The Special Drug Use-results Survey (All-Case Surveillance) of Ofev® Capsules in Patients With Idiopathic Pulmonary Fibrosis (IPF) in Japan
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

ABCD
 
Non-interventional Study Protocol
 
Document Number:
c03498541-04
BI Study Number:
1199. 202
BI Investigational
Product(s):
Nintedanib
Title:
The special drug use-results survey (All-Case Surveillance) of 
Ofev® Capsules in patients with Idiopathic Pulmonary Fibrosis
(IPF) in Japan
Brief lay title:
Japanese PMS of Nintedanib in IPF
Protocol version 
identifier:
4.0
Date of last version of 
protocol:
21 November 2016
PASS:
Yes
EU PAS register 
number:
EUPAS10891
Active substance:
Nintedanib
Medicinal product:
Ofev® Capsules 100mg
Ofev® Capsules 150mg
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
To evaluate real-world safety and effectiveness of Ofev®
Capsules treatment in patients with IPF
Country(-ies) of study:
Japan
Author:
Marketing authorisation 
holder(s):
MAH contact person:

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EU-QPPV:
Signature of EU-QPPV:
(The signature of the EU-QPPV is provided electronically)
Date:
20 November 2017
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Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF TABLES AND FIGURES...................................................................... 5
3.
LIST OF ABBREVIATIONS................................................................................ 6
4.
RESPONSIBLE PARTIES.................................................................................... 7
5.
ABSTRACT........................................................................................................... 8
FLOW CHART............................................................................................................. 12
6.
AMENDMENTS AND UPDATES..................................................................... 14
7.
MILESTONES..................................................................................................... 15
8.
RATIONALE AND BACKGROUND................................................................ 16
9.
RESEARCH QUESTION AND OBJECTIVES ................................................. 18
10.
RESEARCH METHODS .................................................................................... 19
10.1
STUDY DESIGN............................................................................................ 19
10.2
SETTING........................................................................................................ 20
10.2.1
Site selection ........................................................................................... 20
10.2.2
Selection of population............................................................................ 20
10.2.2.1
Registration period..........................................................................20
10.2.2.2
Patient registration method .............................................................20
10.2.3
Discontinuation of the study by the sponsor ........................................... 20
10.3
VARIABLES .................................................................................................. 21
10.3.1
Exposures ................................................................................................ 21
10.3.2
Outcomes................................................................................................. 21
10.4
DATA SOURCES........................................................................................... 24
10.5
STUDY SIZE.................................................................................................. 24
10.6
DATA MANAGEMENT................................................................................ 25
10.7
DATA ANALYSIS......................................................................................... 25
10.7.1
Analyses of outcome events.................................................................... 25
10.7.2
Interim analyses....................................................................................... 26
10.8
QUALITY CONTROL................................................................................... 27
10.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 27
10.10 OTHER ASPECTS ......................................................................................... 27
10.10.1
Informed consent, data protection, study records ................................... 27

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10.10.1.1
Study approval, patient information, and informed consent...........27
10.10.1.2
Data quality assurance ....................................................................27
10.10.1.3
Records ...........................................................................................28
10.10.1.3.1
Source documents...................................................................................28
10.10.1.3.2
Direct access to source data and documents...........................................28
10.10.1.4
Statement of confidentiality............................................................28
11.
PROTECTION OF HUMAN SUBJECTS .......................................................... 29
12.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 30
12.1
DEFINITTIONS OF ADVERSE EVENT...................................................... 30
12.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING......................................................................................... 31
12.3
REPORTING TO HEALTH AUTHORITIES................................................ 33
13.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 34
14.
REFERENCES .................................................................................................... 35
14.1
PUBLISHED REFERENCES......................................................................... 35
14.2
UNPUBLISHED REFERENCES................................................................... 35
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 36
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 37
ANNEX 3. THE CLASSIFICATION OF MODIFIED MRC DYSPNEA SCALE..... 44

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2.
LIST OF TABLES AND FIGURES
Table  10.3.3: 1
Disease Severity..........................................................................................23
Table 10.6: 1
Contract research organizations.....................................................................25

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3.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANA
Anti nuclear antibody
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
b.i.d.
Bis In Die (twice a day)
BNP
Brain natriuretic peptide
Cr
Creatinine
CK
Creatine Kinase
CRF
Case Report Form
CRP
C-reactive protein
CTP
Clinical Trial Protocol
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
FEV1
Forced Expiratory Volume in 1 second
EU-QPPV
European Union-Qualified Person for Pharmacovigilance
FVC
Forced Vital Capacity
GGT
Gamma-glutamyltransferase
GPSP
Good Post-marketing Study Practice
IIP
Idiopathic Interstitial Pneumonia
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
J-RMP
Japanese Risk Management Plan
KL-6
Krebs von den Lungen-6
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health Labour and Welfare
PaO2
Arterial O2 Pressure
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
PSUR
PT-INR
Periodic Safety Update Report
Prothrombin time- international normalized ratio
RF
Rheumatoid factor
SAE
Serious Adverse Event
SP-A
Surfactant protein A
SP-D
Surfactant protein D
SpO2
Oxygen Saturation on pulse oximetry

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4.
RESPONSIBLE PARTIES
Contact details and the list of all investigators will be kept in a stand-alone document. 
This document will be managed in the special drug use-results survey (All-Case 
Surveillance) tracking system which manage the contracts with site and investigators 
name.

