the local Risk Management Plan in Japan (J-RMP) to be 
submitted to PMDA at New Drug Application. After 4 or 6 years from approval of 
registration, the data collected in the PMS are required to be submitted to the 
Pharmaceuticals and Medical Devices Agency (PMDA), the local regulatory agency in 
Japan according to the process of re-examination.

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8.
RESEARCH QUESTION AND OBJECTIVES
This PMS is designed to investigate the safety, effectiveness and appropriate use of 
Micatrio® Combination Tablets in patients with hypertension under real-world use
according to the Japanese package insert.
The number of elderly patients was small in clinical trials (34/217[5.7%] in 1348.1 and 
1348.2 studies). Also data in Japanese patients and in patients who were administered 
Micatrio® Combination Tablets for a long period are limited (see Section 7).

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on new data collection to gather real-world 
information (i.e., data under routine medical practice) on safety and effectiveness of the 
Micatrio® Combination Tablets treatment.
The study will be initiated after the approval of Micatrio® Combination Tablets in Japan. 
The study will consist of a baseline visit and follow-up visits at Week 4, 8, 12, 24, 36 
and 52 for patients who have newly initiated Micatrio® Combination Tablets. The 
patients will be followed up until discontinuation of Micatrio® Combination Tablets
treatment, death or the end of study.
As this is an observational study, no specific treatment is mandated or withheld from the 
patients. The choice of maintenance treatment for hypertension must be according to 
regular medical practice and at the discretion of the physician (i.e., no randomised 
assignment of patient to treatment is performed).
All patients administrated Micatrio® Combination Tables after the launch at the sites 
contracted with the sponsor will be registered.
Patients participating in the subsequent follow-up will undergo regular observations.
These observations should be reported after approximately Week 4, 8, 12, 24, 36 and 52
since the initiation of Micatrio® Combination Tablets as long as they continue to receive 
the treatment. Patients will not be followed any longer once they are reported to have 
discontinued the Micatrio® Combionation Tablets treatment.
The primary outcome of this study is the frequency of patients with any suspected 
adverse drug reactions (ADRs)
The secondary outcome of this study is change from baseline in blood pressure at Week 
52.
9.2
SETTING
9.2.1
Site selection
Nippon Boehringer Ingelheim (NBI) will nominate the candidate sites which satisfy the 
following criteria and NBI ask the nominated sites to participate in the study.
1. Micatrio® Combination Tablets has been delivered to the site.
2. A medical representative will explain the objectives and design of this study
to the investigators at study sites and exchange a written contract with the 
head of the study site (e.g., hospital director).
Planned number of sites: Approximately 100 sites

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9.2.2 Selection of population
9.2.2.1
Inclusion / exclusion criteria
Inclusion criteria
•
Patients who are prescribed with Micatrio® Combination Tablets by the discretion of 
investigators based on the Japanese package insert
•
Patients who have never been treated with Micatrio® Combination Tablets 
before enrolment
Exclusion criteria
•
Patients who are participating/planned to participate in a clinical trial.
*Contraindication as per Japanese Package Insert should be respected.
9.2.2.2
Registration period
From 1 January 2017 to 31 January 2018 (System for registration will be available from 1 
February 2017)
9.2.2.3
Patient registration method
The registration method will be a continuous investigation system. Patients who begin 
treatment with Micatrio® Combination Tablets after the conclusion of the contract will 
be registered by entering necessary information in the EDC within 14 days whenever 
possible from the day of treatment initiation (inclusive).
Patient registration will stop when the target number of the study is reached. After the 
end of the registration period, investigators will use a signed form to confirm that 
patients will be registration continuously at the site. A log of all patients included into 
the study will be maintained at the site.
Patients will be registered by entering necessary information in the electronic data 
capture (EDC) system just after initiation of administration of Micatrio® Combination 
Tablets. The necessary information for registration are gender, date of birth, start date of 
administration,  reason for use of Miactrio® Combination Tablets and previous anti-
hypertensitive medicatons. 
After the end of registration, investigators will use a signed form to confirm that all 
patients were registered at the site.
9.2.3 Discontinuation of the study by the sponsor
A log of all patients included into the study will be maintained at the investigational 
sites.
NBI reserves the right to discontinue the study overall or at a particular study site at any 
time for the following reasons:
1. Failure to meet expected registration goals overall or at a particular study site

