DRUG USE INVESTIGATION OF SELARA(REGISTERED). TABLETS(AN INVESTIGATION FOR CHRONIC HEART FAILURE)
Conditions: Chronic Heart Failure
Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 1 of 32
Drug Use Investigation of Selara® Tablets
(An investigation for chronic heart failure)
NON-INTERVENTIONAL (NI) STUDY PROTOCOL
.
Pfizer Japan Inc.
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, by
accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it to others
(except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected
breach of this obligation, Pfizer must be promptly notified.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 2 of 32
STUDY INFORMATION
Title
Drug Use Investigation of Selara® Tablets (An investigation for chronic heart
failure)
Protocol ID
A6141122
Protocol version
identifier
Amended Version 1
Date of last version of
protocol
28 March 2017
Active substance
Eplerenone
Medicinal product
Selara® Tablets 25 mg/Selara® Tablets 50 mg
Research question and
objectives
To confirm the safety of this drug in chronic heart failure (CHF) patients,
particularly CHF patients with moderate renal impairment, under actual
medical practice.
Author of the protocol
Post-Marketing Study Strategy and Management Division
Study Strategy and Management Promotion Group 1
PPD

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 3 of 32
TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS.................................................................................................................... 4
2. RESPONSIBLE PARTIES........................................................................................................................ 6
3. AMENDMENTS AND UPDATES........................................................................................................... 7
4. MILESTONES........................................................................................................................................... 8
5. RATIONALE AND BACKGROUND...................................................................................................... 8
6. RESEARCH QUESTION AND OBJECTIVES........................................................................................ 8
6.1. Safety Specifications ........................................................................................................................ 8
6.2. Research question and primary objectives........................................................................................ 9
6.3. Research question and secondary objectives.................................................................................... 9
7. RESEARCH METHODS .......................................................................................................................... 9
7.1. Study design ..................................................................................................................................... 9
7.2. Setting............................................................................................................................................... 9
7.2.1. Inclusion criteria ................................................................................................................ 10
7.2.2. Exclusion criteria ............................................................................................................... 10
7.2.3. Study sites .......................................................................................................................... 10
7.2.4. Planned study period.......................................................................................................... 10
7.2.5. Study method ..................................................................................................................... 11
7.2.6. Observation period............................................................................................................. 11
7.3. Variables......................................................................................................................................... 11
7.3.1. Patient Background............................................................................................................ 13
7.3.2. Administration record of targeted drug.............................................................................. 15
7.3.3. Whether or not treatment with this drug is continued........................................................ 15
7.3.4. Previous treatment drugs and concomitant drugs .............................................................. 16
7.3.5. Tests/clinical laboratory tests............................................................................................. 17
7.3.6. Clinical evaluation ............................................................................................................. 17
7.3.7. Presence/absence of pregnancy (in women only) .............................................................. 18
7.3.8. Adverse events................................................................................................................... 18
7.3.9. Survival confirmation ........................................................................................................ 19
7.3.10. Major investigation items................................................................................................. 19
7.4. Data sources.................................................................................................................................... 20
7.5. Sample size..................................................................................................................................... 20
7.5.1. Planned sample size ........................................................................................................... 20
7.5.2. Rationale for sample size ................................................................................................... 20
7.6. Data management ........................................................................................................................... 21
7.6.1. Data collection method ...................................................................................................... 21
7.6.2. Patient registration ............................................................................................................. 21
7.6.3. Point of consider for completion, revision, and submission of CRF.................................. 21
7.7. Data analyses.................................................................................................................................. 22

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 4 of 32
7.8. Quality control................................................................................................................................ 22
7.9. Limitations of the research methods............................................................................................... 22
7.10. Other aspects ................................................................................................................................ 23
8. PROTECTION OF HUMAN SUBJECTS .............................................................................................. 23
8.1. Patient information and consent ..................................................................................................... 23
8.2. Patient withdrawal.......................................................................................................................... 23
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ...................................... 23
8.4. Ethical conduct of the study ........................................................................................................... 23
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS............... 23
9.1. Requirements.................................................................................................................................. 23
9.2. Reporting period............................................................................................................................. 24
9.3. Causality assessment ...................................................................................................................... 24
9.4. Definitions of safety events ............................................................................................................ 25
9.4.1. Adverse events................................................................................................................... 25
9.4.2. Serious adverse events ....................................................................................................... 26
9.4.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours ................................... 27
9.5. Single reference safety document................................................................................................... 29
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS............................ 29
11. ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION ............................................... 29
12. NAME, ADDRESS AND OUTSOURCED OPERATIONS OF THE PERSON WHO WAS 
CONTRACTED WITH THE OPERATIONS ...................................................................................... 30
13. ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE STUDY 
RESULTS AND CRITERIA FOR DETERMINATION OF THE INITIATION................................. 30
14. SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR REPORTING 
OF STUDY IMPLEMENTATION STATUS AND EVALUATION OF OBTAINED 
RESULTS TO THE PMDA .................................................................................................................. 30
15. OTHER ASPECTS................................................................................................................................ 30
17. REFERENCES ...................................................................................................................................... 31
18. LIST OF TABLES................................................................................................................................. 31
19. LIST OF FIGURES ............................................................................................................................... 31
LIST OF STAND ALONE DOCUMENTS ................................................................................................ 31
ADDITIONAL INFORMATION................................................................................................................ 31
1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 5 of 32
Al-P
Alkaline phosphatase
BNP
brain natriuretic peptide
BUN
Blood urea nitrogen
γ-GTP
γ-glutamyl transpeptidase
GOT
Glutamate oxaloacetate transaminase
GPT
Glutamate pyruvate transaminase
IEC
Independent Ethics Committee
IRB
Institutional review board
LAD
Left atrial diameter
LDH
Lactate dehydrogenase isozyme
LVDd
Left ventricular end‐diastolic dimension
LVEF
Left ventricular ejection fraction
NA
Not applicable
NIS
Non interventional study
NYHA
New York Heart Association
PT
Prothrombin
SAE
Serious adverse event
SRSD
Single Reference Safety Document
UACR
Urinary albumin/creatinine ratio

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 6 of 32
2. RESPONSIBLE PARTIES
The Japan Good Post marketing Study Practice officer
Principal Investigator(s) of the Protocol
NA

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 7 of 32
3. AMENDMENTS AND UPDATES
Protocol
version
identifier
Date
Amendment of
plan/others
Amended
section
Summary of
amendment
Reason
Amended
Version 1
01 December 2018
Others
Front page
Added Pfizer
Japan Inc.
For description
adjustment
Amended
Version 1
01 December 2018
Others
9.4.1. Adverse
events
Drug
discontinuation
was changed to
drug withdrawal.
For description
adjustment
Amended
Version 1
01 December 2018
Others
12.
NAME,
ADDRESS AND
OUTSOURCED
OPERATIONS
OF THE
PERSON WHO
WAS
CONTRACTED
WITH THE
OPERATIONS
Addition
associated with
establishment of
Pfizer R&D Japan
G.K.
For description
adjustment
Amended
Version 1
01 December 2018
Others
16.1.
Contact
information for
the contents of
the study
Change of
description
associated with
establishment of
Pfizer R&D Japan
G.K.
Addition of e-mail
address
For description
adjustment
Initial
Version
28 March 2017
NA
NA
NA
NA