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5.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Ofev® Capsules
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 August 2015
1199. 202
Ver. 4.0
20 November 2017
Title of study:
The special drug use-results survey (All-Case Surveillance) of Ofev®
Capsules in patients with Idiopathic Pulmonary Fibrosis (IPF) in Japan
Rationale and 
background:
Treatment strategies for IPF are limited and the unmet medical need 
for efficacious and safe treatment of IPF remains high.
In pooled data of the multicentre international phase III trials 1199.32 
and 1199.34, treatment with Ofev® Capsules 150 mg b.i.d. for 52 
weeks significantly reduced the annual decline in FVC compared to 
placebo. Most patients experienced any AEs, with slightly higher 
incidence in the Ofev® Capsules group than in the placebo group.
There was no difference in the proportion of patients experiencing 
serious adverse events between the treatment groups.
A total of 76 Japanese patients in 1199.32 and 1199.34 were 
administered Ofev® Capsules 150 mg b.i.d. However, there may be 
limitations in the clinical trial setting such as limited experience of 
nintedanib use in Japanese patients, limited concomitant drugs and 
exclusion of complicating diseases as defined in the study protocol. 
Therefore, it is considered important to generate complementary data 
for real-world effectiveness and safety of nintedanib in a non-
interventional study based on newly collected data in Japanese patients 
with IPF.
Japanese regulation related to PMS
The Japanese Law for Ensuring the Quality, Efficacy, and Safety of 
Drugs and Medical requires accumulating safety and effectiveness 
data of launched products in Japan for re-examination. After 10 years 
from approval, the results of the PMS are needed to be submitted to 
the Japanese regulatory authority, the PMDA, as a part of the re-
examination dossier. The PMS plan is a part of the J-RMP and the J-
RMP will be submitted to the PMDA with J-CTD and need to be 
approved by PMDA as approval condition.
Japanese regulation related to All-Case Surveillance
The All-Case Surveillance means a use-results survey that is 
conducted to collect information on all patients who have used the 
product since its launch until a data from certain number of cases have 
been accumulated. The All-Case Surveillance is required for products 
that needs the background information of patients treated with the 
product as well as safety and effectiveness issues related to the product 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Ofev® Capsules
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 August 2015
1199. 202
Ver. 4.0
20 November 2017
for reaffirming approval details and collecting information which is 
essential for proper use at the earliest possible stage, thoroughly.
For example, the regulatory agency may require the implementation of 
the All-Case Surveillance for a pharmaceutical product as an approval 
condition when there are only a small number, or even no cases 
existing in clinical trials in Japan and when there are any concerns 
about the pharmaceutical product regarding the occurrence of serious 
adverse drug reactions. Necessity for the All-Case Surveillance is 
determined by the following steps: review in PMDA1), subsequent 
discussion by the Pharmaceutical Affairs and Food Sanitation Council, 
and the final decision by MHLW.
Research question 
and objectives:
The safety of Ofev® Capsules has been confirmed by the results of 
clinical trials. However, there is a possibility in a real world that Ofev®
Capsules are administered to patients with more severe IPF than 
patients in clinical trials. Also data in Japanese patients and in patients 
who were administered Ofev® Capsules for a long period are limited. 
Futheremore , according to the pharmacological action, the possibility 
of the occurrence of some risks defined in the J-RMP cannot be 
excluded.
As stated above, safety and effectiveness of Ofev® Capsules need to be 
carefully examined under a Japanese real world setting.
Study design:
Non-interventional study based on newly collected data.
The study will consist of a baseline visit and follow-up visits at Week 
4, 13, 26, 39, 52, 65, 78, 91 and 104 for patients who have newly
initiated Ofev® Capsules. The patients will be followed up until 
discontinuation of Ofev® Capsules treatment, death, lung 
transplantation and the end of study, which ever comes first and will 
be censored if one of the event occurs.
All patients administrated Ofev® Capsules after the launch at the sites 
contracted with the sponsor will be registered. CRFs of 1000 patients 
will be collected. 
However the patient registration continues until the approval condition 
has been removed.
Population:
Essentially, patients are diagnosed with IPF based upon the most recent 
ATS/ERS/JRS/ALAT guideline.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Ofev® Capsules
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 August 2015
1199. 202
Ver. 4.0
20 November 2017
Variables:
Exposure to Ofev® Capsules is estimated as time from the day Ofev®
Capsules is initiated until the day the drug is last administrated on a 
patient-level (or the final contact with the patient for the last regular 
observation) and considering dosage.
Outcomes: 
Safety
Any suspected ADRs, Serious AEs and AEs leading to treatment 
discontinuation, Priority survey items (at least occurrence of 
gastrointestinal symptoms including diarrhoea and nausea, hepatic 
function disorder, thromboembolism, gastrointestinal perforation, 
bleeding and drug-induced interstitial pneumonia), and Laboratory
tests
Effectiveness
Absolute change from baseline in FVC at Week 104, and the 
further outcomes including the incidence of acute exacerbation of 
IPF.
Others
Demographics including e.g. smoking status, Baseline 
characteristics of disease, Comorbidities, Previous drug/Co-
medications for IPF and for the others except IPF
Data sources:
CRFs for individual patients will be gathered by the EDC system.
When a site does not accept the EDC system, paper CRFs will be used 
to collect the data.
After the medical examination and observation at the specified points
(Baseline, Week 4, Week 13, Week 26, Week 39, Week 52, Week 65, 
Week 78, Week 91 and Week 104 or discontinuation/ dropout) are 
completed, the investigator needs to immediately enter data of the 
registered patients (including withdrawals and dropouts) in the EDC.
Four case books will be used, data are to be transmitted immediately 
after being entered into EDC at Week 13 (Book 1), Week 52 (Book 2), 
Week 78 (Book 3) and Week 104 (Book 4) after the start of treatment 
or at discontinuation. Baseline data are to be entered and transmitted 
within two weeks after the start of treatment.
In case that any adverse events occur, the data should be immediately 
entered into EDC and transmitted.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Ofev® Capsules
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 August 2015
1199. 202
Ver. 4.0
20 November 2017
Study size:
It is planned to register patients over a time period of about one year
until it is confirmed that 1000 patients with IPF can be included in the
safety analysis in consideration of feasibility. With a sample size of 
1000 patients, any ADR with frequency of 0.3% or higher can be 
detected with probability of 95% or greater in at least one patient. The 
proportion of overall patients with maximum ALT and/or AST ≥5 
Upper Limit of Normal was 2.2% in nintedanib group on the pooled 
data of trials 1199.32 and 1199.34. If the true proportion of patients 
with liver enzymes elevation is assumed to be 2-fold (i.e., 4.4%), the 
sample size of 626 is required to have 90% power for rejecting the 
null hypothesis of incidence=2.2% by using one sample chi-square test 
with a 0.05 two-sided significance level.
Data analysis:
Analyses are descriptive in nature including means, standard 
deviation, Q1, medians, Q3, frequency and percentages. For safety 
outcomes, incidence rates with corresponding 95% confidence 
intervals will also be calculated. For effectiveness outcomes, the point 
estimate and 95% confidence intervals from statistical models will be 
calculated for exploratory purpose. Given the non-interventional 
setting and that this all user-registry does include a very heterogenous 
population, results cannot be directly compared to RCT results. If 
comparisons are conducted only comparable subgroups could be 
evaluated with caution.
Due to the nature of the observational study, no confirmatory 
statistical testing is foreseen in this study.
Milestones:
Start of data collection: The end of August 2015
  (Expected Launch : the end of August 2015)
End of data collection: 30 June 2020 (in plan)
Interim report: After Week  52 data will be collected
Final report of study results: 1Q 2021 (in plan)