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2. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study
3. Violation of Good Post-marketing Study Practice (GPSP), the NIS protocol, or the 
contract by a study site or investigator, disturbing the appropriate conduct of the study
The study site will be reimbursed for reasonable expenses incurred in case of study 
termination (except in case of the third reason).
9.3
VARIABLES
9.3.1 Exposures
Exposure to Micatrio® Combination Tablets is estimated as time from the day Micatrio®
Combination Tablets is initiated until the day the drug is last administrated on a patient-
level and considering dosage.
Dosage and administration: Usually for adults, this fixed dose combination 
(telmisartan/amlodipine/hydrochlorothiazide 80 mg/5 mg/12.5 mg) is orally 
administered once a day.
9.3.2 Outcomes
Safety
Safety will be assessed with a focus on the following variables, frequencies and 
percentages.

Any suspected ADRs (primary outcome)

Serious AEs
 
How to assess and report AEs including the definitions are described in section 11.
Effectiveness
Effectiveness will be assessed with a focus on the following variable as secondary 
outcome.

Change from the baseline in clinic diastolic blood pressure (DBP)[mmHg] at Week 
52

Change from the baseline in clinic systolic blood pressure (SBP)[mmHg] at Week
52

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9.3.3 Other
Baseline characteristics and observation items
The following items, demographics, previous/concomitant medications, blood pressure, 
pulse rate, laboratory tests will be considered as the minimum baseline characteristics. 
During the observation period, administration of Micatrio® Combination Tablets is also 
added. For all interventions/measures dates will be recorded.
Demographics:

Age

Diagnosis

Diagnosis start date

Weight

Height

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Administration of Micatrio® Combination Tablets:

Treatment period (Start date, end data)

Primary reason of discontinuation

Adherence
Previous/Concomitant medications:
Blood pressure, pulse rate:
Laboratory tests (if applicable):
 
9.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be gathered by the EDC system.
In the EDC system, two case books will be set up; Book 1 includes baseline, Week 4 and 8. 
Book 2 includes Week 12, 24 and 52.
Data are to be transmitted immediately after being entered into the EDC system at Week 8 
(Book 1) and Week 52 (Book 2) after the start of treatment or at discontinuation.
For any adverse events, the data should be immediately entered into the EDC system and 
transmitted. 
9.5
STUDY SIZE
It is planned to collect 500 patients with hypertension.

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With a sample size of 500 patients, any ADR with frequency of 0.6% or higher can be 
detected with probability of 95% or greater in at least one patient. 
- Long-time use:
In Micombi® combination tablets AP/BP PMS (502.542) and Micamlo® combination tablets 
AP PMS (1235.38), the ratio of patients that each drug was used more than 52 weeks was 
48.7% in 502.542 and 45.7% in 1235.38. Assuming collection of data from 500 patients, at 
least 200 patients (based on lower bound of 95% confidence interval for point estimate of 
45.7% in 1235.38) will be used more than 52 weeks.
- Elderly:
In Micardis® tablets PMS (502.500), Micombi® combination tablets AP/BP PMS (502.542) 
and Micamlo® combination tablets AP PMS (1235.38), the ratio of elderly (more than 65 yrs / 
more than 75yrs) patients was 54.2% / 22.1% in 502.500, 66.7% / 36.8% in 502.542 and 
57.9% / 48.7% in 1235.38. Assuming collection of data from 500 patients, at least 260
patients more than 65 yrs old (based on lower bound of 95% confidence interval for point 
estimate of 54.2% in 502.500) and 125 patients more than 75 yrs old  (based on lower bound 
of 95% confidence interval for point estimate of 22.1% in 502.500) will be collected.
- Patients with renal dysfunction:
In Micombi® combination tablets AP/BP PMS (502.542) and Micamlo® combination tablets 
AP PMS (1235.38), the ratio of patients with renal dysfunction was 8.8% in 502.542 and 
9.6% in 1235.38. Assuming collection of data from 500 patients, at least 30 patients with 
renal dysfunction (based on lower bound of 95% confidence interval for point estimate of 
8.8% in 502.542) will be collected.
9.6
DATA MANAGEMENT
Patients’ data will be gathered by the EDC system provided by external vendor below.
Contract research organizations 1
Name
9.7
DATA ANALYSIS
This is a non-interventional study based on new data collection to gather real-world 
information (i.e., data under routine medical practice) on safety and effectiveness of the 
Micatrio® combination tablets treatment in patients with hypertension. Analyses for safety, 
effectiveness and baseline characteristics are descriptive in nature including means, standard 
deviation, min, Q1, medians, Q3, max, frequency and percentages.
Per local regulation, any patient who meets at least one of the following criteria is treated as 
ineligible for all analyses: 
No follow-up visit data are available

