SPECIAL INVESTIGATION OF PREGABALIN FOR FIBROMYALGIA
Conditions: Pain Associated With Fibromyalgia
Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Lyrica® Capsule
Special Investigation
- Investigation on the Use in Patients with Fibromyalgia -
Protocol
Pfizer Japan Inc.
Date prepared: December 15, 2014 
(Version 2)
Protocol No.: A0081282
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Introduction
Pregabalin, an active ingredient of Lyrica Capsule (hereinafter called “the product”) is one of the 
derivatives of γ-aminobutyric acid (GABA) developed at Northwestern University, USA.
In the excessively stimulated excitable nervous system, pregabalin binds with high affinity to α2δ 
protein (an auxiliary subunit of voltage-gated calcium channels), which supposedly reduces
calcium inflow into presynaptic nerve terminals and suppresses the synaptic release of excitatory 
neurotransmitters, consequently leading to manifestation of analgesic activity.
As of February 2012, the product has been approved for indications of neuropathic pain 
(peripheral neuropathic pain and central neuropathic pain) and the like in 120 countries of the 
world, including the US, European Union countries, Australia and Canada. In Japan, the product 
has been approved for indications of peripheral neuropathic pain in October 2010, and pain 
associated with fibromyalgia in June 2012.
The special investigation on Lyrica Capsule (hereinafter called “the survey”) will be undertaken to 
collect or check information about the incidence of each type of disorder arising from adverse 
reactions to the product and the information on quality, efficacy and safety of the product in 
routine clinical use. The information collected through the survey will be supplied as the
information on proper use of the product to medical facilities and used to prepare the application
materials for reexamination of the product. To this end, the survey needs to be carried out in 
compliance with the Good Post-marketing Surveillance Practice (Ministry of Health, Labour and 
Welfare [MHLW] Ordinance No. 171, dated December 20, 2004). The case data collected 
through this survey will be reported to the MHLW pursuant to the Pharmaceutical and Medical 
Device Act. If applicable, the data including names of drugs, adverse reactions, gender and age 
by decade may be disclosed as a listing of patients in the “Pharmaceuticals and Medical Devices 
Safety Information” and “Pharmaceuticals
and Medical Devices
Information Website
(http://www.info.pmda.go.jp)” which are issued and managed, respectively, by the MHLW. The 
collected case data may be also disclosed if the MHLW is requested to disclose them pursuant to 
the “Act on Access to Information Held by Administrative Organs” (Act No. 42, dated May 14, 
1999). In any of the above cases, the report does not cover the name of the physicians, facilities 
or the like involved, and these pieces of information will never be published or disclosed.
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1
Objectives
The objectives of this survey are to obtain information about (1) the incidence of adverse 
reactions to the product under actual use conditions, and (2) the factors which may affect the
safety and efficacy of the product in routine clinical practice for patients with fibromyalgia.
The following events will be evaluated as major investigation items;
Peripheral edema and edema-related events*
Dizziness, somnolence, loss of consciousness, syncope and potential for accidental 
injury
Vision-related events
*: Adverse events of the cardiovascular and respiratory systems will be also checked.
2
Study population
Patients with a diagnosis of fibromyalgia. The patients should not have used the product 
before the survey.
The standards used for the diagnosis of fibromyalgia will be also checked.
(International diagnostic criteria: (i) Classification Criteria for Fibromyalgia of American 
College of Rheumatology [ACR] 1990, (ii) Preliminary Diagnostic Criteria for Fibromyalgia of 
ACR 2010(*), (iii) Fibromyalgia Activity Scale [FAS-31], (iv) others [e.g., revision of (*)])
The indications, dosage and administration of the product for fibromyalgia are specified 
below:
Indication: Pain associated with fibromyalgia
Dosage and Administration: The usual starting dose in adults is 150 mg/day of 
pregabalin orally administered in 2 divided doses, which
may be gradually increased to 300 mg/day over one 
week or longer. Subsequently, the dose is maintained at 
300 to 450 mg/day. The dose may be adjusted 
depending on age and symptoms as appropriate, 
provided the daily dose may not exceed 450 mg and the 
product should be orally administered in 2 divided doses
regardless of the daily dose.
The latest version of the package insert should be 
referred to when the product is prescribed.
3
Target sample size
The target sample size is 500 patients. At least 50 male patients with fibromyalgia will be 
included in the survey.
[Rationale]
The adverse reactions included in the major investigation items for the product and the 
incidence in 250 patients with fibromyalgia treated with pregabalin in the phase 3 study 
conducted in Japan (Study No. A0081208, 16 weeks) were as follows: peripheral edema (17 
patients, 6.8%), edema (3 patients, 1.2%), dizziness (72 patients, 28.8%), somnolence (113 
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patients, 45.2%), loss of consciousness (1 patient, 0.4%), syncope (0 patient, 0%), and 
vision-related events (23 patients, 9.2%). These results suggested that there are no 
significant difference in anticipated risks between the population with peripheral neuropathic 