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FLOW CHART
Time
Item
Registr
ation*1
Book 1
Book 2
Book 3
Book 4
Baseline
(before 
treatment
of Ofev®
Capsules)
Week 4 and 
13
or at
discontinuati
on
Week 26, 39
and 52 or at 
discontinuati
on
Week 65 
and 78
or at 
discontinu
ation
Week 91 
and 104 or 
at 
discontinuat
ion
Visit date
X
X
X
X
X
X
Date of start administration 
X
X
Date of last administration 
X
X
X
Daily dosage 
X
X
X
X
Demographics*2
X
X
X
(pregnancy
test only)
X
(pregnancy
test only)
X
(pregnancy
test only)
X
(pregnancy
test only)
Japanese IIPs severity 
grade*3, 4
X
X
X 
X 
X
Pulmonary function test*5: 
FVC*6, FVC % predicted,
FEV1 [mL]*7, FEV1 %  
predicted*7
X
X
X
X
X
Chest HRCT evaluation
X
Surgical lung biopsy
X
Faminly history of 
pulmonary fibrosis
X
Vital signs
X
Symptoms of IPF
X
X
X
X
X
Hepatic impairment 
classified according to 
Child-Pugh class A to C
X
History of surgery within  
four weeks before 
administration
X
Genetic predisposition
X
Prolonged immobility
X
Comobidities
X
X
X
X
X
Treatment states of Ofev®
X
X
X
X
X
Previous drug for IPF and 
the other except IPF
X
Co-medication for IPF and 
the other except IPF
X
X
X
X
X
Laboratory test*5
X
X
X
X
X

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FLOW CHART (continued)
Adverse events*8, including 
laboratory tests (if 
corresponding AEs are 
reported)
X
X
X
X
X
Observation / Evaluation time points are approximate. Collected data should be reported as those to the 
closest available visit.
Demographics at the registration time point are confirmed before treatment of Ofev® Capsules.
*1: All patients administrated Ofev® Capsules will be registered at the sites contracted with the sponsor  
(see section 9.2).
*2: Age and gender will be collected at registration and baseline. Pregnancy test result will be collected if 
a patient has become pregnant.
*3: Collect not only severity grade but also the measured values of PaO2(at rest) and SpO2(at 6-minutes 
walk test)
*4: Japanese IIPs severity grade evaluated within each book is collected, regardless of visit.
*5: If applicable
*6: All FVC results obtained within one year prior to the first administration of Ofev® Capsule in 
addition to baseline FVC result will be collected as much as possible.
*7: FEV1 [mL] and FEV1 % predicted will be collected at baseline only.
*8: Acute exacerbation of IPF will be identified by treating physicians. 
If report acute exacerbation of IPF, collect the following items additionally.
Check if a) to d) are applicable,
a)
Exacerbation of dyspnea within a month
b)
Newly developing bilateral ground-glass opacity and/or infiltrative shadow on a background 
honeycomb pattern
-
Check using image evaluation for diagnosis,
HRCT
Chest X-ray
None
c)
Deterioration of hypoxemia (decrease of PaO2 more than 10 mmHg under the same condition)
-
Describe the amount of decrease in PaO2
d)
Exclusion of pulmonary infection, pneumothorax, malignancy, pulmonary thromboembolism and 
heart falure
-
Check using evaluation for exclusion of pulmonaly infection
Endotracheal aspirate
Bronchoalveolar lavage
Other

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6.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
2
10 December 
2015
9.2.2
Delete the set of 
“Inclusion/exclusio
n criteria”
By PMDA’s 
instruction.
As the principle
of “all-case 
surveillance”
should include 
all cases who 
take the drug, 
the 
inclusion/exclus
ion criteria is 
deleted.
3
21 November
2016
9.2.1
9.2.2
Alternative method 
for contract in order 
to achieve the 
registration within 
14 days from 
initiation of the 
drug.
Registration 
timeline was added.
By PMDA’s 
instruction. The 
patients should 
be basically 
registered 
within 14 days 
from initiation 
of the drug.
4
20 November
2017
6
9.1
9.6
End of data 
collection and final 
report of study 
results was changed
The patients who 
need to collect CRF 
was added.
Two contract 
research 
organization ‘s 
name were changed 
and new contract 
research 
organization was 
added.
By PMDA’s 
instruction.
Transferring  to 
only 
registeration 
phase (no CRF 
collection) from 
16 October
2017.  