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 8 of 32
4. MILESTONES
5. RATIONALE AND BACKGROUND
Selara® Tablets 25 mg, 50 mg, and 100 mg (generic name: eplerenone) are a selective aldosterone
blocker developed by Pfizer. In Japan, these were approved for the indication of “hypertension” on July
31, 2007, and Selara® Tablets 25 mg and 50 mg (hereinafter, this drug) were approved for the indication
of “chronic heart failure (CHF)” on December 19, 2016.
The purpose of the Drug Use Investigation of Selara® Tablets (An investigation for CHF) is to confirm
the safety of this drug when used in CHF patients, particularly CHF patients with moderate renal
impairment, under actual medical practice. Information obtained in this study shall be used to report
Ministry of Health, Labour and Welfare (MHLW), Pharmaceuticals and Medical Devices Agency
(PMDA) and Pfizer Inc. which is the corporate parent of marketing authorization holder (or sponsor) of
this study. It shall be used for application of re-examination (including Japan Periodic Safety Report),
re-evaluation, preparation of material for proper use information of this drug, academic articles and
activities for information service.
This Study shall be conducted in strict compliance with the “MHLW Ordinance on the Standard for
Post-Marketing Studies and Clinical Trials of Medical Products” (MHLW Ordinance No. 171, dated
December 20, 2004) , the “Enforcement of the MHLW Ordinance on the Standard for Post-marketing
Studies and Clinical Trials of Medical Products” (PFSB Notification No. 1220008, dated December 20,
2004), “MHLW Ordinance on the Partially Revision of the MHLW Ordinance on the Standard for Post-
marketing Safety Control of Medical Products, Quasi-medical Products, Cosmetics, and Medical
Devices and on the Partially Revision of the MHLW Ordinance on the Standard for Post-marketing
Studies and Clinical Trials of Medical Products” (MHLW Ordinance No. 26, dated March 11, 2013),
and the “Enforcement of the MHLW Ordinance on the Partially Revision of the MHLW Ordinance on
the Standard for Post-marketing Safety Control of Medical Products, Quasi-medical Products,
Cosmetics, and Medical Devices, and on the Partially Revision of the MHLW Ordinance on the
Standard for Post-marketing Studies and Clinical Trials of Medical Products” (PFSB Notification No.
0311-7, dated March 11, 2013).
Data obtained from the patients registered in this Study will be reported to the MHLW pursuant to the
Pharmaceutical and Medical Device Act; pertinent to which, data may be publicly posted in MHLW's
“Pharmaceutical and Medical Device Safety Information” and “Pharmaceuticals and Medical Devices
Information Website (http://www.info.pmda.go.jp)” as a listing of patients, which will present the
names of drugs, adverse reactions, gender, age (increment of 10 years), and other relevant information.
Furthermore, data collected may also be disclosed if the MHLW is required to disclose such information
in accordance with the “Act on Access to Information Held by Administrative Organs” (Law No. 42
dated May 14, 1999); provided that in no event will the names of physicians, medical institutions, and
other personal information be subject to such disclosure, nor will it be posted or disclosed in any form
or shape.
6. RESEARCH QUESTION AND OBJECTIVES
6.1. Safety Specifications
Important Identified Risks:
Milestone
Planned date
Start of data collection
July 2017
End of data collection
June 2020
Final study report
June 2020

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 9 of 32

Hyperkalaemia

Events related to hypotension
Important Potential Risks:

Renal impairment

Concomitant use of CYP3A4 inhibitor
Important Missing Information:

Safety in the diabetes patients with micro albuminuria or proteinuria

Safety in the patients with renal impairment
6.2. Research question and primary objectives
To confirm the safety of this drug when used in CHF patients with moderate renal impairment under
actual medical practice.
[Reason for this objective]
Moderate renal impairment was contraindication in the indication of hypertension but not in the
indication of CHF. In the domestic phase III study, use experience in Japanese CHF patients with
moderate renal impairment was limited.
In the Drug Use Investigation in Japanese hypertension patients, 470 in total 3166 patients with
moderate or severer renal impairment received, even though eplerenone was contraindicated in those
patients. The incidence rate of treatment-related AEs observed in these 470 patients was higher than that
in the other population. Hyperkalaemia was observed at the highest incidence rate in these patients.
Treatment-related adverse events observed in more than 3 patients were hyperkalaemia in 8 patients
(1.70%), renal impairment in 4 patients (0.85%) and blood potassium increased in 3 patients (0.64%).
For the risk mitigation, following sentences are added in the Dosage and Administration section (for
CHF indication) in J-PI: Patients with moderate renal impairment should start with 25 mg every other
day and the maximum dosage should be 25 mg once daily ; dose should be reduced or interrupted
according to serum potassium level and patient's conditions. In view of this situation, it is important to
confirm safety on use in Japanese CHF patients with moderate renal impairment for risk management of
this drug. Therefore, drug use investigation for Japanese CHF patients with moderate renal impairment
will be conducted.
6.3. Research question and secondary objectives
To confirm the safety of this drug when used in CHF patients under actual medical practice.
To confirm the effectiveness of this drug when used in CHF patients under actual medical practice.
7. RESEARCH METHODS
7.1. Study design
This study is a multi-center cohort study of patients with CHF receiving this drug. The investigators
complete the case report form (CRF) based on source documents such as medical records that include
data obtained in daily medical practice.
7.2. Setting
Subjects of this study are patients who meet the inclusion criteria and are registered within 14 days
including the start date of administration of this drug.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 10 of 32
7.2.1. Inclusion criteria
Patients in whom treatment with this drug is for CHF
The Indication, and Dosage and Administration at approval for this drug are as follows. When using this
drug, refer to the latest package insert of this drug.
7.2.2. Exclusion criteria
Patients who were previously registered for this study.
Patients who received this drug within the past three months regardless of the reason for use.
7.2.3. Study sites
Conduct the study at 150 sites including Department of Cardiology, Department of Cardiovascular
Medicine, etc.
7.2.4. Planned study period
The planned period covered by this study is as follows.
Investigation period: July 2017 to June 2020
Registration period: July 2017 to June 2018
(Even before the end of the registration period, the registration will be terminated if the target number of
subjects is reached.)
[Indication]
Patients currently receiving angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist, β blocker, diuretic, or
other products as a standard treatment of:
  Chronic Heart Failure
[Dosage and Administration]
In adults, usually, administer the initial dose of 25 mg once daily, and according to the patient's conditions and serum potassium
level, increase dosage up to 50 mg once daily after 4 weeks; patients with moderate renal impairment should start with 25 mg
once every other day and the maximum dosage should be 25 mg once daily.
Also, dose should be reduced or interrupted according to serum potassium level and patient's conditions.
[Precautions for Dosage and Administration]


Patients with moderate renal impairment (a creatinine clearance more than 30- less than 50 mL/min) should commence on
25 mg of this drug once every other day and dosage can be increased up to 25 mg once daily after 4 weeks depending on the
serum potassium level and patient’s condition. The maximum dosage should be 25 mg once daily. [Regarding to the
adjustment based on eGFR used in clinical studies, see “Clinical studies”]