pain and the population with fibromyalgia. Thus, the safety profile of the product in patients 
with fibromyalgia will be investigated by comparing the results of the present survey with the 
adverse reaction profiles in the currently ongoing drug use investigation in 3000 patients with 
peripheral neuropathic pain. The target sample size of 500 patients is expected to have a 
95% or higher probability to detect adverse reactions occurring at the incidence of 1% or 
higher, which include peripheral edema, edema, dizziness, somnolence, and vision-related 
events.
4
Planned survey period
The survey period and the period for registration into the survey are specified below:
Survey period: December 2012 to September 2016
Registration period*: December 2012 to September 2015
*: Patient registration will be continued until the number of registered patients reaches the 
target sample size.
5
Survey procedures
5.1 Survey method
The survey will be conducted with the central registration system.
5.2 Data collection method
In this survey, data will be collected using the survey form provided by Pfizer Japan Inc. 
(hereinafter called “the sponsor”). The investigator will complete the survey forms and 
submit them to the sponsor during the survey.
5.3 Patient registration
(1) Registration
When the product is administered to the patients satisfying the eligibility criteria shown 
below, the investigator will fill in the following items for registration in the registration 
forms and fax them to the Registration Center to register patients until the targeted 
number of patients is reached. Considering that the incidence of adverse events
included in the major investigation items (peripheral edema, dizziness, etc.) was 
highest during the early stage of treatment with the product, registration of patients 
should be done within 7 days as a rule (within 14 days at latest), counting the day of the 
start of treatment with the product as Day 1, with the aim of enabling appropriate 
collection of information on these adverse events.
1)
Eligibility criteria
Patients with a diagnosis of fibromyalgia.
Patients having never used the product before the survey
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2)
Registration items
Basic information including name initials of the patient (as needed), ID code, 
gender, birth date (or age), starting date for treatment with the product and eligibility 
to the survey.
(2) Exclusion from registration
Patients who are found to be ineligible for registration after reception of the patient 
registration forms by the Registration Center will be excluded from registration.
[Registration Center]
ACRONET Co., Ltd
FAX number: +81-120-770-190 (toll-free)
5.4 Observation period
The observation period will start on the first day of treatment with the product (Day 1)
and last until Week 52 (Day 364).
For patients who are continuing treatment as of Week 52, safety will be evaluated on the 
day of the first visit after the end of the observation period (including the last day of the 
observation period), and safety information will be collected.
In cases where treatment has been completed or discontinued before Week 52, safety 
will be evaluated until the day of the first visit following 7-day period after the completion 
(discontinuation) of treatment, and safety information will be collected for this period.
Completion of treatment means cases where further treatment with the product is 
judged unnecessary because of achievement of the purpose of treatment set at the 
start of treatment (e.g., cure of target diseases).
5.5 Precautions in completion of survey form, correction and confirmation
(1) Completion of survey form
The investigator should check each survey item and write down data using an 
inerasable pen or ballpoint pen, on the basis of the records of healthcare (medical 
records, test reports, etc.). Data entry sample etc. should be referred to for detailed 
procedure.
(2) Data correction
The investigator should correct entries by drawing double strikethrough (=) on the 
mistake and affix a seal on the strikethrough while keeping the original entries legible. If 
the sponsor places inquiry about the entered information, the investigator should check 
the above-mentioned healthcare records again and, as needed, correct the information 
on the survey form and submit the form again. When any information related to 
evaluation of efficacy and safety is corrected, the reason for correction and the date of 
correction should also be entered in principle.
(3) Data confirmation
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Upon completion of entry and correction of all survey data, the investigator should
check the information on the completed survey form and the re-inspection form again.
The investigator should print his/her name and affix a seal, or instead put his/her 
signature, on the checked form.
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6
Items and time of survey
The investigator will conduct the survey in accordance with the observation schedule 
given below. After conclusion of the contract on the survey, the investigator will register 
eligible patients. Then, the investigator will check the data on each registered patient 
(including the data on background variables at the start of treatment) and fill in the survey 
form for each patient.
[Observation schedule]
Registration 
form
Survey form
Time point of observation
Survey items
At 
registration1)
Observation period
Start of 
treatment
Week 
4
Week 
13
Week 
26
Week 52
(or completion/
discontinuation)
Identifiable patient 
information
ID code