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No required registration procedure is followed
No valid site contract is available
9.7.1
Analyses of outcome events
All outcome events are based on reported AE data which will be handled according to BI 
standards (see the section below).
9.7.2
Safety analyses
The safety analysis will include all patients registered in the study and receiving the 
Micatrio® combination tablets treatment except for who meet the ineligible criteria.
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To this 
end, all AEs occurring between first intake of Micatrio® combination tablets prescribed at 
baseline visit and within 1 days (inclusive) after the last intake will be considered ‘treatment 
emergent’. An AE is considered to be an ADR if either the physician who has reported the 
AE or the sponsor assesses its causal relationship as ‘related’.
The frequency and percentages of ADRs, SAEs, and other AEs will be tabulated by system 
organ class and preferred term for overall and for subgroups based on the important baseline 
characteristics (details will be described in the TSAP).
No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard.
Descriptive statistics will be calculated for pulse rate.
9.7.3
Effectiveness analyses
Descriptive statistics will be calculated for continuous secondary 
 
For overtime the descriptive statistics will be provided by visit, including actual values and 
change from baseline
No imputation is planned for missing value of blood pressure.
9.7.4
Interim analyses
Several interim analyses will be performed for the purpose of creating Japanese Periodic 
Safety Update Reports (PSUR) to the Japanese authority (every 6 to 12 months depending on 
the time from the approval).

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9.8
QUALITY CONTROL
All processes are conducted according to GPSP SOPs <102-MLS-90-119> and GPSP 
working instruction <102-MLW-90-118-51>. Appropriate records and documents are stored 
based on the GPSP SOPs and these processes are checked by internal self-check.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The general scientific objective of this non-interventional study is to obtain an estimate of the 
occurrence of the adverse events in the population under study. Due to the nature of a single 
cohort observational study, however, there are issues that may impose limitations in 
particular on the validity of the assessment based on the study data such as selection bias, loss 
to follow up, channeling bias and information and recall bias. Thus, comparisons and causal 
conclusions cannot be made, except for the investigator reported drug-related AEs.
9.10
OTHER ASPECTS
9.10.1
Informed consent, data protection, study records
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the patient’s treating physician.
The rights of the investigator and of the sponsor with regard to publication of the results of 
the use-results survey are described in the contract. As a general rule, no results should be 
published prior to finalization of the Study Report.
9.10.1.1
Study approval, patient information and informed consent
The review by Institutional Review Board (IRB) is not mandatory for conducting the PMS in 
Japanese GPSP. The sponsor will enter into a contract with a representative (i.e., head of 
hospital) in accordance with GPSP. Written informed consent prior to patient participation in 
the trial is not a regulatory or legal requirement in accordance with GPSP.
9.10.1.2
Data quality assurance
This PMS is to be conducted in accordance with both the in-house PMS SOP and working 
instructions which are in compliance with GPSP.
9.10.1.3
Records
CRFs for individual patients will be provided by the sponsor via the EDC system.
9.10.1.3.1 Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 

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medical records must be available. For eCRFs, all data must be delivered from source 
documents.
9.10.1.3.2 Direct access to source data and documents
Direct access to source data and documents for PMS is not allowed in Japan.
9.10.1.4
Statement of confidentiality
Individual patient medical information obtained as a result of this PMS is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Data generated as a result of the PMS needs to be submitted on request by the regulatory 
authorities.