Serum potassium should be monitored periodically. Adjust the dosage in accordance with Table 1. [See “Important
Precautions”]
Table 1. Adjustment of Dosage and Administration according to Serum Potassium Level
Serum Potassium Level (K+) mEq/L
Adjustment of Dosage and Administration
less than 5.0
In the case of 50 mg once daily: Maintain
In the case of 25 mg once daily: Increase to 50 mg once daily
In the case of 25 mg every other day: Increase to 25 mg once daily
5.0-5.4
Maintain
5.5-5.9
In the case of 50 mg once daily: Decrease to 25 mg once daily
In the case of 25 mg once daily: Decrease to 25 mg every other day
In the case of 25 mg every other day: Withhold
not less than 6.0
Withhold
It can be restarted at a dose of 25 mg every other day when K+ has fallen below 5.0 mEq/L.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 11 of 32
7.2.5. Study method
This study will be conducted with Central registration system that patients who meet the conditions of
this study will be registered until data are collected on a target number of patients.
7.2.6. Observation period
7.2.6.1. Observation period
One year (52 weeks) from the start date of administration.
However, in patients who discontinue treatment with this drug, the period will be from the start date of
administration to the first consultation day after the discontinuation day of treatment with this drug.
Figure 1. Observation Period for Each Booklet
7.2.6.2. Rationale for observation period
Regarding efficacy, a 1-year observation period was considered to be necessary because the overall
mortality, cardiovascular deaths, etc. specified as efficacy endpoints in this study will be compared to
the results of other researches/studies for the following reasons.
Based on the data of the domestic epidemiological study CHART-11) (N=1154) and JCARE-CARD2)
(N=847a), the results on all-cause mortality before year one of the assessment period are 7.3% and 8.9%
respectively, showing that life prognosis of CHF patients as the target patients of this study is not good.
Regarding the overall mortality and cardiovascular deaths in this study, the number of deaths and death
rate (%), death rate (%) after 1 year observation period, death rate based on person-year method (the
number of deaths in 100 person-year) will be calculated and compared to the results of the domestic
Phase III study or domestic epidemiological studies.
Regarding safety, a 1-year observation period was considered to be long enough to collect and confirm
the safety data under daily medical practice sufficiently.
As shown above, the observation period of this study was determined to be 1 year (52 weeks).
a: CHF patients with systolic dysfunction to be able to be followed up
1)
Shiba N, Watanabe J, Shinozaki T, et al. Circ J. 2004(5);68:427-34.
2)
Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, et al. Circ J. 2009;73(10):1893-900.
7.3. Variables
This study will be conducted according to the following schedule of observation.
Booklet 01
(Observation period: The start date of
administration to Week 26)
Booklet 02
(Observation period: Week 27 to Week 52)
The start date of
administration
(Day 1)
Week 26
Week 52

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 12 of 32
Table 2. Schedule of Observation
Registration
Form
CRF
Timing     
Variables
At the time
of
registration
Observation period
Booklet 01
Booklet
02
Before
administration
Start date of 
administration
to Week 26
Week 27
to Week
52
Patient
Background
ID number (other than medical
record number)
●
Gender
●
Age
●
Inclusion criteria/Exclusion
criteria
●
Start date of administration
(MMDDYYYY)
●
Body weight
●
Serum creatinine
●
Height
●
Hospitalization status
(inpatient/outpatient)
●
History of hospitalization due
to cardiovascular event
●
Disease to be investigated
(CHF) and disease duration
●
NYHA Functional
Classification
●
Underlying heart disease
●
Reason for treatment with this
drug
●
History of treatment with
device therapy
●
Presence/absence and severity
of hepatic impairment
●
Presence/absence and severity
of renal impairment
●
Disease history
●
Targeted drug use record
Whether or not treatment with this drug is
continued
History of previous treatment drugs for the
targeted
disease
(in
past
3
months) and
concomitant drugs
Tests/clinical
laboratory
tests
Blood pressure/body weight
Cardiac function test
Clinical laboratory tests
Clinical
evaluation
NYHA Functional
Classification
Clinical effectiveness (doctor’s
evaluation)
Presence/absence of pregnancy (in women only)
Adverse events (any adverse event)

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 13 of 32
Registration
Form
CRF
Timing     
Variables
At the time
of
registration
Observation period
Booklet 01
Booklet
02
Before
administration
Start date of 
administration
to Week 26
Week 27
to Week
52
Survival confirmation
7.3.1. Patient Background
1. Input the information in the Registration Form at the administration of this drug.
a. ID number (other than medical record number)
b. Gender
c. Age
d. Setting (inclusion criteria/exclusion criteria)
e. Start date of administration (MMDDYYYY)
f. Body weight (kg) (latest measurement result by one month before the administration of
treatment)
g. Serum creatinine (mg/dL) (latest measurement result by one month before the administration of
treatment)
2. The following will be recorded in CRF at the administration of this drug.
a. Height (cm) 
b. Hospitalization status (inpatient/outpatient)
c. History of hospitalization due to cardiovascular event (before the administration of treatment
with this drug)
(i)
Presence/absence of hospitalization due to cardiovascular event
(ii) Number of times of hospitalization due to cardiovascular event
d. Disease to be investigated (CHF)
(i)
Onset time
e. Underlying heart disease
(i)
Ischaemic heart disease
(ii)
Non-ischaemic heart disease
Hospitalization due to cardiovascular event is defined as hospitalization due to any
of the following:
࡮
Cardiac failure
࡮
Myocardial infarction
࡮
Angina unstable
࡮
Arrhythmia (Atrial fibrillation, Atrial flutter, Arrhythmia supraventricular, or
Ventricular arrhythmia)
࡮
Stroke or cerebrovascular attack
࡮
Other causes related to cardiovascular system
Hospitalization for treatment of a cardiovascular event existing from before the
study, excluding those not associated with the development of a new
cardiovascular event or with a worsening of the existing cardiovascular disease
(e.g., for work-up of persistent lab abnormality observed from before treatment
with this drug)

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 14 of 32
f. NYHA Functional Classification (most recent within one month before the administration of
treatment with this drug)
(i)
Presence/absence of evaluation
(ii)
Evaluation result
g. Reason for treatment with this drug
h. History of treatment with device therapy (before the administration of treatment with this drug)
(i) Presence/absence of history of treatment with device therapy
(ii) Details of treatment with device therapy
i. Presence/absence and severity of hepatic impairment: If hepatic impairment is present, classify
the severity by reference to the criteria in Table 3.
Table 3. Rough Standards for Determination of Severity of Hepatic Impairment
Severity
Variable
Mild
Moderate
Severe
Total bilirubin
(mg/dL)
1.6 to <3.0
3.0 to <10
≥10
GOT, GPT
(U)
1.25×N to <2.5×N
50 to <100
2.5×N to <12×N
100 to <500
≥12×N
≥500
Al-P
1.25×N to <2.5×N
2.5×N to <5×N
≥5×N
γ-GTP
≥1.5×N
―
―
LDH
≥1.5×N
―
―
PT
―
―
≤40%
Symptom, etc.
―
Jaundice,
Hepatomegaly,
Right hypochondrial pain,
Hepatic steatosis
Bleeding tendency,
Symptoms of hepatic failure
such as consciousness
disturbed (Hepatitis
fulminant),
Hepatic cirrhosis, Hepatic
tumour, Jaundice persisting
for ≥6 months
N: Upper limit of normal for each institution
(Source: PAB/SD Notification No. 80 dated June 29, 1992 “Seriousness Grading Criteria for
Adverse Reactions to Pharmaceuticals”)
j. Presence/absence and severity of renal impairment: If renal impairment is present, classify the
severity by reference to the criteria in Table 4.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 15 of 32
Table 4. Rough Standards for Determination of Severity of Renal Impairment
Severity
Variable
Mild
Moderate
Severe
BUN
(mg/dL)
Higher than 1×N to <25
25 to <40
≥40
Creatinine (mg/dL)
Higher than 1×N to <2
2 to <4
≥4
Urine protein
1+
2+ to 3+
Higher than 3+
Haematuria
Microscopic
Macroscopic
Macroscopic, Clotting blood
Urine output
―
≤500 mL/24 hr or
oliguria/polyuria*
≤100 mL/24 hr or anuria
Serum potassium
level
( mEq /L )
―
5.0 to <5.5
≥5.5
Other symptom,
etc.
―
―
Nephrotic syndrome,
Acute renal failure
(interstitial nephritis,
tubulonecrosis, renal
necrosis, renal papillary
necrosis, renal cortical
necrosis),
Chronic renal failure
(interstitial nephritis,
tubulonecrosis, renal
necrosis, renal papillary
necrosis, renal cortical
necrosis),
Uraemia,
Hydronephrosis
N: Upper limit of normal for each institution
Note)* Polyuria: It refers to renal diabetes insipidus.
(Source: PAB/SD Notification No. 80 dated June 29, 1992 “Seriousness Grading Criteria for
Adverse Reactions to Pharmaceuticals”)
Important: Hepatic impairment/renal impairment refer to an event requiring follow-up observation to which
clinical attention should be paid, not transient lab abnormality.
k. Presence/absence of pregnancy
l. Disease history: Enter the presence/absence of relevant diseases and syndromes. Enter
“Previous” if a disease was healed before the administration of this drug and enter “Current” if
a disease has developed at the administration of this drug. If the disease history includes
diabetes mellitus, enter whether or not diabetes mellitus is associated with micro albuminuria
(UACR ≥30) or proteinuria (not including false positive (±)).However, if it has developed or
occurred after the start date of administration of this drug, enter its details in the section of
adverse events.
7.3.2. Administration record of targeted drug
Enter the daily dose level of this drug administered from the start date of administration to the last day
of the observation period, as well as the treatment period. If the daily dose is changed or this drug is
ceased, also enter the reason for dose change/cessation of this drug.
1. Daily dose
2. Treatment period
3. Reason for dose change/cessation of this drug
7.3.3. Whether or not treatment with this drug is continued
1. Whether or not treatment with this drug is continued
2. First consultation day after the discontinuation day of treatment with this drug
3. Reason for discontinuation of treatment with this drug