Name initials (not 
indispensable)


Gender


Birth date (age)


First day of treatment with the 
product

Eligibility

Background variables
Height/body weight2)

Hospitalization status 
(inpatient/outpatient)

Target disease, severity, 
duration

Tender points based on “ACR 
1990 Criteria for Classification 
of Fibromyalgia”

Widespread pain index (WPI) 
and symptom severity (SS) 
scores based on 
“Fibromyalgia Activity Scale
(FAS-31)”3)

Presence/absence of 
hepatic/renal dysfunction and 
severity

Creatinine clearance4)

Presence/absence of 
hemodialysis

Presence/absence of ocular 
disease 
history/complications5)

Disease history (information 
other than the target disease)

History of previous treatment 
drugs for the target disease 6)

Pregnancy status and date of 
delivery/planned date of 
delivery (females only)

Number of days of absence 
from work (including 
housework and school) 
because of fibromyalgia in 
past four weeks


Records of treatment with the product
Information regarding hemodialysis (if 
observed)
Concomitant therapy (concomitant 
drug therapy/concomitant non-drug 
therapy)
Test
Body weight, creatinine 
clearance





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Presence/absence of 
withdrawal symptom/rebound 
phenomenon as of 7 days 
after 
completion/discontinuation7)

Presence/absence of 
hyperalgesia


Laboratory test
Clinical evaluation
Pain score





Quality of sleep score





Questionnaire about mind 
and body (PHQ-9)





Questionnaire about health 
status (EQ-5D)





Fibromyalgia Activity Scale
(FAS-31)





Japanese version of the 
Revised Fibromyalgia Impact 
Questionnaire (JFIQR)





Patient’s impression (PGIC)

Physician’s impression 
(CGIC)

Patient summary

Adverse events
Data to be entered; Printed on survey form
1):
Entry at the time of patient registration. These pieces of information related to patient registration will be registered within 7 days 
after the start of treatment, as a rule, and within 14 days at the latest.
2):
Body weight at the start of treatment will be entered in the field of “Body weight” of Tests.
3):
To be entered in Clinical Evaluation [FAS-31].
4):
Creatinine clearance at the start of treatment will be entered in the field of “Creatinine clearance” of Tests.
5):
To be entered in Background variables (disease history).
6):
The drugs previously used for the treatment of target disease in the period from 14 days to 1 day before the start of treatment with 
the product will be entered.
7):
For patients who have completed (discontinued) administration of the product, withdrawal symptom/rebound phenomena observed 
in the period from the day of completion (discontinuation) of treatment to 7 days later will be entered.
6.1 Information necessary for identifying patients
The following data will be entered at the time of patient registration.
[1]
Identification code*
[2]
Name initials (as needed)*
*: Data to be collected on the registration form (to be printed on the survey form).
6.2 Background variables
(1) The following information will be entered as of the day of start of administration of the 
product.
[1]
Gender*
[2]
Birth date (age)*
[3]
First day of treatment with the product
[4]
Height
[5]
Body weight
[6]
Hospitalization status (inpatient/outpatient)
[7]
Target disease, severity, duration
[8]
Tender points based on “American College of Rheumatology (ACR) 1990
Criteria for Classification of Fibromyalgia”
[9]
Widespread pain index (WPI) and symptom severity (SS) scores based on 
“Fibromyalgia Activity Scale (FAS-31)” (reference values)
[10] Presence/absence of hepatic/renal dysfunction and severity
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[11] Creatinine clearance
[12] Whether the patient is on hemodialysis or not
[13] Presence/absence of ocular disease history/complications (This item will be
entered in the field of disease history.)
[14] Disease history (information other than the target disease)