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7.
MILESTONES
Milestone
Planned Date
Start of data collection
31 August 2015 
End of data collection
30 June 2020 (in plan)
Interim report
After Week  52 data will be collected
Registration in the EU 
PASS register
17 August 2015
Final report of study results
1Q 2021 (in plan)

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8.
RATIONALE AND BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing 
interstitial pneumonia of unknown cause, occurring primarily in older adults. While IPF 
is the most common of the 7 major idiopathic interstitial pneumonias, it is a rare and 
fatal disease with a median survival time of 2 to 3 years following diagnosis [P11-
07084]. The natural history of IPF is variable and unpredictable [P12-03241]. Disease 
progression is manifested by increasing respiratory symptoms, worsening pulmonary 
function test results, acute respiratory decline, or death.
Ofev® Capsule is a small-molecule tyrosine kinase inhibitor. It is an indolinone 
derivative that blocks the kinase activity of the fibroblast growth factor receptors 
(FGFR) 1-3, the platelet derived growth factor receptors (PDGFR) α and β, and the 
vascular endothelial growth factor receptors (VEGFR) 1-3 [P08-08684]. Theoretical 
and pharmacological models suggest that inhibition of these kinase receptors may 
interfere with the fibrotic signaling cascade. 
Pharmaceutical treatments indicated for IPF are limited. Nintedanib and pirfenidone are 
the two drugs approved for the treatment of IPF in the US and the EU. In addition, so 
far pirfenidone is the only drug approved for IPF in Japan, South Korea, India, China, 
Argentina and Canada. Other pharmacologic options include corticosteroids, 
immunosuppressive agents, and N-acetyl cysteine, albeit none of these have been 
proven efficacious compared with placebo. Despite the availability of pirfenidone and 
lung transplantation option, the medical need for efficacious and safe treatment of 
patients with IPF remains high.
In pooled data of the 2 phase III trials, 1199.32 and 1199.34, most patients experienced 
any adverse events (AEs), with a slightly higher incidence in the Ofev® Capsules group 
than in the placebo group. There was no difference in the proportion of patients with 
serious adverse events between both treatment groups. AEs leading to death were 
slightly less frequent in the Ofev® Capsules group than in the placebo group. The most 
commonly reported AEs were gastrointestinal disorders. Of those, the most frequent 
event was diarrhea. Most of these events were of mild or moderate intensity.
Administration of Ofev® Capsules was associated with liver enzyme (ALT, AST, ALP, 
and γ-GTP) and bilirubin elevations which were reversible upon dose reduction, 
treatment interruption or withdrawal. No Hy’s law case was reported in patients treated 
with nintedanib.
Japanese regulation related to Post Marketing Surveillance (PMS)
This PMS is planned according to the Japanese Law for Ensuring the Quality, Efficacy, 
and Safety of Drugs and Medical. The law requires in principle that data on the safety 
and effectiveness of all launched products to be accumulated under real-world clinical 
practice. The data collected in the PMS are required to be submitted to the 
Pharmaceuticals and Medical Devices Agency (PMDA), the local regulatory agency in 
Japan, according to the process of re-examination which will take place 10 years after 
approval of registration. The PMS is a part of the local Risk Management Plan in Japan 
(J-RMP) to be submitted to PMDA at New Drug Application.

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Japanese regulation related to All-Case Surveillance
The All-Case Surveillance means a use-results survey that is conducted to collect
information on all patients who have used the product since its launch until a data from
certain number of cases have been accumulated. The All-Case Surveillance is required
for products that needs the background information of patients treated with the product
as well as safety and effectiveness issues related to the product for reaffirming approval
details and collecting information which is essential for proper use at the earliest
possible stage, thoroughly.
For example, the regulatory agency may require the implementation of the All-Case
Surveillance for a pharmaceutical product as an approval condition when there are only
a small number, or even no cases existing in clinical trials in Japan and when there are
any concerns about the pharmaceutical product regarding the occurrence of serious
adverse drug reactions. Necessity for the All-Case Surveillance is determined by the
following steps: review in PMDA1), subsequent discussion by the Pharmaceutical
Affairs and Food Sanitation Council, and the final decision by MHLW.

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9.
RESEARCH QUESTION AND OBJECTIVES
The safety of Ofev® Capsules has been confirmed by the results of clinical trials. 
However, there is a possibility in a real world that Ofev® Capsules are administered to 
patients with more severe IPF than patients in clinical trials. Also data in Japanese 
patients and in patients who were administered Ofev® Capsules for a long period are 
limited. Futheremore , according to the pharmacological action, the possibility of the
occurrence of some risks defined in the J-RMP cannot be excluded.
As stated above, safety and effectiveness of Ofev® Capsules need to be carefylly 
examined under a Japanese real world setting.