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 16 of 32
If treatment with this drug is not continued until the last day of the observation period in this study,
select and enter the reason for it from among the following. If any adverse event is selected, enter its
details in the section of adverse events. If other is selected, enter the reason for it as well.
1. Insufficient clinical effectiveness
2. Adverse event
3. No re-visit a)
4. Other b)
a.
Enter it only in Booklet 02.
b.
If “Other,” enter the reason for it; for example, the patient’s will unrelated to the adverse
event.
7.3.4. Previous treatment drugs and concomitant drugs
7.3.4.1. Treatment drugs for chronic heart failure/hypertension; Contraindicated concomitant
drugs; Concomitant drugs requiring caution (Collect information for all subjects)
Select the presence/absence of treatment with drugs falling under “7.3.4.1.1. Relevant drugs” from
among drugs used between three months before the start date of administration and the last day of the
observation period.
If “Yes” is selected as the presence of treatment in the above section, enter the name of the drug(s) 
administered in the section of “Nonproprietary name or product name” and then enter the treatment
period, etc.
It is not necessary to enter drugs other than those under any of the following categories.
7.3.4.1.1. Relevant drugs

Diuretics (excluding potassium-conserving diuretics)

Potassium-conserving diuretic (*contraindication for concomitant use) a)

Angiotensin-converting enzyme (ACE) inhibitors b)

Angiotensin II receptor blockers (ARB) b)

β blockers

Ca antagonists

Other antihypertensive drugs (α blockers, direct renin inhibitors, etc.)

Digitalis preparations

Antiarrhythmic drugs

Antiplatelet drugs

Oral anticoagulant drugs

Statin drugs

Itraconazole (*contraindication for concomitant use) c)

Ritonavir (*contraindication for concomitant use) c)

Nelfinavir (*contraindication for concomitant use) c)

Other CYP3A4 inhibitors b)

Aliskiren b), d)

Cyclosporin b)

Tacrolimus b)

Drospirenone b)

Nonsteroidal anti-inflammatory drugs (NSAIDs) e)

Potassium preparations b)
a.
Contraindicated concomitant drugs (When they are used concomitantly, the potassium-retaining
action may be potentiated, thereby possibly elevating the serum potassium level)
b.
Concomitant drugs requiring caution (When they are used concomitantly, the potassium-retaining
action may be potentiated, thereby possibly elevating the serum potassium level)

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 17 of 32
c.
Contraindicated concomitant drugs (Potent CYP3A4 inhibitors inhibit the metabolism of this drug,
and consequently the plasma concentration of this drug may be elevated, thereby possibly inducing
an elevation in the serum potassium level)
d.
Describe in the section of other antihypertensive drugs (α blockers, direct renin inhibitors, etc.).
e.
Concomitant drugs requiring caution (Clear mechanisms are unknown, but when the production of
prostaglandin is suppressed, the sodium-retaining action may diminish the antihypertensive action,
and the potassium-retaining action may elevate the serum potassium level. The occurrence of
severe hyperkalaemia was reported in patients with renal impairment when they were used
concomitantly.)
7.3.4.2. Other previous treatment drugs and concomitant drugs (Collect information for subjects
who have any adverse event corresponding to “renal impairment”)
If any adverse event corresponding to “renal impairment” is observed, select the presence/absence of
treatment with drugs other than this drug and “7.3.4.1.1. Relevant drugs” from among drugs used
between three months before the start date of administration and the last day of the observation period.
If “Yes” is selected as the presence of treatment in the above section, enter the name of the drug(s) 
administered in the section of “Nonproprietary name or product name” and then enter the treatment
period.
7.3.5. Tests/clinical laboratory tests
Enter whether or not tests are implemented and test results for the clinical course from before
administration of this drug to the last day of the observation period. Before administration of this drug,
enter the latest test results for tests implemented during the period from three months before the start of
administration to immediately before the start of administration (including the start date of
administration) (For cardiac function tests: from six months before the start of administration). At the
end of the observation period, enter the test results within one month after the last day of the
observation period. If there are no test results for appropriate dates, enter the test results for the day of
tests closest to the last day of the observation period. For any test results, enter the implementation date
and test results. Regarding clinically-problematic abnormal changes in test values compared to the
values before the start of administraiton, enter the details in the section of adverse events as well.
7.3.5.1. Blood pressure/body weight
Blood pressure systolic, blood pressure diastolic, and body weight
7.3.5.2. Cardiac function test
Left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVDd), and left
atrial diameter (LAD) confirmed by echocardiography
7.3.5.3. Clinical laboratory tests
Serum creatinine, serum potassium, BUN, plasma BNP, and serum NT-proBNP
7.3.6. Clinical evaluation
Enter the evaluation result obtained by using the following evaluation scale for clinical evaluation.
7.3.6.1. NYHA Functional Classification
For clinical evaluation, enter whether or not evaluation based on NYHA Functional Classification is
done and the evaluation result. The evaluation result to be entered should be the one obtained on the last
day of the observation period. If treatment with this drug is discontinued, enter the result of evaluation
implemented on the last day of observation. However, if no evaluation is done in the relevant period,
enter the evaluation result obtained in the period closest to the relevant period.
(1) Whether or not evaluation based on the NYHA Functional Classification is done
(2) Date of evaluation based on the NYHA Functional Classification