Name of disease or syndrome

Whether the disease is a past one or is present now.
The name of chronic disease (including allergy), disease requiring treatment, disease 
or disorder requiring or causing surgery, hospitalization or sequelae, and other 
possibly problematic disease or syndrome will be recorded. The disease or syndrome 
which has healed before the start of treatment with the product is counted as “past 
disease” and the disease or syndrome present at the start of treatment is counted as 
“present disease.”
[15] History of previous treatment drugs for the target disease (name, dosage form 
category, daily dose, administration period, and reason for discontinuation of 
the drugs used during the period from 14 days to 1 day before the start of 
treatment with the product)
*: Data to be collected on the registration form (to be printed on the survey form).
(2) The following status from the day of start of treatment with the product through the day 
of safety evaluation will be entered.
[1]
Pregnancy status and date of delivery/planned date of delivery (females only)
(3) The following items of evaluation will be checked and record the results before the start 
of treatment with the product and at Week 52. In cases where treatment has been 
completed or discontinued before Week 52, the data at the time of completion 
(discontinuation) of treatment will be entered.
[1]
Number of days of absence from work (including housework and school) 
because of fibromyalgia in past four weeks
6.3 Records of treatment with the product
The following information about the product administration until the day of safety evaluation 
will be entered:
[1]
Daily dose
[2]
Number of doses per day
[3]
Timing of administration
[4]
Dosing period
[5]
Reason for change of dose levels
In cases receiving hemodialysis, the following information will be also entered:
[6]
Frequency of dialysis
[7]
Duration of each session of dialysis
[8]
Supplemental dose after dialysis
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6.4 Concomitant therapy
(1) Concomitant drug therapy
The following information will be entered about all drugs used by the day of safety 
evaluation.
Medications administered for treatment of adverse events should be also entered.
[1]
Name of drug (brand name)
[2]
Dosage form category
[3]
Daily dose
[4]
Number of doses per day
[5]
Dosing period
[6]
Reasons for the use of drugs
(2) Concomitant non-drug therapy
The following information will be entered about the non-drug therapies administered by 
the day of safety evaluation.
Non-drug therapy administered for treatment of adverse events should be also entered.
[1]
Name of therapy
[2]
Period of use
[3]
Reason for use
6.5 Test
(1) Body weight, creatinine clearance
The following information will be entered. The body weight will be measured before the 
start of treatment with the product, at Week 4, Week 13, Week 26 and Week 52 and by 
the day of safety evaluation. If the investigator considers that the change in any of these 
values from the pre-treatment level is abnormal, it will be reported as an adverse event.
[1]
Date of evaluation
[2]
Results
(2) Presence/absence of withdrawal symptom/rebound phenomenon
For patients who have completed (discontinued) administration of the product, 
withdrawal symptom/rebound phenomena observed in the period from the day of 
completion (discontinuation) of treatment to 7 days later will be entered.
[1]
Results
(3) Presence/absence of hyperalgesia
Information will be entered about the presence/absence of hyperalgesia before the start 
of treatment and at Week 52 or at the time point of last observation. In cases where 
treatment has been completed or discontinued before Week 52, the data at the time of 
completion (discontinuation) of treatment will be entered. If the investigator considers 
that the change in the condition of hyperalgesia from the pre-treatment status, it will be
reported as an adverse event.
[1]
Results
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(4) Laboratory test
The results of the following tests conducted before the start of treatment with the 
product through the day of safety evaluation will be entered. The latest results of the 
tests conducted before the start of treatment will be entered in the field of the tests 
before the start of treatment with the product.
[Test items]
Serum creatinine
Serum amylase
Free thyroxine (Free T4) or serum total thyroxine (T4)
Thyroid-stimulating hormone (TSH)
Blood sugar (fasting)
Hemoglobin A1c (HbA1c)
Creatine kinase (CPK)
Triglyceride
LDL -cholesterol (LDL-Cho)
Prolactin
[Matters to be entered]
[1]
Date of measurement
[2]
Results
6.6 Clinical evaluation
The product is evaluated with the following items of evaluation before the start of 
treatment with the product and at Week 4, Week 13, Week 26, and Week 52 or at the 
time point of last observation, and the date and results of evaluation will be entered. In 
cases where treatment has been completed or discontinued before Week 52, the data 
at the time of completion (discontinuation) of treatment will be entered.
1)
Pain score: The pain from fibromyalgia experienced during the past 24 hours will be
rated at the time of getting up in the morning on a 11-grade scale, ranging from 0 
(no pain) to 10 (the most severe pain possible).
2)
Quality of sleep score: The quality of sleep experienced during the past 24 hours 
will be rated at the time of getting up in the morning on a 11-grade scale, ranging 