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10.
RESEARCH METHODS
10.1
STUDY DESIGN
This is a non-interventional study based on new data collection to gather real-world 
information (i.e., data under routine medical practice) on safety and effectiveness of the 
Ofev® Capsules treatment.
The study will be initiated after the approval of Ofev® Capsules in Japan. The study will 
consist of a baseline visit and follow-up visits at Week 4, 13, 26, 39, 52, 65, 78, 91 and 
104 for patients who have newly initiated Ofev® Capsules. The patients will be 
followed up until discontinuation of Ofev® Capsules treatment, death, lung 
transplantation and the end of study, which ever comes first and will be censored if one 
of the event occurs.
As this is an observational study, no specific treatment is mandated or withheld from 
the patients. The choice of maintenance treatment for IPF must be according to regular 
medical practice and at the discretion of the physician (i.e., no randomised assignment 
of patient to treatment is performed).
All patients  administrated Ofev® Capsules after the launch at the sites contracted with 
the sponsor will be registered. CRFs of 1000 patients will be collected. However the 
patient registration continues until the approval condition has been removed.
Patients participating in the subsequent follow-up will undergo regular observations.
These observations should be reported after approximately Week 4, 13, 26, 39, 52, 65, 
78, 91 and 104 since the initiation of Ofev® Capsules as long as they continue to receive 
the treatment. Patients will not be followed any longer once they are reported to have 
discontinued the Ofev® Capsules treatment.
Information will be collected via CRFs for patients who have been administered OFEV 
up to and including 15 October 2017. For patients administered Ofev after that time 
point, no pre-specified information will be collected via CRFs. Following this time 
point, patients will only be registered in order to count the number of patients being 
administered Ofev at every site, for so long as it is required by PMDA. 
AEs occurring after 15 October 2017 will not be collected in the CRF. These events 
will be reported spontaneously according to local regulations.
The primary outcome of this study is the frequency of patients with any suspected 
adverse drug reactions (ADRs)
The secondary outcome of this study is absolute change from baseline in FVC [mL] at 
Week 104.

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10.2
SETTING
10.2.1 Site selection
!
All sites that Ofev® Capsules have been delivered to, will participate in this study.
!
A medical representative will explain the objectives and design of this study to the 
investigators at study sites and exchange a written contract with the head of the 
study site (e.g., hospital director).
!
If the written contract could not be concluded until the first patient who initiates 
Ofev® Capsules, registration will be done by the written agreement using “request 
for cooperation / agreement for the all-case study”. 
10.2.2
Selection of population
Essentially, patients are diagnosed with IPF based upon the most recent 
ATS/ERS/JRS/ALAT guideline.
10.2.2.1
Registration period
The patient registration should continue until the approval condition has been removed.
10.2.2.2
Patient registration method
At each study site, all patients who initiate treatment with Ofev® Capsules after the 
launch will be consecutively registered into this study basically within 14 days from 
initiation of Ofev® Capsules.
Patients will be registered by entering necessary information in the electronic data 
capture (EDC) system just after initiation of administration of Ofev® Capsules. When a 
site does not accept the EDC system, paper registration form will be used to collect 
necessary information and will be sent to the sponsor by fax. The necessary information 
for registration is site name, therapeutic course, Dr. name, subject ID, gender, date of 
birth, start date of administration of Ofev® Capsules, the reason for use, whether the 
patient has taken Ofev® Capsules before participation in this study and whether the 
patient has a contraindication to Ofev® Capsules. 
Periodically, investigators will use a signed form to confirm that all patients were
registered at the site.
End of registration
Patient registration will be stopped after the approval condition has been removed.
10.2.3
Discontinuation of the study by the sponsor
A log of all patients included into the study will be maintained at the investigational 
sites.

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reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons:
1. Failure to meet expected registration goals overall or at a particular study site
2. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study
3. Violation of Good Post-marketing Study Practice (GPSP), the CTP, or the contract 
by a study site or investigator, disturbing the appropriate conduct of the study
The study site will be reimbursed for reasonable expenses incurred in case of study 
termination (except in case of the third reason).
10.3
VARIABLES
10.3.1
Exposures
Exposure to Ofev® Capsules is estimated as time from the day Ofev® Capsules is 
initiated until the day the drug is last administrated on a patient-level (or the final 
contact with the patient for the last regular observation) and considering dosage.
Dosage and administration: Usually initial dose in adult patients is nintedanib 150 mg 
twice daily; oral administration with food in morning and evening.
The dosage should be reduced to nintedanib 100 mg twice dailyaccording to the 
patient’s symptoms or in case of adverse events.
10.3.2
Outcomes
Safety
Safety will be assessed with a focus on the following variables, calculated as incidences 
(events per personyears), frequencies and percentages, always stratified by the different 
treatment types prior to baseline (in case of conflicting results those of the treatment 
naïve ones are decisive).
!
Any suspected ADRs (primary outcome)

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Effectiveness
Effectiveness will be assessed with a focus on the following variable.
!
Absolute change from baseline in FVC [mL] at Week 104 (secondary outcome)

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10.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be gathered by the EDC system.
When a site does not accept the EDC system, paper CRFs will be used.
In the EDC system, four case books will be set up; Book 1 includes baseline, Week4 
and Week 13. Book 2 includes Week 26, Week 39 and Week 52, Book 3 includes Week 
65 and 78, 104, Book 4 includes Week 91 and 104.
Data are to be transmitted immediately after being entered into the EDC system at 
Week 13 (Book 1), Week 52 (Book 2), Week 78 (Book 3) and Week 104 (Book 4) 
after the start of treatment or at discontinuation. Baseline data are to be entered and 
transmitted within two weeks after the start of treatment.
In case that any adverse events occur, the data should be immediately entered into the 
EDC system and transmitted. 
10.5
STUDY SIZE
1000 patients with IPF will be included in the safety analysis.
With a sample size of 1000 patients, any ADR with frequency of 0.3% or higher can be 
detected with probability of 95% or greater in at least one patient. 
The proportion of overall patients with maximum ALT and/or AST ≥5 Upper Limit of 
Normal was 2.2% in nintedanib group on the pooled data of trials 1199.32 and 1199.34. 
If the true proportion of patients with liver enzymes elevation is assumed to be 2-fold 
(i.e., 4.4%), the sample size of 626 is required to have 90% power for rejecting the null 
hypothesis of incidence=2.2% by using one sample chi-square test with a 0.05 two-
sided significance level.