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 18 of 32
(3) Results of evaluation based on the NYHA Functional Classification
Reference) NYHA Functional Classification
Class I: Having a heart disease, but with no limitation of physical activity. Ordinary physical
activity does not cause marked fatigue, palpitations, dyspnoea, or anginal pain.
Class II: Having a mild limitation of physical activity. No symptom at rest. Ordinary physical
activity causes fatigue, palpitations, dyspnoea, or anginal pain.
Class III: Having a severe limitation of physical activity. No symptom at rest. Exertion less
than ordinary activity causes fatigue, palpitations, dyspnoea, or anginal pain.
Class IV: Any physical activity is limited due to a heart disease. A symptom of heart failure
or anginal pain is present even at rest. These symptoms can be exacerbated by slight
exertion.
(Source: Igaku Shoin’s Medical Dictionary 2nd Edition, issued on February 15, 2009)
7.3.6.2. Clinical effectiveness (investigator’s evaluation)
The investigator will evaluate this drug based on the following items for judging the clinical
effectiveness on the last day of the observation period as compared to the status before the
administration of this drug (including the start date of administration), and enter the evaluation date and
its results. If treatment with this drug is discontinued, enter the result of evaluation implemented on the
last day of observation. However, if there is no result for the relevant period, enter the result obtained in
the period closest to the relevant period.
Clinical effectiveness
(1) Yes
(2) No
(3) Unavailable (In this case, the reason should be recorded.)
7.3.7. Presence/absence of pregnancy (in women only)
    Enter the presence/absence of pregnancy between the start date of administration and the last day of the
observation period.
7.3.8. Adverse events
Regardless of causal relationship with this drug, the following information related to all adverse events that
occur between the start of administration and the last day of the observation period (the last day of
observation if treatment is discontinued) should be entered in the section of adverse events. Conduct a
detailed investigation separately if the sponsor judges it necessary.

Presence/absence of adverse event

Name of adverse event

Category of adverse event
Also enter whether the entered adverse event is an “event related to hypotension” or an “event
related to hyperkalaemia.”

Date of occurrence

Procedure ([1] Change of treatment with this drug; [2] Additional treatment for the adverse event)

Seriousness

Whether or not the event(s) has led to death; Whether or not the event(s) has led to hospitalization
If the event has led to death, enter information on whether or not it is “cardiovascular death,” or if
the event has led to hospitalization, enter information on whether or not it is “hospitalization due
to a cardiovascular event.”

Outcome of the adverse event to present; Outcome date

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 19 of 32
x
Causal relationship with this drug
If there is any adverse event related to abnormal changes in test values from clinical laboratory tests and  
physiological function tests, etc., enter the following information in the section of tests related to adverse
events.
x
Laboratory parameter
x
Site reference value
x
Unit
x
Test date
x
Results
If any adverse event corresponding to “renal impairment” is observed, enter information on drugs other
than this drug and “7.3.4.1.1. Relevant drugs” (Refer to the section “7.3.4.2. Other previous treatment 
drugs and concomitant drugs [collect information for subjects who have any adverse event
corresponding to “renal impairment”]).
Note: Adverse events are any and all unfavorable events (including clinically significant abnormal
changes in laboratory tests) occurring in patients after starting treatment with this drug regardless of
their causal relationship. Serious adverse events are any unfavorable medical occurrences that result in
death, are life-threatening, require (or prolong) hospitalization, cause persistent or significant
disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which
represent significant health hazards.
7.3.9. Survival confirmation
Regarding the status from the start of administration to Week 52, enter the following information in the
section of survival confirmation.
x
Last date of survival confirmation
x
Result of survival confirmation
7.3.10. Major investigation items
7.3.10.1. Hyperkalaemia
Due to the mechanisms of action of this drug, a risk of hyperkalaemia is expected. It was observed as an
adverse reaction in clinical studies by the time of approval. It is also known as a clinically-significant
adverse reaction to similar drugs, and may become severe at the time of onset, thereby possibly
threatening the life, and as such, it is specified as an important identified risk. For this event specified as
a major investigation item, information on the onset date of the adverse event, procedure (change of
treatment with this drug; additional treatment for the adverse event), seriousness, outcome, causal
relationship with this drug, and factors for the adverse event other than this drug will be collected, and
risk factors and onset time will be investigated.
7.3.10.2. Events related to hypotension
Due to the mechanisms of action of this drug, the possibility that adverse events related to hypotension
may occur cannot be ruled out, and associated secondary events (fall, loss of consciousness, etc.) may
occur, possibly leading to clinically-significant events, and therefore these events are specified as
important identified risks. For this event specified as a major investigation item, information on the
onset date of the adverse event, procedure (change of treatment with this drug; additional treatment for
Cardiovascular deaths are defined as deaths due to any of the following causes:
࡮
Cardiac failure
࡮
Myocardial infarction
࡮
Arrhythmia (Atrial fibrillation, Atrial flutter, Arrhythmia supraventricular, or Ventricular
arrhythmia)
࡮
Stroke or cerebrovascular attack
࡮
Other causes related to cardiovascular system

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 20 of 32
the adverse event), seriousness, outcome, causal relationship with this drug, and factors for the adverse
event other than this drug will be collected, and risk factors and onset time will be investigated.
7.4. Data sources
In this study, the investigators extract the necessary information from source documents such as medical
records in accordance with the protocol.
7.5. Sample size
7.5.1. Planned sample size
A total of 1000 CHF patients as subjects included in the safety analysis set (including at least 300
patients with moderate renal impairment)
7.5.2. Rationale for sample size
Table 5 shows the number and proportion of cases of adverse events related to hyperkalaemia and renal
impairment that occurred within 52 weeks (364 days) after the start of administration, for which a
causal relationship could not be ruled out, in all CHF patients and patients with moderate renal
impairment in the domestic Phase III study (Study A6141114) and the foreign Phase III study (Study
EMPHASIS-HF).
Table 5.
Adverse Events related to Hyperkalaemia and Renal Impairment that
Occurred within 52 Weeks (364 Days) after the Start of Administration
in Eplerenone Group for which Causal Relationship Could Not Be
Ruled Out - Safety Analysis Set
Preferred Term
Patients with moderate renal
impairment
All CHF patients
eGFR < 50 mL/min/1.73m2
Study A6141114
N=37
N=111
 Hyperkalaemia
2 (5.4)
3 (2.7)
 Chronic kidney disease
0
1 (0.9)
Renal impairment
1 (2.7)
1 (0.9)
Study EMPHASIS-HF
N=224 a
N=1360
Hyperkalaemia
20 (8.9)
56 (4.1)
Renal failure
1 (0.4)
4 (0.3)
Renal impairment
6 (2.7)
12 (0.9)
n (%)
a: Including two patients with eGFR <30 mL/min/1.73m2.
In Study A6141114, the ratio of patients with moderate renal impairment to all CHF patients in
Japanese was 34.4% (76/221). Taking into account this result and the results of a Japanese
epidemiological survey3), the ratio of patients with moderate renal impairment to CHF patients in Japan
is estimated to be approximately 30%. Given that the target sample size of all CHF patients is 1000
patients, the number of patients with moderate renal impairment is expected to be approximately 300-
350.
As shown in Table 5, the incidence rate of adverse events related to renal impairment for which a causal
relationship could not be ruled out was 3.1% (8/261) in patients with moderate renal impairment in the
combined results from Study A6141114 and Study EMPHASIS-HF conducted in CHF patients with
systolic dysfunction in which the same primary endpoint (cardiovascular deaths or hospitalization due
to heart failure) was compared to a placebo treatment group. Assuming that 3.1% is the true incidence
rate of adverse events related to renal impairment for which a causal relationship cannot be ruled out in
patients with moderate renal impairment, the expected number of cases of adverse events related to