from 0 [the best sleep possible] to 10 [the worst sleep possible].)
3)
Questionnaire about mind and body (Patient Health Questionnaire [PHQ-9]):
Symptoms related to depression will be evaluated based on the following 9 
questions: 1 (little interest or pleasure in doing things), 2 (feeling down, depressed, 
or hopeless), 3 (trouble falling or staying asleep, or sleeping too much), 4 (feeling 
tired or having little energy), 5 (poor appetite or overeating), 6 (feeling bad about 
yourself – or that you are a failure or have let yourself or your family down), 7 
(trouble concentrating on things, such as reading the newspaper or watching 
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television), 8 (moving or speaking so slowly that other people could have noticed. 
Or the opposite – being so fidgety or restless that you have been moving around a 
lot more than usual), 9 (thoughts that you would be better off dead, or of hurting 
yourself).
4)
Questionnaire about health status (EuroQol-5 Dimension [EQ-5D]): Health status 
will be evaluated based on the following 5 questions: mobility, self-care, usual 
activity (e.g., work, study, housework, family or leisure activities), pain/discomfort, 
and anxiety/depression.
5)
Fibromyalgia Activity Evaluation List (FAS-31)
Widespread pain index (WPI): Applicable symptoms will be evaluated;
(Jaw [left/right], shoulder [left/right], upper arm [left/right], forearm [left/right], chest, 
abdomen, thigh [left/right], lower leg [left/right], neck, back [upper/lower], buttocks 
[left/right]).
Symptom severity (SS) Symptoms: Applicable symptoms will be evaluated;
(Having difficulty in getting over from fatigue, 0 [no problem], 1 [mild], 2 [moderate], 
3 [severe]; feeling discomfort or feeling that something is wrong when getting up, 0 
[no problem], 1 [mild], 2 [moderate], 3 [severe]; easily forgetting time and place, 0 
[no problem], 1 [mild], 2 [moderate], 3 [severe]).
Symptom severity (SS) General physical symptoms: Applicable symptoms will be
evaluated;
(Muscle pain, feeling that the abdomen is swollen/sense of distension, getting tired 
easily, decreased thinking ability, decreased muscle strength, headache, twitching 
in the upper part of the abdomen, numbness, dizziness, difficulty in falling 
asleep/sleep disorder, feeling melancholic, constipation, pain in the upper part of 
the abdomen, feeling nauseous, nervous, pain in the chest, visual impairment, 
pyrexia, diarrhea, dry mouth/decreased salivary secretion, itchiness, wheezing like 
asthma, coldness in fingers and toes, urticaria, tinnitus, vomiting, feeling sick at 
stomach/heartburn, stomatitis, feeling taste different than usual when eating or 
drinking, spasm, dry eye/decreased tear secretion, breath shortness, decreased 
appetite, rash, sensitive to light, having difficulty in hearing/deafness, becoming 
bruised easily, hair loss, going to bathroom frequently/pollakiuria, feeling pain on 
urination, pain in the lower part of the abdomen).
6)
Japanese version of the Revised Fibromyalgia Impact Questionnaire (JFIQR)
Duration (years) after the onset of the symptoms of fibromyalgia
Duration (years) after the first diagnosis of fibromyalgia
The following activities will be evaluated: (brushing or combing hair), (walking 
continuously for 20 minutes), (preparing a homemade meal), (vacuuming, wiping 
or sweeping floor), (lifting and carrying shopping bags and other slightly heavy 
materials), (climbing one flight of stairs), (changing bed sheet), (sitting on a chair 
for 45 minutes), and (going shopping for groceries).
To what extent the following situations are true of each patient will be evaluated; 
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(Failing to carry out works and daily activities because of fibromyalgia), and 
(mentally exhausted because of fibromyalgia] will be evaluated).
Evaluation will be made concerning the following questions; How much pain did 
you have? How much vitality did you have? How stiff was your body? How was the 
quality of your sleep (how did you feel when you woke up in the morning)? How 
depressed did you feel? How easily did you forget? How much anxiety did you 
feel? How much pain did you feel when your body was pressed or touched? How 
much dizziness did you feel or how easily did you fall? How sensitive were you to 
loud sound, strong light, smell, or coldness?
The patient’s and physician’s impressions about the patient’s condition will be evaluated 
at Week 52 or at the time point of last observation as compared with the impressions
before the start of treatment with the product in order to evaluate the efficacy of this drug,
and the date and results of evaluation will be entered. In cases where treatment has 
been completed or discontinued before Week 52, the data at the time of completion 
(discontinuation) of treatment will be entered.
7)
Patient’s impression (Patient Global Impression of Change [PGIC])
1. Markedly improved
2. Improved
3. Slightly improved
4. Unchanged
5. Slightly worsened
6. Worsened
7. Markedly worsened
8)
Physician’s impression (Clinical Global Impression of Change [CGIC])
1. Markedly improved
2. Improved
3. Slightly improved
4. Unchanged
5. Slightly worsened
6. Worsened
7. Markedly worsened
6.7 Patient summary
The appropriateness of continuation of treatment with the product will be checked on 
the day of safety evaluation. In cases where continuation of treatment with the product 