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10.6
DATA MANAGEMENT
Patients’ data will be gathered by the EDC system provided by external vendor below.
Table 10.6: 1
Contract research organizations
Contract research 
organizations 1
Contract research 
organizations 2
Contract research 
organizations 3
Name
10.7
DATA ANALYSIS
This is a non-interventional study based on new data collection to gather real-world 
information (i.e., data under routine medical practice) on safety and effectiveness of the 
Ofev® Capsules treatment in patients with IPF. Analyses are descriptive in nature 
including means, standard deviation, Q1, medians, Q3, frequency and percentages. For 
safety outcomes, incidence rates with corresponding 95% confidence interavals will 
also be calculated. For the effectiveness outcomes, the point estimate and 95% 
confidence intervals from statistical models will also be calculated for exploratory 
purpose. Given the non-interventional setting and that this all user-registry does include 
a very heterogenous population, results cannot be directly compared to RCT results. If 
comparisons are conducted only comparable subgroups could be evaluated with caution, 
see section 10.9.
Subgroup analysis will be performed according to prior treatment (see section 10.7.1) 
and in addition, if numbers are large enough and allow stratification further subgroup 
analysis will be performed. Due to the nature of the observational study, no 
confirmatory statistical testing is foreseen in this study and in this orphan drug 
indication the numberof patients will be too small to do any sufficiently powered 
comparisons and draw any causal conclusions.
Per local regulation, any patient who meets at least one of the following criteria is 
treated as ineligible for all analyses: 
!
No follow-up visit data are available
!
No required registration procedure is followed
!
No valid site contract is available
10.7.1
Analyses of outcome events
All outcome events are based on reported AE data which will be handled according to 
BI standards (see the section below). In addition, patients will for all analysis be 
stratified by (i) no prior IPF treatment (ii) prior Pirfenidone treatment (switch)
(iii) prior Pirfenidone treatment (add-on) (iv) other prior IPF treatment (switch) 
(v) other prior IPF treatment (add-on). In case of conflicting results the results of 
the first strata ((i) no prior IPF treatment)) are decisive, because in new users potential 
bias is the smallest.

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Safety
In general, safety analyses will be descriptive in nature, and will be based on BI 
standards, and will focus on any suspected ADRs, serious AEs, AEs leading to death,
AEs leading to treatment discontinuation, and priority survey items.
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To 
this end, all AEs occurring between first intake of Ofev® Capsules prescribed at 
baseline visit and within 28 days (inclusive) after the last intake will be considered 
‘treatment emergent’. An AE is considered to be an ADR if either the physician who 
has reported the AE or the sponsor assesses its causal relationship as ‘related’.
The frequency and incidence of AEs/ADRs will be tabulated by system organ class and 
preferred term for overall and for subgroups based on the important baseline 
characteristics (see section 10.3.3). 
No imputation is planned for missing AE data except for missing onset dates which will 
be handled according to BI standard.
Effectiveness
Change from baseline in effectiveness outcomes (continuous variables) will be analysed 
using Mixed Effects Model for Repeated Measures (MMRM) with fixed effects for visit, 
gender, baseline age, baseline height, baseline FVC (or FVC% predicted),and baseline 
FVC (or FVC% predicted)-by-visit and random effect for patient. Within-patient errors 
are modelled by compound symmetry covariance matrix. With the model described 
above, the mean of the change from baseline at each visit (time points) will be 
estimated.
Annual rate of decline in FVC over 104 weeks will be analysed using random 
coefficient regression (random slopes and intercepts) model. The decrease in FVC is 
assumed to be linear within each patient over the 104 weeks. The intercepts and slopes 
will be assumed to be normally distributed with arbitrary covariance matrix. The within 
patient error will be assumed to be independent and normally distributed with mean 
zero and a common variance. The Roger-Kenward approximation will be used to 
estimate denominators degree of freedom. With the model described above, the mean of 
the sople will be estimated. The annual rate of decline in FVC over 104 weeks may be 
compared before and after the treatment.
The details of the analysis plan will be described in the statistical analysis plan.
10.7.2
Interim analyses
Several interim analyses will be performed for the purpose of creating periodic safety 
update reports to the local authority (every 6 to 12 months depending on the time from 
the approval). In addition, interim analysis will be performed after all patients without 
prematurely discontinuation of Ofev® Capsules treatment are followed up for 52 weeks. 
All available data at that point will be analysed and the results will be submitted to the 
local authority for removing the approval condition and abolishing restrictions on the 
use of Ofev® Capsules.

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10.8
QUALITY CONTROL
All processes are conducted according to GPSP SOPs <102-MLS-90-119> and GPSP 
working instruction <102-MLW-90-118-51>. Appropriate records and documents are 
stored based on the GPSP SOPs and these processes are checked by internal self-check.
10.9
LIMITATIONS OF THE RESEARCH METHODS
The general scientific objective of this non-interventional study is to obtain an estimate 
of the occurrence of the events of interest in the population under study. Due to the 
nature of a single cohort observational study, however, there are issues that may impose 
limitations in particular on the validity of the assessment based on the study data such 
as selection bias, loss to follow up, channeling bias and information and recall bias.
Thus, comparisons and causal conclusions cannot be made, except for the investigator 
reported drug-related AEs.
It is not mandatory to collect pulmonary function test data and biomarker data in this 
setting, in addition the spirometrie devices will not be identical in each study site and 
measurements not standardized, which may lead to measurement and random error.
These sources of bias and confounding should be fully taken into account as limitations
of this study design when conducting, analysing the study and interpreting results.
Especially, the comparability of the results from this survey and RCTs cannot be 
ensured due to the various type of bias mentioned above.
10.10
OTHER ASPECTS
10.10.1
Informed consent, data protection, study records
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the patient’s treating physician.
The rights of the investigator and of the sponsor with regard to publication of the results 
of the use-results survey are described in the contract. As a general rule, no results 
should be published prior to finalization of the Study Report.
10.10.1.1
Study approval, patient information, and informed consent
The review by Institutional Review Board (IRB) is not mandatory for conducting the 
PMS in Japanese GPSP. The sponsor will enter into a contract with a representative
(i.e., head of hospital) in accordance with GPSP. Written informed consent prior to 
patient participation in the trial is not a regulatory or legal requirement in accordance 
with GPSP.
10.10.1.2
Data quality assurance
The use-results survey is to be conducted in accordance with both the in-house PMS 
SOP and working instructions which are in compliance with GPSP.