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 21 of 32
renal impairment for which a causal relationship cannot be ruled out is 9.3-10.9 when collecting 300-
350 patients with moderate renal impairment.
Also, assuming that 8.4% (22/261) is the true incidence rate of adverse events related to hyperkalaemia
for which a causal relationship cannot be ruled out in patients with moderate renal impairment, similarly
to the above-mentioned method, the expected number of cases of adverse events related to
hyperkalaemia for which a causal relationship cannot be ruled out is 25.2-29.4.
If events which true incidence rate is 3.1% and 8.4% are observed in 300 patients, the estimated
incidence rate will be 1.1%-5.1% and 5.3%-11.5%, respectively, with a probability of approximately
95%.
Assuming that the true incidence rate of adverse events related to renal impairment and hyperkalaemia
in all CHF patients for which a causal relationship cannot be ruled out is 1.2% (18/1471) and 4.0%
(59/1471), respectively, the expected number of cases of adverse events for which a causal relationship
cannot be ruled out is 12.0 and 40.0, respectively, when collecting 1000 CHF patients. Events can be
observed in approximately 6-19 patients and 28-53 patients, respectively, with a probability of
approximately 95%.
If events which true incidence rate is 1.2% and 4.0% are observed in 1000 patients, the estimated
incidence rate will be 0.5%-1.9% and 2.8%-5.2%, respectively, with a probability of approximately
95%.
As described above, regarding adverse events related to hyperkalaemia and renal impairment for which
a causal relationship cannot be ruled out, a target sample size of 1000 patients may enable evaluation of
the safety profile between clinical studies and use-results surveys in terms of patient background
including the presence/absence of comorbid moderate renal impairment as well as seriousness, outcome,
etc. of adverse events.
3)
Hamaguchi S, Tsuchihashi-Makaya M, Kinugawa S, et al. Circ J 2009;73:1442.
7.6. Data management
7.6.1. Data collection method
The data for this study will be entered in CRFs and confirmed using an electronic post-marketing data
collection system for drugs (Electronic Data Capture or EDC, hereinafter referred to as this system) 
provided by the sponsor on the Internet.
7.6.2. Patient registration
The investigator will enter registration items on the patient registration screen of this system. Patient
registration will be performed within 14 days including the start date of administration.
7.6.3. Point of consider for completion, revision, and submission of CRF
7.6.3.1. Data entry
The investigator shall, upon confirming the study items, enter the data in this system based on source
documents such as medical records.
7.6.3.2. Data revision
Upon receiving Sponsor's inquiry on the entered contents of the CRF (query forms), the investigator
will again confirm the information of source documents such as medical records described earlier, and
as required, correct relevant contents.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 22 of 32
7.6.3.3. Submission
After completion of all entries and revisions of study items, the investigator will again confirm the
entered contents of the CRF and re-investigation, and affix his or her electronic signature.
7.7. Data analyses
1)
Definition of analysis sets
The safety analysis set (SAS) is defined as patients in whom treatment with this drug was
confirmed.
The efficacy analysis set is defined as patients in whom treatment with this drug was confirmed
and the efficacy could be evaluated in CHF patients.
2)
Method of Analysis
(1)
Safety analysis
Events for which a causal relationship with this drug cannot be ruled out will be handled as
adverse reactions, and the number and proportion of cases of adverse reactions will be aggregated
by System Organ Class and Preferred Term.
For patients with renal impairment, moderate renal impairment, or hepatic impairment, elderly
patients (≥65 years, ≥75 years), pediatric patients (<15 years), and diabetes patients with micro
albuminuria or proteinuria, the safety will be comparatively investigated versus other populations.
In addition, the occurrence status of adverse reactions related to hyperkalaemia, renal impairment,
or blood pressure decreased will be investigated in terms of risk factors and onset time.
(2)
Efficacy analysis
Regarding each evaluation item for clinical evaluation, the number and proportion of cases will be
aggregated by level from the results. Regarding the overall mortality and cardiovascular deaths in
the study, the number of deaths and death rate (%), death rate (%) after 1 year observation period,
death rate based on person-year method (the number of deaths in 100 person-year) will be
calculated. For reference, the results will be compared to the domestic Phase III study or Japanese
epidemiological surveys (CHART-1, CHART-2, JCARE-CARD, etc.). These comparisons will be
performed with adjustment of factors such as patient background that are considered available or
appropriate at the time of evaluation or setting of appropriate subgroups. a)
a.
For the domestic Phase III study, comparisons to death rates adjusted for age, gender, and
NYHA Functional Classification by using individual data such as patient background
collected in the study will be considered; and for the Japanese epidemiological surveys,
comparisons to death rates adjusted for gender and NYHA Functional Classification by using
aggregate data such as patient background from published papers, etc. will be considered.
Detailed methodology for statistical analyses of data collected in this study will be documented in a
Statistical Analysis Plan (SAP), which will be stored by Pfizer. The SAP may modify the plans outlined in
the Study Protocol; any major modifications of primary endpoint definitions or their analyses will be also
reflected in amendment of the Protocol.
7.8. Quality control
The site staff will explain the contents of the protocol, etc. to the investigator prior to the implementation
of this study and ask the investigator to prepare a CRF based on medical records.
7.9. Limitations of the research methods
The following matters are considered for this study:
1.
Since no control group is set in the study, there is a limitation to the judgment on whether or not a risk
of developing adverse events and adverse reactions increases due to the administration of the targeted
drug.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 23 of 32
2.
The consideration for confounding factors may not be adequate because the background information
may not be sufficiently obtained.
3.
Since this is a study that collects the information described in medical records, the set data may not be
collected or there may be missing information.
7.10. Other aspects
NA
8. PROTECTION OF HUMAN SUBJECTS
8.1. Patient information and consent
All parties will ensure protection of patient personal data and will not include patient names on any
sponsor forms, reports, publications, or in any other disclosures, except where required by laws. In case of
data transfer, Pfizer will maintain high standards of confidentiality and protection of patient personal data.
In this study, the information will be collected by transcribing medical record information described in
routine medical practice. In doing so, the informed consent will not be used because the information
collected from medical records is anonymized and does not contain any information that identifies
individual patients.
8.2. Patient withdrawal
NA
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
In this study, the review by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) is
not essential.
8.4. Ethical conduct of the study
This study is excluded from the subject since it is included in the scope of application of the “Good Post-
Marketing Study Practice” (Ordinance of Ministry of Health, Labour and Welfare No. 171 of December
20, 2004).
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS
For an event that needs to be reported by the investigator within 24 hours, the site staff will request the
investigator to report it at the start of the study and regularly visit the investigator during the investigation
period to request the investigator to report it.
The handling of each event in the case where the investigator becomes aware of any event concerning the
safety information should be prescribed as follows:
For an event that needs to be reported to the sponsor within 24 hours, the investigator must report it using
the designated “Non-Interventional Study AE Report Form (hereinafter referred to as “NIS AE Report
Form”).”
9.1. Requirements
The table below summarizes the requirements for recording safety events in the CRF and for reporting
safety events by the NIS AE Report Form to Pfizer Safety. These requirements are delineated for three
types of events: (1) serious adverse events (SAEs); (2) non-serious AEs (as applicable); and (3) scenarios
involving drug exposure, including exposure during pregnancy, exposure during breastfeeding, medication
error, overdose, misuse, extravasation, and occupational exposure. These events are defined in the section
“Definitions of safety events.”