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10.
PROTECTION OF HUMAN SUBJECTS
There is no need for a clinical trial type insurance of well-being and rights of participants 
because this is a non-interventional study and there is no risk of an experimental treatment. 
There is no regulation or requirement for ensuring the well-being and rights of participants.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalization, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasia or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Adverse Event of Special Interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this 
study, e.g. the potential for AEs based on knowledge from other compounds in the same 
class. 

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No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection and Reporting of AEs 
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the (e) CRF via the EDC system from 
first intake of Micatrio® Combination Tablets at baseline visit and within 1 day (inclusive) 
after last intake.
-
all AEs (serious and non-serious)
-
all ADRs and AEs with fatal outcome in patients exposed to Micatrio® Combination 
Tablets as soon as possible 
All AEs including those persisting after study completion must be followed up until they are 
resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event:
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
-
An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal

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relationship could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:            Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
The intensity of adverse events should be classified and recorded according to the above 
referenced definition in the (e)CRF.
Pregnancy
In rare cases, pregnancy might occur in a study. Once a subject, has been enrolled into the 
study after having taken Micatrio® Combination Tablets, the investigator must report any 
drug exposure during pregnancy which occurred in a female subject or in a partner to a male 
subject to the Sponsor by means of Part A of the Pregnancy Monitoring Form. The outcome 
of the pregnancy associated with the drug exposure during pregnancy must be followed up 
and reported by means of Part B of the Pregnancy Monitoring Form.
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed. 
The investigator will report the Pregnancy Monitoring Forms as soon as possible via the 
unique entry point described in the Site Materials.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
the Micatrio® Combination Tablets according to the local regulatory requirements for 
spontaneous AE reporting at the investigator’s discretion by using the locally established 
routes and AE report forms. The term AE includes drug exposure during pregnancy, and, 
regardless of whether an AE occurred or not, any abuse, off-label use, misuse, medication 
error, occupational exposure, lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The interim and final report will be submitted PMDA in Japanese Periodic Safety Update 
Report (PSUR) and re-examination documents. And the interim and final report are also 
planned to be used for related publications.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
Not applicable.
13.2
UNPUBLISHED REFERENCES
 
 
 

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ANNEX 1. SUMMARY OF SAFETY SPECIFICATION IN LOCAL RMP
 
 

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ANNEX 2. GRADE FOR RENAL AND HEPATIC DYSFUNCTION
Investigator should judge the grade for renal dysfunction by using lab data category as
described below and symptoms/concomitant diagnoses.
Enzymatic method:
eGFR（mL/min/1.73 m2）= 194×Creatinine（mg/dL）－1.094×Age－0.287
For female, ×0.739
Jaffe rate assay:
eGFR（mL/min/1.73 m2）= 175×Creatinine（mg/dL）－1.154×Age－0.203
For female, ×0.742

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c04592560
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clinical-trial-protocol
The special drug use-results survey on long-term use of telmisartan 80
mg/amlodipine 5 mg/hydrochlorothiazide 12.5 mg fixed dose combination tablets in
Patients with Hypertension
Approval-Trial Clinical Monitor
13 Dec 2016 03:30 CET
Approval-
 Pharmacovigilance
13 Dec 2016 03:32 CET
Author-Trial Statistician
13 Dec 2016 03:45 CET
Approval-Medical 
13 Dec 2016 05:39 CET
Approval-
 Safety Evaluation
Therapeutic Area
13 Dec 2016 08:10 CET
Approval-Team Member Medicine
13 Dec 2016 09:07 CET
Approval-Other
19 Dec 2016 11:27 CET
Approval-
 Established Core
Products
20 Dec 2016 08:44 CET

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