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10.10.1.3
Records
CRFs for individual patients will be provided by the sponsor via the EDC system.
When a site does not accept the EDC system, paper CRFs will be used to gather the 
data.
10.10.1.3.1 Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
10.10.1.3.2 Direct access to source data and documents
Direct access to source data and documents for the use-results survey is not allowed in 
Japan.
10.10.1.4
Statement of confidentiality
Individual patient medical information obtained as a result of the use-results survey is 
considered confidential and disclosure to third parties is prohibited with the exceptions 
noted below. Patient confidentiality will be ensured by using patient identification code 
numbers.
Data generated as a result of the use-results survey needs to be submitted on request by 
the regulatory authorities.

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11.
PROTECTION OF HUMAN SUBJECTS
There is no need for a clinical trial type insurance of well-being and rights of 
participants because this is a non-interventional study and there is no risk of an 
experimental treatment. There is no regulation or requirement for ensuring the well-
being and rights of participants.

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12.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
12.1
DEFINITTIONS OF ADVERSE EVENT 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An adverse event can 
therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious 
and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse 
reactions may arise from use of the product within or outside the terms of the marketing 
authorisation or from occupational exposure. Conditions of use outside the marketing 
authorization include off-label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death,
-
is life-threatening,
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly/birth defect
Life-threatening in this context refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if more severe.
Medical and scientific judgement should be exercised in deciding whether other 
situations should be considered serious reactions, such as important medical events that 
might not be immediately life threatening or result in death or hospitalisation but might 
jeopardise the patient or might require intervention to prevent one of the other outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse. Any suspected transmission via 
a medicinal product of an infectious agent is also considered a serious adverse reaction.
Adverse Event of Special Interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as 
being of particular concern for prospective safety monitoring and safety assessment 
within this study, e.g. the potential for AEs based on knowledge from other compounds 
in the same class. 
No AESIs have been defined for this study.

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12.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
COLLECTION AND REPORTING 
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection and Reporting of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of 
the studied BI drug. For this reason the following AE collection and reporting 
requirements have been defined.
The following must be collected by the investigator in the (e) CRF via the EDC system 
from first intake of Ofev® Capsules at baseline visit and within 28 days (inclusive) after 
last intake. When a site does not accept the EDC system, paper CRFs will be used to 
gather the data.:
-
all AEs (serious and non-serious)
-
all ADRs and AEs with fatal outcome in patients exposed to Ofev® Capsules as 
soon as possible
All AEs including those persisting after study completion must be followed up until 
they are resolved, have been sufficiently characterized, or no further information can be 
obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the 
information below.
Causal relationship of adverse event:
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal 
relationship between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases 
and relevant history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population
not exposed to drugs (e.g. Stevens-Johnson syndrome).

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

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AE report forms. The term AE includes drug exposure during pregnancy, and, 
regardless of whether an AE occurred or not, any abuse, off-label use, misuse, 
medication error, occupational exposure, lack of effect, and unexpected benefit.
AEs occurring after 15 October 2017 will not be collected in the CRF. These events 
will be reported spontaneously according to local regulations.
12.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to 
local and international regulatory requirements.

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13.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The progress reports and final reports will be submitted PMDA in Japanese Periodic 
Safety Update Report (PSUR). And also final report will be submitted PMDA in re-
examination documents.

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14.
REFERENCES
14.1
PUBLISHED REFERENCES
P11-07084
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management. Am J Respir Crit Care Med 183 (6), 788-824 (2011)
P12-03241
King TE, Pardo A, Selman M Idiopathic pulmonary fibrosis. Lancet 378 
(9807) , 1949-1961 (2011)
P08-08684
Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, 
Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, 
Rettig WJ BIBF 1120: triple angiokinase inhibitor with sustained 
receptor blockade and good antitumor efficacy. Cancer Res 68 (12), 
4774-4782 (2008)
14.2
UNPUBLISHED REFERENCES
Not applicable

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMEA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 2, amended)
Adopted by the ENCePP Steering Group on 14/01/2013
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
(ENCePP) welcomes innovative designs and new methods of research. This Checklist has 
been developed by ENCePP to stimulate consideration of important principles when designing 
and writing a pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is 
intended to promote the quality of such studies, not their uniformity. The user is also 
referred to the ENCePP Guide on Methodological Standards in Pharmacoepidemiology which 
reviews and gives direct electronic access to guidance for research in pharmacoepidemiology 
and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has 
been addressed in the study protocol. If the answer is “Yes”, the page number(s) of the 
protocol where this issue has been discussed should be specified. It is possible that some 
questions do not apply to a particular study (for example in the case of an innovative study 
design). In this case, the answer ‘N/A’ (Not Applicable) can be checked and the “Comments” 
field included for each section should be used to explain why. The “Comments” field can also 
be used to elaborate on a “No” answer. 
This Checklist should be included as an Annex by marketing authorisation holders when 
submitting the protocol of a non-interventional post-authorisation safety study (PASS) to a 
regulatory authority (see the Guidance on the format and content of the protocol of non-
interventional post-authorisation safety studies). Note, the Checklist is a supporting 
document and does not replace the format of the protocol for PASS as recommended in the 
Guidance and Module VIII of the Good pharmacovigilance practices (GVP). 
Study title: 
Specific Use-Result Surveillance of Spiriva Respimat in asthmatics (patients with 
severe persistent asthma)
Study reference number: BI Study Number: 1199.202
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