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 24 of 32
Safety event
Recorded on the data collection
tool (e.g. CRF) 
Reported on the NIS AE
Report Form to Pfizer Safety
within 24 hours of awareness
SAE
All
All
Non-serious AE
All
None
Scenarios involving exposure to a
drug under study, including exposure
during pregnancy, exposure during
breastfeeding, medication error,
overdose, misuse, extravasation, lack
of efficacy, and occupational
exposure
All (regardless of whether
associated with an AE), except
occupational exposure
All (regardless of whether
associated with an AE)
For each AE, the investigator must pursue and obtain information adequate both to determine the outcome
of the AE and to assess whether it meets the criteria for classification as a SAE (refer to section “Serious
Adverse Events” below).
Safety events listed in the table above must be reported to Pfizer within 24 hours of awareness of the event
by the investigator regardless of whether the event is determined by the investigator to be related to a drug
under study. In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made
immediately, irrespective of the extent of available event information. This timeframe also applies to
additional new (follow-up) information on previously forwarded safety event reports. In the rare situation
that the investigator does not become immediately aware of the occurrence of a safety event, the
investigator must report the event within 24 hours after learning of it and document the time of his/her first
awareness of the events.
For safety events that are considered serious or that are identified in the far right column of the table above
that are reportable to Pfizer within 24 hours of awareness, the investigator is obligated to pursue and to
provide any additional information to Pfizer in accordance with this 24-hour time frame. In addition, an
investigator may be requested by Pfizer to obtain specific follow-up information in an expedited fashion.
This information is more detailed than that recorded in the data collection tool (e.g. CRF). In general, this
will include a description of the AE in sufficient detail to allow for a complete medical assessment of the
case and independent determination of possible causality. Any information relevant to the event, such as
concomitant medications and illnesses must be provided. In the case of a patient death, a summary of
available autopsy findings must be submitted as soon as possible to Pfizer or its designated representative.
9.2. Reporting period
For each patient, the safety events reporting period begins at the time of the patient’s first dose of this drug,
and lasts through the end of the observation period of the study, which must include at least 28 calendar
days following the last administration of a drug under study; a report must be submitted to Pfizer Safety
(or its designated representative) for any of the types of safety events listed in the table above occurring
during this period.  If a patient was administered a drug under study on the last day of the observation
period, then the reporting period should be extended for 28 calendar days following the end of observation.
If the investigator becomes aware of a SAE occurring at any time after completion of the study and s/he
considers the SAE to be related to this drug, the SAE also must be reported to Pfizer Safety.
9.3. Causality assessment
The investigator is required to assess and record the causal relationship. For all AEs, sufficient information
should be obtained by the investigator to determine the causality of each AE. For AEs with a causal
relationship to this drug, follow-up by the investigator is required until the event and/or its sequelae resolve
or stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 25 of 32
An investigator’s causality assessment is the determination of whether there exists a reasonable possibility
that this drug caused or contributed to an AE. If the investigator’s final determination of causality is
“unknown” and s/he cannot determine whether this drug caused the event, the safety event must be
reported within 24 hours.
If the investigator cannot determine the etiology of the event but s/he determines that this drug did not
cause the event, this should be clearly documented in the data collection tool (e.g. CRF) and the NIS AE
Report Form.
9.4. Definitions of safety events
9.4.1. Adverse events
An AE is any untoward medical occurrence in a patient administered a medicinal product. The event need
not necessarily have a causal relationship with the product treatment or usage.

Abnormal test findings (see below for circumstances in which an abnormal test finding constitutes an
adverse event);

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/aggravation of underlying disease;

Lack of efficacy;

Drug abuse;

Drug dependency.
Additionally, for medicinal products, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Off-label use;

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure during breastfeeding;

Medication error;

Occupational exposure.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 26 of 32
Abnormal test findings
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as
follows:

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, and/or

Test result leads to a change in study dosing or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy, and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test result, in the absence of any of the above conditions, does not constitute
an AE. Any abnormal test result that is determined to be an error does not require reporting as an AE.
9.4.2. Serious adverse events
A SAE is any untoward medical occurrence in a patient administered a medicinal or nutritional product
(including pediatric formulas) at any dose that:

Results in death;

Is life-threatening;

Requires inpatient hospitalization or prolongation of hospitalization (see below for circumstances that
do not constitute AEs);

Results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct
normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important medical
event. An important medical event may not be immediately life-threatening and/or result in death or
hospitalization. However, if it is determined that the event may jeopardize the patient or may require
intervention to prevent one of the other outcomes listed in the definition above, the important medical
event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of
drug dependency or drug abuse.
Additionally, any suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-
pathogenic, is considered serious. The event may be suspected from clinical symptoms or laboratory
findings indicating an infection in a patient exposed to a Pfizer product. The terms “suspected
transmission” and “transmission” are considered synonymous. These cases are considered unexpected and
handled as serious expedited cases by pharmacovigilance (PV) personnel. Such cases are also considered
for reporting as product defects, if appropriate.
Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or equivalent
healthcare facility or any prolongation to an existing admission. Admission also includes transfer within
the hospital to other department or an acute/intensive care unit (e.g., from the psychiatric wing to a medical
floor, medical floor to a coronary care unit, neurological floor to a tuberculosis unit). An emergency room

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 27 of 32
visit does not necessarily constitute a hospitalization; however, an event leading to an emergency room
visit should be assessed for medical importance.
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. For example,
the following hospitalization without a medical AE are not to be reported.

Social admission (e.g., patient has no place to sleep)

Administrative admission (e.g., for yearly medical examination)

Optional admission not associated with a sudden change in clinical condition (e.g., for elective
cosmetic surgery)

Hospitalization for observation without a medical AE

Admission for treatment of a pre-existing condition not associated with the development of a new AE
or with a worsening of the pre-existing condition (e.g., for work-up of persistent pre-treatment lab
abnormality)

Protocol-specified admission during clinical study (e.g., for tests or procedures required by the study
protocol)
9.4.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication error,
overdose, misuse, extravasation, lack of efficacy, and occupational exposure are described below.
Exposure during pregnancy
An exposure during pregnancy (EDP) occurs if:
A female becomes, or is found to be, pregnant either while receiving or having been exposed to (e.g.,
environmental) this drug, or a female becomes, or is found to be, pregnant after discontinuing and/or being
exposed to this drug (maternal exposure).
An example of environmental exposure would be a case involving direct contact with a Pfizer product in a
pregnant woman (e.g., a nurse reports that she is pregnant and has been exposed to chemotherapeutic
products).
A male has been exposed, either due to treatment or environmental exposure to this drug prior to or around
the time of conception and/or is exposed during the partner pregnancy (paternal exposure).
As a general rule, prospective and retrospective EDP reports from any source are reportable irrespective of
the presence of an associated AE and the procedures for SAE reporting should be followed.
If a study participant or study participant’s partner becomes, or is found to be, pregnant during the study
participant’s treatment with this drug, this information must be submitted to Pfizer, irrespective of whether
an AE has occurred using the NIS AE Report Form and the EDP Supplemental Form.
In addition, the information regarding environmental exposure to this drug in a pregnant woman (e.g., a
subject reports that she is pregnant and has been accidentally exposed to a cytotoxic product by inhalation
or spillage) must be submitted using the NIS AE Report Form and the EDP Supplemental Form. This must
be done irrespective of whether an AE has occurred.  
Information submitted should include the anticipated date of delivery (see below for information related to
termination of pregnancy).