is not possible, one major reason should be selected from the alternatives given below. 
If adverse events, abnormalities in laboratory parameters or the death of patient is 
selected as a major reason, the information should be entered in the “adverse event” 
field.
In cases where treatment has been completed or discontinued before Week 52, the 
status at the time of completion (discontinuation) of treatment will be checked and the 
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data will be entered.
[1]
Insufficient clinical efficacy
[2]
Recovery (effective)
[3]
Adverse events
[4]
Abnormalities in laboratory parameters
[5]
Death of patient
[6]
Lost to follow-up
[7]
Others
In cases where no revisit has been made after the start of treatment, it should be 
entered in the “Confirmation of re-visit after the start of treatment” field.
6.8 Adverse events
For evaluation of safety, the incidence of adverse events following the start of treatment 
with the product through the date of safety evaluation will be checked, and the following 
information will be entered. If any adverse event occurs, the investigator should take 
appropriate measures, immediately report it to the sponsor and, as a rule, observe the 
course and outcome of the event until disappearance of the symptom(s).
A detailed investigation will be separately carried out if patients develop serious adverse 
reactions or adverse reactions included in the major investigation items and the sponsor 
deems it necessary.
Presence/absence of adverse events related to the major investigation items, potential 
risks of the product (suicidal ideation [including suicide attempt and suicide after start of 
treatment]), and other risks (pathologic changes in appetite and activity) is checked.
[1]
Day of safety evaluation
[2]
Presence/absence of adverse events
[3]
Name of adverse event
[4]
Date of onset
[5]
Measures taken
[6]
Seriousness
[7]
Outcome
[8]
Causal relationship to the product
[The following information should be entered if the adverse event is associated with 
abnormal changes in test data such as laboratory tests.]
[9]
Name of test
[10]
Reference value at the facility
[11]
Unit
[12]
Date of measurement
[13]
Results
Supplementary note: Adverse events mean all events unfavorable for the patient, arising 
after treatment with the product, regardless of presence/absence 
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of causal relationship to the product (including clinically significant 
abnormal changes in laboratory parameters). Serious adverse 
events mean death, life-threatening events, and events possibly 
causing hospitalization, extension of hospital stay period, 
permanent 
or 
marked 
disorders/disabilities, 
congenital 
anomalies/defects or other medically significant events/disorders.
6.9 Major investigation items
The following events should be evaluated as major investigation items in this survey.
[1]
Peripheral edema and edema-related events
Information will be collected about the presence/absence of events related to 
peripheral edema and the course of patients before and after the onset of events. 
The situations on development of these events will be analyzed by means of 
factor analysis, including analysis of the site affected, dose of the product, 
concomitant therapy, background variables, etc. The package insert gives 
precautions on congestive heart failure in patients presenting symptoms related 
to edema. In 30 overseas placebo-controlled studies, the incidence of 
hypertension and dyspnea was higher in the patients developing peripheral 
edema than in patients free of peripheral edema, although the incidence of the 
other events did not differ markedly between these two groups. In view of these 
facts, information on cardiac function and the incidence of adverse events of the 
respiratory system will be also collected.
[2]
Dizziness, somnolence, loss of consciousness, syncope and potential for 
accidental injury
Information will be collected about the presence/absence of events related to 
dizziness, somnolence, loss of consciousness, syncope and potential for 
accidental injury and the course of patient’s condition before and after the onset 
of the events. The situations on development of these events will be analyzed by 
factor analysis, including analysis of the dose of the product, concomitant 
therapy, background variables and so on.
[3]
Vision-related events
Information will be collected about the presence/absence of events related to the 
eyes and the course of patient’s condition before and after the onset of the 
events. The situations on development of the events will be analyzed by factor 
analysis, including analysis of the dose of the product, concomitant therapy, 
background variables and so on.
Patients developing adverse events included in the major investigation items will be 
separately investigated in detail if the sponsor deems it necessary.
7
Items to be analyzed and analysis methods
7.1 Analysis set
Safety analysis set will include patients who satisfy the eligibility criteria and have been 
confirmed to have taken the product at least once. Efficacy analysis set will include 
patients who are evaluable for efficacy in accordance with the separately set analysis 
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10
References
Attachment 1: Adverse event report
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