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Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
15
15
15
15
15
15
Comments:
     none
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1 Does the formulation of the research question 
and objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to 
address an important public health concern, a risk 
identified in the risk management plan, an emerging 
safety issue)
2.1.2 The objective(s) of the study?
18
18
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
2.1.4 Which formal hypothesis(-es) is (are) to 
be tested? 
2.1.5 If applicable, that there is no a priori
hypothesis?
18
Comments:
none
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1 Is the study design described? (e.g. cohort, case-
control, randomised controlled trial, new or alternative 
design) 
19
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated?
19

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Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.3 Does the protocol describe the measure(s) of 
effect? (e.g. relative risk, odds ratio, deaths per 1000 
person-years, absolute risk, excess risk, incidence rate 
ratio, hazard ratio, number needed to harm (NNH) per 
year)
19
Comments:
     none
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1 Is the source population described?
4.2 Is the planned study population defined in 
terms of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
4.2.5 Co-morbidity?
4.2.6 Seasonality?
20
22
22
22
4.3 Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)  
20
Comments:
     none
Section 5: Exposure definition and 
measurement
Yes
No
N/A
Page 
Number(s)
5.1 Does the protocol describe how exposure is 
defined and measured? (e.g. operational details for 
defining and categorising exposure)
21
5.2 Does the protocol discuss the validity of 
exposure measurement? (e.g. precision, accuracy, 
prospective ascertainment, exposure information recorded 
before the outcome occurred, use of validation sub-study)
5.3 Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
5.4 Is exposure classified based on biological 
mechanism of action and taking into account 
the pharmacokinetics and pharmacodynamics 
of the drug?
5.5 Does the protocol specify whether a dose-
dependent or duration-dependent response is 
measured?
Comments:

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none
Section 6: Endpoint definition and 
measurement
Yes
No
N/A
Page 
Number(s)
6.1 Does the protocol describe how the endpoints 
are defined and measured? 
21
6.2 Does the protocol discuss the validity of 
endpoint measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, 
prospective or retrospective ascertainment, use of 
validation sub-study)
Comments:
none
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1 Does the protocol address known 
confounders? (e.g. collection of data on known 
confounders, methods of controlling for known 
confounders)
21
7.2 Does the protocol address known effect 
modifiers? (e.g. collection of data on known effect 
modifiers, anticipated direction of effect)
21
Comments:
none
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
8.1.2 Endpoints? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics, etc.)
8.1.3 Covariates? 
21
21
21
8.2 Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug 
quantity, dose,  number of days of supply prescription, 
daily dosage,  prescriber)
8.2.2 Endpoints? (e.g. date of occurrence, multiple 
event, severity measures related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
21
21
22
8.3 Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10)
25

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Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.3.2 Endpoints? (e.g. Medical Dictionary for 
Regulatory Activities (MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, 
Anatomical Therapeutic Chemical (ATC)Classification 
System)
25
8.4 Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other)
Comments:
none    
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power 
calculated? 
19
Comments:
none    
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1 Does the plan include measurement of 
excess risks?
25
10.2 Is the choice of statistical techniques 
described? 
25
10.3 Are descriptive analyses included?
25
10.4 Are stratified analyses included?
25
10.5 Does the plan describe methods for adjusting 
for confounding?
10.6 Does the plan describe methods addressing 
effect modification?
Comments:
   none  
Section 11: Data management and quality 
control
Yes
No
N/A
Page 
Number(s)
11.1 Is information provided on the management 
of missing data?
25
11.2 Does the protocol provide information on 
data storage? (e.g. software and IT environment, 
database maintenance and anti-fraud protection, 
archiving)
24
11.3 Are methods of quality assurance described?
27

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Section 11: Data management and quality 
control
Yes
No
N/A
Page 
Number(s)
11.4 Does the protocol describe possible quality 
issues related to the data source(s)?
27
11.5 Is there a system in place for independent 
review of study results? 
Comments:
none
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1 Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such 
biases, validation sub-study, use of validation and 
external data, analytical methods)
27
12.2 Does the protocol discuss study feasibility? 
(e.g. sample size, anticipated exposure, duration of 
follow-up in a cohort study, patient recruitment)
12.3 Does the protocol address other limitations? 
Comments:
   none 
Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1 Have requirements of Ethics 
Committee/Institutional Review Board 
approval been described?
27
13.2 Has any outcome of an ethical review 
procedure been addressed?
27
13.3 Have data protection requirements been 
described?
Comments:
  none   
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1 Does the protocol include a section to 
document future amendments and 
deviations? 
Comments:
none 
Section 15: Plans for communication of study 
results
Yes
No
N/A
Page 
Number(s)

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ANNEX 3. THE CLASSIFICATION OF MODIFIED MRC 
DYSPNEA SCALE
Grade
Questionnaire
0
I only ge breathless with strenuous exercise.
1
I get short of breath when hurrying on the level or walking up a slight.
2
I walk slower than people of the same age on the level because of 
breathlessness, or I have to stop for breath when walking on my own 
pace on the level.
3
I stop for breath after walking about 100 meters or after a few minutes 
on the level.
4
I am too breathless to leave the house or I am breathless when dressing 
or undressing.

 
 
 
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