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 28 of 32
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-up is
conducted to obtain information on EDP outcome for all EDP reports with pregnancy outcome unknown.  
A pregnancy is followed until completion or until pregnancy termination (e.g., induced abortion) and
Pfizer is notified of the outcome. This information is provided as a follow up to the initial EDP report. In
the case of a live birth, the structural integrity of the neonate is assessed at the time of birth. In the event of
a termination, the reason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-procedure test
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (e.g., ectopic pregnancy, spontaneous
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live born, a terminated
fetus, an intrauterine fetal demise, or a neonatal death]), the procedures for reporting SAEs should be
followed.
Additional information about pregnancy outcomes that are reported as SAEs is as follows:

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard to causality, as
SAEs. In addition, infant deaths after 1 month should be reported as SAEs when the investigator
assesses the infant death as related or possibly related to exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested. Further follow-up of
birth outcomes will be handled on a case-by-case basis (e.g., follow-up on preterm infants to identify
developmental delays).  
In the case of paternal exposure, the study participant will be provided with the Pregnant Partner Release
of Information Form to deliver to his partner. It must be documented that the study participant was given
this letter to provide to his partner.
Exposure during breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of an associated
AE. An exposure during breastfeeding report is not created when a Pfizer drug specifically approved for
use in breastfeeding women (e.g., vitamins) is administered in accordance with authorized use. However, if
the infant experiences an AE associated with such a drug’s administration, the AE is reported together with
the exposure during breastfeeding.
Medication error
A medication error is any preventable event that may cause or lead to inappropriate medication use or
patient harm while in the control of the health care professional, patient, or consumer. Such events may be
related to professional practice, health care products, procedures, and systems including: prescribing; order
communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution;
administration; education; monitoring; and use.
Medication errors include:

Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous administration,
which is the accidental use of a product outside of labeling or prescription on the part of the healthcare
provider or the patient/consumer);

Confusion with regard to invented name (e.g., trade name, brand name).
The investigator must submit the following medication errors to Pfizer, irrespective of the presence of an
associated AE/SAE:

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 29 of 32

Medication errors involving patient exposure to the product, whether or not the medication error is
accompanied by an AE.

Medication errors that do not involve a patient directly (e.g., potential medication errors or near
misses). When a medication error does not involve patient exposure to the product, the following
minimum criteria constitute a medication error report:

An identifiable reporter;

A suspect product;

The event of medication error.
Overdose, Misuse, Extravasation
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are reported to
Pfizer by the investigator, irrespective of the presence of an associated AE/SAE.
Lack of efficacy
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, irrespective of the
presence of an associated AE/SAE or the indication for use of the Pfizer product.
Occupational exposure
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the investigator, irrespective
of the presence of an associated AE/SAE.
9.5. Single reference safety document
A Single Reference Safety Document (SRSD) refers to a document that contains the information on the
known safety profile. The package insert of this product will be the SRSD in this study. Pfizer Japan Inc.
will evaluate the safety information reported by the investigator during the study period using the SRSD.
The investigator will also prescribe the drug and give the drug administration guidance based on the
SRSD.
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
The study results may be published during scientific meetings, in research paper, etc. for the purpose
of providing proper use information, etc.
Communication of issues
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable Competent
Authority in any area of the world, or if the investigator is aware of any new information which might
influence the evaluation of the benefits and risks of this product, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures taken by the
investigator to protect the study patients against any immediate hazard, and of any serious breaches of the
Protocol that the investigator becomes aware of.
11. ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION
The organizational system in this study is equivalent to that in Appendix “Organizational System for
Post-marketing Study.” The Supervisor for PMS Plan & Operation will be responsible for post-
marketing study.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 30 of 32
12. NAME, ADDRESS AND OUTSOURCED OPERATIONS OF THE PERSON WHO WAS
CONTRACTED WITH THE OPERATIONS
Address: 3-22-7 Yoyogi, Shibuya-ku, Tokyo
Company name: Pfizer R&D Japan G.K.
Scope of the outsourced operations: Planning of the study and drafting of the plan, and operations
related to study administration, etc.
Address: Sumitomo Fudosan Korakuen Bldg. 9th Floor, 1-4-1 Koishikawa, Bunkyo-ku, Tokyo
Company name: A2 Healthcare Corp.
Scope of the outsourced operations: Operations excluding the management operations of the post-
marketing survey, etc. among the study operations such as the registration reception, establishment of
post-marketing study data collection system (EDC), and data management
Address: JP Tower 29th Floor, 2-7-2 Marunouchi, Chiyoda-ku, Tokyo
Company name: Medidata Solutions, Inc.
Scope of the outsourced operations: Operations related to establishment and operation of post-marketing
study data collection system (EDC), etc.
Address: Acropolis TOKYO Bldg., 6-29 Shinogawamachi, Shinjuku-ku, Tokyo
Company name: EPS Corporation
Scope of the outsourced operations: Aggregation/analysis operations
13. ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE STUDY
RESULTS AND CRITERIA FOR DETERMINATION OF THE INITIATION
Review the risk management plan including the following contents at the scheduled timing of
milestones.
1)
Review the necessity for changing the contents of risk minimization activities for the current safety
specifications.
2)
Review the necessity for changing the contents of this study plan including the presence or absence
of new safety specifications (continuation of the study, implementation of additional study, etc.).
3)
Review the necessity for formulating risk minimization measures for new safety specifications.
14. SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR REPORTING
OF STUDY IMPLEMENTATION STATUS AND EVALUATION OF OBTAINED RESULTS TO
THE PMDA
Investigate and report the safety at the time of submission of Periodic Safety Reports, at the time of
completion of the registration (at the time of preparation of the 3rd or 4th Periodic Safety Report), and
at the time of completion of the study (at the time of preparation of the 6th Periodic Safety Report).
Report the number and ratio of patients with moderate renal impairment to all registered subjects at the
time of completion of the registration (at the time of preparation of the 3rd or 4th Periodic Safety
Report). Also, report the overall results of the study and the discussion of the results at the time of
completion of the study (at the time of preparation of the 6th Periodic Safety Report).
15. OTHER ASPECTS
1)
Amendment of the Protocol
Based on the new knowledge to be obtained according to the progress of this study, the need for
amendment of the Protocol will be examined and the Study Protocol will be amended if necessary.
Also, the need for amendment of the Protocol will be examined and will be amended as necessary
even if the partial change in the Dosage and Administration or Indication is approved during the
reexamination period (except the case when the reexamination period is newly designated), etc.

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 31 of 32
2)
Actions to be taken if any problem or question is observed
In the cases where the onset of any serious and unknown adverse reaction is suggested, a significant
increase in the frequency of adverse reactions is observed, any problem is found in the efficacy and
safety of the drug compared to those prior to the approval, the onset of a different kind of adverse
reaction is suggested, etc., the amendment of the package insert and implementation of a new special
use-results survey or post-marketing clinical study should be considered.
17. REFERENCES
NA
18. LIST OF TABLES
Page 10  Table 1. Adjustment of Dosage and Administration according to Serum Potassium Level
Page 12-13  Table 2. Schedule of Observation
Page 14  Table 3. Rough Standards for Determination of Severity of Hepatic Impairment
Page 15  Table 4. Rough Standards for Determination of Severity of Renal Impairment
Page 20  Table 5. Adverse Events related to Hyperkalaemia and Renal Impairment that Occurred
within 52 Weeks (364 Days) after the Start of Administration in Eplerenone Group for which Causal
Relationship Could Not Be Ruled Out - Safety Analysis Set
19. LIST OF FIGURES
Page 11  Figure 1. Observation Period for Each Booklet
LIST OF STAND ALONE DOCUMENTS
NA
ADDITIONAL INFORMATION
NA
CCI

Selara
A6141122 NON-INTERVENTIONAL STUDY PROTOCOL
Amended1, 01 December 2018 
Pfizer Confidential
Page 32 of 32
CCI